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Osteoporosis, or steroid-induced osteonecrosis of the hip, is accompanied by increased bone marrow adipogenesis. Such a disorder of adipogenic/osteogenic differentiation, affecting bone-marrow-derived mesenchymal stem cells (BMSCs), contributes to bone loss during aging. Here, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on the osteogenic and adipogenic differentiation capacity of naïve (undifferentiated) hBMSCs. We observed that all EV groups increased viability and proliferation capacity and suppressed the apoptosis of naïve hBMSCs. In particular, EVs derived from hBMSCs at late-stage osteogenic differentiation promoted the osteogenic potential of naïve hBMSCs more effectively than EVs derived from naïve hBMSCs (naïve EVs), as indicated by the increased gene expression of COL1A1 and OPN. In contrast, the adipogenic differentiation capacity of naïve hBMSCs was inhibited by treatment with EVs from osteogenic differentiated hBMSCs. Proteomic analysis revealed that osteogenic EVs and naïve EVs contained distinct protein profiles, with pro-osteogenic and anti-adipogenic proteins encapsulated in osteogenic EVs. We speculate that osteogenic EVs could serve as an intercellular communication system between bone- and bone-marrow adipose tissue, for transporting osteogenic factors and thus favoring pro-osteogenic processes. Our data may support the theory of an endocrine circuit with the skeleton functioning as a ductless gland.
Background: Muscle injuries are common in humans and are often associated with irrecoverable damage and disability. Upon muscle injury, TNF-α signaling pathways modulate the healing process and are predominantly associated with tissue degradation. In this study we assumed that TNF-α inhibition could reduce the TNF-α-associated tissue degradation after muscle injury. Materials and methods: Therefore, the left soleus muscle of 42 male Wistar rats was injured using a standardized open muscle injury model. All rats were treated immediately after injury either with infliximab (single i.p. injection; 10 mg/kg b.w.) or saline solution i.p. Final measurements were conducted at day one, four, and 14 post injury. The muscle force, the muscle cell proliferation, the muscle cell coverage as well as the myofiber diameter served as read out parameters of our experiment. Results: Systemic application of infliximab could significantly reduce the TNF-α levels in the injured muscle at day four upon trauma compared to saline treated animals. The ratio of muscle weight to body weight was increased and the twitch muscle force showed a significant rise 14 days after trauma and TNF-α inhibition. Quantification of myofiber diameter in the penumbra zone showed a significant difference between both groups at day one and four after injury, indicated by muscle hypertrophy in the infliximab group. Planimetric analysis of the injured muscle at day 14 revealed increased muscle tissue fraction in the infliximab group compared to the control animals. Muscle cell proliferation did not differ between both groups. Conclusions: These data provide evidence that the TNF-α blockade positively regulates the restauration of skeletal muscles upon injury.
Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABA\(_A\) in NaV1.8-positive sensory neurons (Scn10a\(^{Cre}\);Gabrb3\(^{fl/fl}\)) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABA\(_A\). Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of c-fos mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABA\(_A\) and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I–V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund’s adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8\(^+\) afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABA\(_A\) in NaV1.8\(^+\) nociceptors constitutes an “open gate” pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits.
A fine balance of regulatory (T\(_{reg}\)) and conventional CD4\(^+\) T cells (T\(_{conv}\)) is required to prevent harmful immune responses, while at the same time ensuring the development of protective immunity against pathogens. As for many cellular processes, sphingolipid metabolism also crucially modulates the T\(_{reg}\)/T\(_{conv}\) balance. However, our understanding of how sphingolipid metabolism is involved in T cell biology is still evolving and a better characterization of the tools at hand is required to advance the field. Therefore, we established a reductionist liposomal membrane model system to imitate the plasma membrane of mouse T\(_{reg}\) and T\(_{conv}\) with regards to their ceramide content. We found that the capacity of membranes to incorporate externally added azide-functionalized ceramide positively correlated with the ceramide content of the liposomes. Moreover, we studied the impact of the different liposomal preparations on primary mouse splenocytes in vitro. The addition of liposomes to resting, but not activated, splenocytes maintained viability with liposomes containing high amounts of C\(_{16}\)-ceramide being most efficient. Our data thus suggest that differences in ceramide post-incorporation into T\(_{reg}\) and T\(_{conv}\) reflect differences in the ceramide content of cellular membranes.
Background: The close monitoring of blood pressure during a caesarean section performed under central neuraxial anaesthesia should be the standard of safe anaesthesia. As classical oscillometric and invasive blood pressure measuring have intrinsic disadvantages, we investigated a novel, non-invasive technique for continuous blood pressure measuring. Methods: In this monocentric, retrospective data analysis, the reliability of continuous non-invasive blood pressure measuring using ClearSight\(^®\) (Edwards Lifesciences Corporation) is validated in 31 women undergoing central neuraxial anaesthesia for caesarean section. In addition, patients and professionals evaluated ClearSight\(^®\) through questioning. Results: 139 measurements from 11 patients were included in the final analysis. Employing Bland–Altman analyses, we identified a bias of −10.8 mmHg for systolic, of −0.45 mmHg for diastolic and of +0.68 mmHg for mean arterial blood pressure measurements. Pooling all paired measurements resulted in a Pearson correlation coefficient of 0.7 for systolic, of 0.67 for diastolic and of 0.75 for mean arterial blood pressure. Compensating the interindividual differences in linear regressions of the paired measurements provided improved correlation coefficients of 0.73 for systolic, of 0.9 for diastolic and of 0.89 for mean arterial blood pressure measurements. Discussion: Diastolic and mean arterial blood pressure are within an acceptable range of deviation from the reference method, according to the Association for the Advancement of Medical Instrumentation (AAMI) in the patient collective under study. Both patients and professionals prefer ClearSight\(^®\) to oscillometric blood pressure measurement in regard of comfort and handling.
Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.
This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile.
(1) Background: To evaluate radiomics features as well as a combined model with clinical parameters for predicting overall survival in patients with bladder cancer (BCa). (2) Methods: This retrospective study included 301 BCa patients who received radical cystectomy (RC) and pelvic lymphadenectomy. Radiomics features were extracted from the regions of the primary tumor and pelvic lymph nodes as well as the peritumoral regions in preoperative CT scans. Cross-validation was performed in the training cohort, and a Cox regression model with an elastic net penalty was trained using radiomics features and clinical parameters. The models were evaluated with the time-dependent area under the ROC curve (AUC), Brier score and calibration curves. (3) Results: The median follow-up time was 56 months (95% CI: 48–74 months). In the follow-up period from 1 to 7 years after RC, radiomics models achieved comparable predictive performance to validated clinical parameters with an integrated AUC of 0.771 (95% CI: 0.657–0.869) compared to an integrated AUC of 0.761 (95% CI: 0.617–0.874) for the prediction of overall survival (p = 0.98). A combined clinical and radiomics model stratified patients into high-risk and low-risk groups with significantly different overall survival (p < 0.001). (4) Conclusions: Radiomics features based on preoperative CT scans have prognostic value in predicting overall survival before RC. Therefore, radiomics may guide early clinical decision-making.
Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3–4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3–4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.
Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.
Predicting hypertension subtypes with machine learning using targeted metabolites and their ratios
(2022)
Hypertension is a major global health problem with high prevalence and complex associated health risks. Primary hypertension (PHT) is most common and the reasons behind primary hypertension are largely unknown. Endocrine hypertension (EHT) is another complex form of hypertension with an estimated prevalence varying from 3 to 20% depending on the population studied. It occurs due to underlying conditions associated with hormonal excess mainly related to adrenal tumours and sub-categorised: primary aldosteronism (PA), Cushing’s syndrome (CS), pheochromocytoma or functional paraganglioma (PPGL). Endocrine hypertension is often misdiagnosed as primary hypertension, causing delays in treatment for the underlying condition, reduced quality of life, and costly antihypertensive treatment that is often ineffective. This study systematically used targeted metabolomics and high-throughput machine learning methods to predict the key biomarkers in classifying and distinguishing the various subtypes of endocrine and primary hypertension. The trained models successfully classified CS from PHT and EHT from PHT with 92% specificity on the test set. The most prominent targeted metabolites and metabolite ratios for hypertension identification for different disease comparisons were C18:1, C18:2, and Orn/Arg. Sex was identified as an important feature in CS vs. PHT classification.
Olea europaea L. Cv. Arbequina (OEA) (Oleaceae) is an olive variety species that has received little attention. Besides our previous work for the chemical profiling of OEA leaves using LC–HRESIMS, an additional 23 compounds are identified. An excision wound model is used to measure wound healing action. Wounds are provided with OEA (2% w/v) or MEBO\(^®\) cream (marketed treatment). The wound closure rate related to vehicle-treated wounds is significantly increased by OEA. Comparing to vehicle wound tissues, significant levels of TGF-β in OEA and MEBO\(^®\) (p < 0.05) are displayed by gene expression patterns, with the most significant levels in OEA-treated wounds. Proinflammatory TNF-α and IL-1β levels are substantially reduced in OEA-treated wounds. The capability of several lignan-related compounds to interact with MMP-1 is revealed by extensive in silico investigation of the major OEA compounds (i.e., inverse docking, molecular dynamics simulation, and ΔG calculation), and their role in the wound-healing process is also characterized. The potential of OEA as a potent MMP-1 inhibitor is shown in subsequent in vitro testing (IC\(_{50}\) = 88.0 ± 0.1 nM). In conclusion, OEA is introduced as an interesting therapeutic candidate that can effectively manage wound healing because of its anti-inflammatory and antioxidant properties.
Cerebrospinal fluid (CSF) and serum biomarkers are critical for clinical decision making in neurological diseases. In cerebral small vessel disease (CSVD), white matter hyperintensities (WMH) are an important neuroimaging biomarker, but more blood-based biomarkers capturing different aspects of CSVD pathology are needed. In 42 sporadic CSVD patients, we prospectively analysed WMH on magnetic resonance imaging (MRI) and the biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), chitinase3-like protein 1 (CHI3L1), Tau and Aβ1-42 in CSF and NfL and GFAP in serum. GFAP and CHI3L1 expression was studied in post-mortem brain tissue in additional cases. CSVD cases with higher serum NfL and GFAP levels had a higher modified Rankin Scale (mRS) and NIHSS score and lower CSF Aβ1-42 levels, whereas the CSF NfL and CHI3L1 levels were positively correlated with the WMH load. Moreover, the serum GFAP levels significantly correlated with the neurocognitive functions. Pathological analyses in CSVD revealed a high density of GFAP-immunoreactive fibrillary astrocytic processes in the periventricular white matter and clusters of CHI3L1-immunoreactive astrocytes in the basal ganglia and thalamus. Thus, besides NfL, serum GFAP is a highly promising fluid biomarker of sporadic CSVD, because it does not only correlate with the clinical severity but also correlates with the cognitive function in patients.
Despite considerable morbidity and mortality, numerous cases of endocrine hypertension (EHT) forms, including primary aldosteronism (PA), pheochromocytoma and functional paraganglioma (PPGL), and Cushing’s syndrome (CS), remain undetected. We aimed to establish signatures for the different forms of EHT, investigate potentially confounding effects and establish unbiased disease biomarkers. Plasma samples were obtained from 13 biobanks across seven countries and analyzed using untargeted NMR metabolomics. We compared unstratified samples of 106 PHT patients to 231 EHT patients, including 104 PA, 94 PPGL and 33 CS patients. Spectra were subjected to a multivariate statistical comparison of PHT to EHT forms and the associated signatures were obtained. Three approaches were applied to investigate and correct confounding effects. Though we found signatures that could separate PHT from EHT forms, there were also key similarities with the signatures of sample center of origin and sample age. The study design restricted the applicability of the corrections employed. With the samples that were available, no biomarkers for PHT vs. EHT could be identified. The complexity of the confounding effects, evidenced by their robustness to correction approaches, highlighted the need for a consensus on how to deal with variabilities probably attributed to preanalytical factors in retrospective, multicenter metabolomics studies.
Blood vessel organoids are an important in vitro model to understand the underlying mechanisms of human blood vessel development and for toxicity testing or high throughput drug screening. Here we present a novel, cost-effective, and easy to manufacture vascular organoid model. To engineer the organoids, a defined number of human induced pluripotent stem cells are seeded in non-adhesive agarose coated wells of a 96-well plate and directed towards a lateral plate mesoderm fate by activation of Wnt and BMP4 signaling. We observe the formation of a circular layer of angioblasts around days 5–6. Induced by VEGF application, CD31\(^+\) vascular endothelial cells appear within this vasculogenic zone at approximately day 7 of organoid culture. These cells arrange to form a primitive vascular plexus from which angiogenic sprouting is observed after 10 days of culture. The differentiation outcome is highly reproducible, and the size of organoids is scalable depending on the number of starting cells. We observe that the initial vascular ring forms at the interface between two cell populations. The inner cellular compartment can be distinguished from the outer by the expression of GATA6, a marker of lateral plate mesoderm. Finally, 14-days-old organoids were transplanted on the chorioallantois membrane of chicken embryos resulting in a functional connection of the human vascular network to the chicken circulation. Perfusion of the vessels leads to vessel wall maturation and remodeling as indicated by the formation of a continuous layer of smooth muscle actin expressing cells enwrapping the endothelium. In summary, our organoid model recapitulates human vasculogenesis, angiogenesis as well as vessel wall maturation and therefore represents an easy and cost-effective tool to study all steps of blood vessel development and maturation directly in the human setting without animal experimentation.
Previous EEG research only investigated one stage ultimatum games (UGs). We investigated the influence of a second bargaining stage in an UG concerning behavioral responses, electro-cortical correlates and their moderations by the traits altruism, anger, anxiety, and greed in 92 participants. We found that an additional stage led to more rejection in the 2-stage UG (2SUG) and that increasing offers in the second stage compared to the first stage led to more acceptance. The FRN during a trial was linked to expectance evaluation concerning the fairness of the offers, while midfrontal theta was a marker for the needed cognitive control to overcome the respective default behavioral pattern. The FRN responses to unfair offers were more negative for either low or high altruism in the UG, while high trait anxiety led to more negative FRN responses in the first stage of 2SUG, indicating higher sensitivity to unfairness. Accordingly, the mean FRN response, representing the trait-like general electrocortical reactivity to unfairness, predicted rejection in the first stage of 2SUG. Additionally, we found that high trait anger led to more rejections for unfair offer in 2SUG in general, while trait altruism led to more rejection of unimproving unfair offers in the second stage of 2SUG. In contrast, trait anxiety led to more acceptance in the second stage of 2SUG, while trait greed even led to more acceptance if the offer was worse than in the stage before. These findings suggest, that 2SUG creates a trait activation situation compared to the UG.
Dementia, including Alzheimer's disease, is a growing problem worldwide. Prevention or early detection of the disease or a prodromal cognitive decline is necessary. By means of our long-term follow-up ‘Vogel study’, we aim to predict the pathological cognitive decline of a German cohort (mean age was 73.9 ± 1.55 years at first visit) with three measurement time points within 6 years per participant. Especially in samples of the elderly and subjects with chronic or co-morbid diseases, dropouts are one of the biggest problems of long-term studies. In contrast to the large number of research articles conducted on the course of dementia, little research has been done on the completion of treatment. To ensure unbiased and reliable predictors of cognitive decline from study completers, our objective was to determine predictors of dropout. We conducted multivariate analyses of covariance and multinomial logistic regression analyses to compare and predict the subject's dropout behaviour at the second visit 3 years after baseline (full participation, partial participation and no participation/dropout) with neuropsychiatric, cognitive, blood and lifestyle variables. Lower performance in declarative memory, attention and visual–spatial processing predicted dropout rather than full participation. Lower performance in visual–spatial processing predicted partial participation as opposed to full participation. Furthermore, lower performance in mini-mental status examination predicted whether subjects dropped out or participated partially instead of full participation. Baseline cognitive parameters are associated with dropouts at follow-up with a loss of impaired participants. We expect a bias into a healthier sample over time.
Objective
Alzheimer’s disease (AD) is a growing challenge worldwide, which is why the search for early-onset predictors must be focused as soon as possible. Longitudinal studies that investigate courses of neuropsychological and other variables screen for such predictors correlated to mild cognitive impairment (MCI). However, one often neglected issue in analyses of such studies is measurement invariance (MI), which is often assumed but not tested for. This study uses the absence of MI (non-MI) and latent factor scores instead of composite variables to assess properties of cognitive domains, compensation mechanisms, and their predictability to establish a method for a more comprehensive understanding of pathological cognitive decline.
Methods
An exploratory factor analysis (EFA) and a set of increasingly restricted confirmatory factor analyses (CFAs) were conducted to find latent factors, compared them with the composite approach, and to test for longitudinal (partial-)MI in a neuropsychiatric test battery, consisting of 14 test variables. A total of 330 elderly (mean age: 73.78 ± 1.52 years at baseline) were analyzed two times (3 years apart).
Results
EFA revealed a four-factor model representing declarative memory, attention, working memory, and visual–spatial processing. Based on CFA, an accurate model was estimated across both measurement timepoints. Partial non-MI was found for parameters such as loadings, test- and latent factor intercepts as well as latent factor variances. The latent factor approach was preferable to the composite approach.
Conclusion
The overall assessment of non-MI latent factors may pose a possible target for this field of research. Hence, the non-MI of variances indicated variables that are especially suited for the prediction of pathological cognitive decline, while non-MI of intercepts indicated general aging-related decline. As a result, the sole assessment of MI may help distinguish pathological from normative aging processes and additionally may reveal compensatory neuropsychological mechanisms.
Thin films of transition metal oxides open up a gateway to nanoscale electronic devices beyond silicon characterized by novel electronic functionalities. While such films are commonly prepared in an oxygen atmosphere, they are typically considered to be ideally terminated with the stoichiometric composition. Using the prototypical correlated metal SrVO\(_{3}\) as an example, it is demonstrated that this idealized description overlooks an essential ingredient: oxygen adsorbing at the surface apical sites. The oxygen adatoms, which are present even if the films are kept in an ultrahigh vacuum environment and not explicitly exposed to air, are shown to severely affect the intrinsic electronic structure of a transition metal oxide film. Their presence leads to the formation of an electronically dead surface layer but also alters the band filling and the electron correlations in the thin films. These findings highlight that it is important to take into account surface apical oxygen or—mutatis mutandis—the specific oxygen configuration imposed by a capping layer to predict the behavior of ultrathin films of transition metal oxides near the single unit-cell limit.
Thermoelectric materials utilizing ionic transport open-up entirely new possibilities for the recuperation of waste heat. Remarkably, solid state electrolytes which have entered the focus of battery research in recent years turn-out to be promising candidates also for ionic thermoelectrics. Here, the dynamics of ionic transport and thermoelectric properties of a methacrylate based polymer blend in combination with a lithium salt is analyzed. Impedance spectroscopy data indicates the presence of just one transport mechanism irrespective of lithium salt concentration. In contrast, the temperature dependent ionic conductivity increases with salt concentration and can be ascribed to a Vogel–Fulcher–Tammann (VFT) behavior. The obtained Seebeck coefficients of 2 mV K\(^{−1}\) allow for high power outputs while the polymer matrix maintains the temperature gradient by its low thermal conductivity. Adding multi-walled carbon nanotubes to the polymer matrix allows for variation of the Seebeck coefficient as well as the ionic and electronic conductivities. As a result, a transition between a high temperature VFT regime and a low temperature Arrhenius regime appears at a critical temperature, T\(_{c}\), shifting upon addition of salt. The observed polarity change in Seebeck voltage at T\(_{c}\) suggests a new mode of thermoelectric operation, which is demonstrated by a proof-of-concept mixed electronic-ionic-thermoelectric generator.
We have investigated the photoionization of ammonia borane (AB) and determined adiabatic ionization energy to be 9.26±0.03 eV for the X\(^{+}\) \(^{2}\)E←X \(^{1}\)A\(_{1}\) transition. Although the threshold photoelectron spectrum appears at first glance to be similar to the one of the isosteric ethane, the electronic situation differs markedly, due to different orbital energies. In addition, an appearance energy AE\(_{0K}\)-(NH\(_{3}\)BH\(_{3}\), NH\(_{3}\)BH\(_{2}\)\(^{+}\))= 10.00±0.03 eV has been determined, corresponding to the loss of a hydrogen atom at the BH\(_{3}\)-site. From the data, a 0 K bond dissociation energy for the B−H bond in the cation of 71.5±3 kJ mol\(^{-1}\) was derived, whereas the one in the neutral compound has been estimated to be 419±10 kJ mol\(^{-1}\).
Spatiotemporal Fusion Modelling Using STARFM: Examples of Landsat 8 and Sentinel-2 NDVI in Bavaria
(2022)
The increasing availability and variety of global satellite products provide a new level of data with different spatial, temporal, and spectral resolutions; however, identifying the most suited resolution for a specific application consumes increasingly more time and computation effort. The region’s cloud coverage additionally influences the choice of the best trade-off between spatial and temporal resolution, and different pixel sizes of remote sensing (RS) data may hinder the accurate monitoring of different land cover (LC) classes such as agriculture, forest, grassland, water, urban, and natural-seminatural. To investigate the importance of RS data for these LC classes, the present study fuses NDVIs of two high spatial resolution data (high pair) (Landsat (30 m, 16 days; L) and Sentinel-2 (10 m, 5–6 days; S), with four low spatial resolution data (low pair) (MOD13Q1 (250 m, 16 days), MCD43A4 (500 m, one day), MOD09GQ (250 m, one-day), and MOD09Q1 (250 m, eight day)) using the spatial and temporal adaptive reflectance fusion model (STARFM), which fills regions’ cloud or shadow gaps without losing spatial information. These eight synthetic NDVI STARFM products (2: high pair multiply 4: low pair) offer a spatial resolution of 10 or 30 m and temporal resolution of 1, 8, or 16 days for the entire state of Bavaria (Germany) in 2019. Due to their higher revisit frequency and more cloud and shadow-free scenes (S = 13, L = 9), Sentinel-2 (overall R\(^2\) = 0.71, and RMSE = 0.11) synthetic NDVI products provide more accurate results than Landsat (overall R\(^2\) = 0.61, and RMSE = 0.13). Likewise, for the agriculture class, synthetic products obtained using Sentinel-2 resulted in higher accuracy than Landsat except for L-MOD13Q1 (R\(^2\) = 0.62, RMSE = 0.11), resulting in similar accuracy preciseness as S-MOD13Q1 (R\(^2\) = 0.68, RMSE = 0.13). Similarly, comparing L-MOD13Q1 (R\(^2\) = 0.60, RMSE = 0.05) and S-MOD13Q1 (R\(^2\) = 0.52, RMSE = 0.09) for the forest class, the former resulted in higher accuracy and precision than the latter. Conclusively, both L-MOD13Q1 and S-MOD13Q1 are suitable for agricultural and forest monitoring; however, the spatial resolution of 30 m and low storage capacity makes L-MOD13Q1 more prominent and faster than that of S-MOD13Q1 with the 10-m spatial resolution.
Flavonoids are polyphenolic natural products and have shown significant potential as disease-modifying agents against neurodegenerative disorders like Alzheimer's disease (AD), with activities even in vivo. Hybridization of the natural products taxifolin and silibinin with cinnamic acid led to an overadditive effect of these compounds in several phenotypic screening assays related to neurodegeneration and AD. Therefore, we have exchanged the flavonoid part of the hybrids with different flavonoids, which show higher efficacy than taxifolin or silibinin, to improve the activity of the respective hybrids. Chemical connection between the flavonoid and cinnamic acid was realized by an amide instead of a labile ester bond to improve stability towards hydrolysis. To investigate the influence of a double bond at the C-ring of the flavonoid, the dehydro analogues of the respective hybrids were also synthesized. All compounds obtained show neuroprotection against oxytosis, ferroptosis and ATP-depletion, respectively, in the murine hippocampal cell line HT22. Interestingly, the taxifolin and the quercetin derivatives are the most active compounds, whereby the quercetin derivate shows even more pronounced activity than the taxifolin one in all assays applied. As aimed for, no hydrolysis product was found in cellular uptake experiments after 4 h whereas different metabolites were detected. Furthermore, the quercetin-cinnamic acid amide showed pronounced activity in an in vivo AD mouse model at a remarkably low dose of 0.3 mg/kg.
Multichromophoric macrocycles and cyclophanes are important supramolecular architectures for the elucidation of interchromophoric interactions originating from precise spatial organization. Herein, by combining an axially chiral binaphthol bisimide (BBI) and a bay-substituted conformationally labile twisted perylene bisimide (PBI) within a cyclophane of well-defined geometry, we report a chiral PBI hetero-cyclophane (BBI-PBI) that shows intramolecular energy and solvent-regulated chirality transfer from the BBI to the PBI subunit. Excellent spectral overlap and spatial arrangement of BBI and PBI lead to efficient excitation energy transfer and subsequent PBI emission with high quantum yield (80–98 %) in various solvents. In contrast, chirality transfer is strongly dependent on the respective solvent as revealed by circular dichroism (CD) spectroscopy. The combination of energy and chirality transfer affords a bright red circularly polarized luminescence (CPL) from the PBI chromophore by excitation of BBI.
Although solid-state nuclear magnetic resonance (NMR) is a versatile analytical tool to study polymorphs and phase transitions of pharmaceutical molecules and products, this work summarizes examples of spontaneous and unexpected (and unwanted) structural rearrangements and phase transitions (amorphous-to-crystalline and crystalline-to-crystalline) under magic angle spinning (MAS) conditions, some of them clearly being due to the pressure experienced by the samples. It is widely known that such changes can often be detected by X-ray powder diffraction (XRPD); here, the capability of solid-state NMR experiments with a special focus on \(^{1}\)H-\(^{13}\)C frequency-switched Lee–Goldburg heteronuclear correlation (FSLG HETCOR)/MAS NMR experiments to detect even subtle changes on a molecular level not observable by conventional 1D NMR experiments or XRPD is presented. Furthermore, it is shown that a polymorphic impurity combined with MAS can induce a crystalline-to-crystalline phase transition. This showcases that solid-state NMR is not always noninvasive and such changes upon MAS should be considered in particular when compounds are studied over longer time spans.
The pseudopeptide backbone provided by N-(2-aminoethyl)-glycine oligomers with attached nucleobases has been widely utilized in peptide nucleic acids (PNAs) as DNA mimics. Here we demonstrate the suitability of this backbone for the formation of structurally defined dye stacks. Toward this goal a series of peptide merocyanine (PMC) dye oligomers connected to a N-(2-aminoethyl)-glycine backbone were prepared through peptide synthesis. Our concentration-, temperature- and solvent-dependent UV/Vis absorption studies show that under the control of dipole–dipole interactions, smaller-sized oligomers consisting of one, two or three dyes self-assemble into defined duplex structures containing two up to six chromophores. In contrast, upon further extension of the oligomer, the chosen peptide backbone cannot direct the formation of a defined duplex architecture anymore due to intramolecular aggregation between the dyes. For all aggregate species a moderate aggregation-induced emission enhancement is observed.
In π-conjugated organic photovoltaic materials, an excimer state has been generally regarded as a trap state which hinders efficient excitation energy transport. But despite wide investigations of the excimer for overcoming the undesirable energy loss, the understanding of the relationship between the structure of the excimer in stacked organic compounds and its properties remains elusive. Here, we present the landscape of structural dynamics from the excimer formation to its relaxation in a co-facially stacked archetypical perylene bisimide folda-dimer using ultrafast time-domain Raman spectroscopy. We directly captured vibrational snapshots illustrating the ultrafast structural evolution triggering the excimer formation along the interchromophore coordinate on the complex excited-state potential surfaces and following evolution into a relaxed excimer state. Not only does this work showcase the ultrafast structural dynamics necessary for the excimer formation and control of excimer characteristics but also provides important criteria for designing the π-conjugated organic molecules.
Herein we devise and execute a new synthesis of a pristine boron-doped nanographene. Our target boron-doped nanographene was designed based on DFT calculations to possess a low LUMO energy level and a narrow band gap derived from its precise geometry and B-doping arrangement. Our synthesis of this target, a doubly B-doped hexabenzopentacene (B\(_{2}\)-HBP), employs six net C−H borylations of an alkene, comprising consecutive hydroboration/electrophilic borylation/dehydrogenation and BBr\(_{3}\)/AlCl\(_{3}\)/2,6-dichloropyridine-mediated C−H borylation steps. As predicted by our calculations, B\(_{2}\)-HBP absorbs strongly in the visible region and emits in the NIR up to 1150 nm in o-dichlorobenzene solutions. Furthermore, B\(_{2}\)-HBP possesses a very low LUMO level, showing two reversible reductions at −1.00 V and −1.17 V vs. Fc\(^{+}\)/Fc. Our methodology is surprisingly selective despite its implementation of unfunctionalized precursors and offers a new approach to the synthesis of pristine B-doped polycyclic aromatic hydrocarbons.
Background
Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS).
Materials and Methods
In this bicentric analysis, we included 184 mCRPC patients treated with \(^{177}\)Lu-PSMA RLT. Response to treatment was defined as decrease in prostate-specific antigen (PSA) levels 8 weeks after the first cycle of RLT (any decline or >50% according to Prostate Cancer Working Group 3). OS of responders and nonresponders was then compared using Kaplan–Meier curves and log-rank comparison.
Results
A total of 114/184 patients (62.0%) showed any PSA decline (PSA response >50%, 55/184 [29.9%]). For individuals exhibiting a PSA decline >50%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95% confidence interval [95% CI] = 0.44–0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95% CI = 0.25–0.60; p < 0.001).
Conclusions
In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50%, RLT should be continued.
We have previously shown that targeting endoneurial macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of Charcot-Marie-Tooth (CMT) 1X and 1B disease, which are genetically-mediated nerve disorders not treatable in humans. The same approach failed in a model of CMT1A (PMP22-overexpressing mice, line C61), representing the most frequent form of CMT. This was unexpected since previous studies identified macrophages contributing to disease severity in the same CMT1A model. Here we re-approached the possibility of alleviating the neuropathy in a model of CMT1A by targeting macrophages at earlier time points. As a proof-of-principle experiment, we genetically inactivated colony-stimulating factor-1 (CSF-1) in CMT1A mice, which resulted in lower endoneurial macrophage numbers and alleviated the neuropathy. Based on these observations, we pharmacologically ablated macrophages in newborn CMT1A mice by feeding their lactating mothers with chow containing PLX5622, followed by treatment of the respective progenies after weaning until the age of 6 months. We found that peripheral neuropathy was substantially alleviated after early postnatal treatment, leading to preserved motor function in CMT1A mice. Moreover, macrophage depletion affected the altered Schwann cell differentiation phenotype. These findings underscore the targetable role of macrophage-mediated inflammation in peripheral nerves of inherited neuropathies, but also emphasize the need for an early treatment start confined to a narrow therapeutic time window in CMT1A models and potentially in respective patients.
Introduction/Aims
Schwann cell clusters have been described at the murine dermis-epidermis border. We quantified dermal Schwann cells in the skin of patients with small-fiber neuropathy (SFN) compared with healthy controls to correlate with the clinical phenotype.
Methods
Skin punch biopsies from the lower legs of 28 patients with SFN (11 men, 17 women; median age, 54 [range, 19-73] years) and 9 healthy controls (five men, four women, median age, 34 [range, 25-69] years) were immunoreacted for S100 calcium-binding protein B as a Schwann cell marker, protein-gene product 9.5 as a pan-neuronal marker, and CD207 as a Langerhans cell marker. Intraepidermal nerve fiber density (IENFD) and subepidermal Schwann cell counts were determined.
Results
Skin samples of patients with SFN showed lower IENFD (P < .05), fewer Schwann cells per millimeter (P < .01), and fewer Schwann cell clusters per millimeter (P < .05) than controls. When comparing SFN patients with reduced (n = 13; median age, 53 [range, 19-73] years) and normal distal (n = 15, median age, 54 [range, 43-68] years) IENFD, the number of solitary Schwann cells per millimeter (p < .01) and subepidermal nerve fibers associated with Schwann cell branches (P < .05) were lower in patients with reduced IENFD. All three parameters correlated positively with distal IENFD (P < .05 to P < .01), whereas no correlation was found between Schwann cell counts and clinical pain characteristics.
Discussion
Our data raise questions about the mechanisms underlying the interdependence of dermal Schwann cells and skin innervation in SFN. The temporal course and functional impact of Schwann cell presence and kinetics need further investigation.
Background and purpose
The aim was to characterize a combined vestibular, ocular motor and postural syndrome induced by deep brain stimulation (DBS) of the subthalamic nucleus in a patient with Parkinson's disease.
Methods
In a systematic DBS programming session, eye, head and trunk position in roll and pitch plane were documented as a function of stimulation amplitude and field direction. Repeat ocular coherence tomography was used to estimate ocular torsion. The interstitial nucleus of Cajal (INC), zona incerta (ZI) and ascending vestibular fibre tracts were segmented on magnetic resonance imaging using both individual and normative structural connectomic data. Thresholded symptom-associated volumes of tissue activated (VTA) were calculated based on documented stimulation parameters.
Results
Ipsilateral ocular tilt reaction and body lateropulsion as well as contralateral torsional nystagmus were elicited by the right electrode in a current-dependent manner and subsided after DBS deactivation. With increasing currents, binocular tonic upgaze and body retropulsion were observed. Symptoms were consistent with an irritative effect on the INC. Symptom-associated VTA was found to overlap with the dorsal ZI and the ipsilateral vestibulothalamic tract, while lying rather distant to the INC proper. A ZI-to-INC ‘incerto-interstitial’ tract with contact to the medial-uppermost portion of the VTA could be traced.
Conclusion
Unilateral stimulation of INC-related circuitry induces an ipsilateral vestibular, ocular motor and postural roll-plane syndrome, which converts into a pitch-plane syndrome when functional activation expands bilaterally. In this case, tractography points to an incerto-interstitial pathway, a tract previously only characterized in non-human primates. Directional current steering proved useful in managing this rare side effect.
3D neuronal cultures attempt to better replicate the in vivo environment to study neurological/neurodegenerative diseases compared to 2D models. A challenge to establish 3D neuron culture models is the low elastic modulus (30–500 Pa) of the native brain. Here, an ultra-soft matrix based on thiolated hyaluronic acid (HA-SH) reinforced with a microfiber frame is formulated and used. Hyaluronic acid represents an essential component of the brain extracellular matrix (ECM). Box-shaped frames with a microfiber spacing of 200 µm composed of 10-layers of poly(ɛ-caprolactone) (PCL) microfibers (9.7 ± 0.2 µm) made via melt electrowriting (MEW) are used to reinforce the HA-SH matrix which has an elastic modulus of 95 Pa. The neuronal viability is low in pure HA-SH matrix, however, when astrocytes are pre-seeded below this reinforced construct, they significantly support neuronal survival, network formation quantified by neurite length, and neuronal firing shown by Ca\(^{2+}\) imaging. The astrocyte-seeded HA-SH matrix is able to match the neuronal viability to the level of Matrigel, a gold standard matrix for neuronal culture for over two decades. Thus, this 3D MEW frame reinforced HA-SH composite with neurons and astrocytes constitutes a reliable and reproducible system to further study brain diseases.
Introduction
In endodontic education, there is a need for thorough training prior to students embarking on clinical treatment. The aim of this study was to use three-dimensional printing technology to create a new model and to compare its suitability for training purposes with resin blocks and extracted teeth.
Materials and Methods
Multi-jet-modelling (MJM) produced the 3D model replicating a common difficulty in root-canal morphology. An evaluation study comprising 88 students was run in the sixth semester (summer 2018 and winter 2018/2019). A new questionnaire assessed students’ perception of training models and educational environment. Welch's t-test analysed significant differences.
Results
The most pronounced differences between models were noted when rating material hardness, radiopacity, root-canal configuration and suitability for practising. Students estimated their learning outcome as greater with 3D-printed teeth compared to resin blocks. Three-dimensionally printed teeth received significantly lower ratings with regard to enthusiasm, the learning of fine motor skills and spatial awareness, when compared to human teeth (p ≤ .001). However, 3D-printed teeth were appreciated for additional benefits, such as their cleanliness, availability and standardisation of training opportunities with complex root-canal configurations.
Conclusion
Students preferred extracted human teeth to 3D-printed teeth with respect to their physical characteristics and training experience. However, educational advantages may compensate for the shortcomings. The new questionnaire proved both adequate and accurate to assess the models and educational environment in endodontic training. The new 3D-printed teeth enhanced the learning opportunities.
Against the background of the current COVID-19 infection dynamics with its rapid spread of SARS-CoV-2 variants of concern (VOC), the immunity and the vaccine prevention of healthcare workers (HCWs) against SARS-CoV-2 continues to be of high importance. This observational cross-section study assesses factors influencing the level of anti-SARS-CoV-2-spike IgG after SARS-CoV-2 infection or vaccination. One thousand seven hundred and fifty HCWs were recruited meeting the following inclusion criteria: age ≥18 years, PCR-confirmed SARS-CoV-2 infection convalescence and/or at least one dose of COVID-19 vaccination. anti-SARS-CoV-2-spike IgG titers were determined by SERION ELISA agile SARS-CoV-2 IgG. Mean anti-SARS-CoV-2-spike IgG levels increased significantly by number of COVID-19 vaccinations (92.2 BAU/ml for single, 140.9 BAU/ml for twice and 1144.3 BAU/ml for threefold vaccination). Hybrid COVID-19 immunized respondents (after infection and vaccination) had significantly higher antibody titers compared with convalescent only HCWs. Anti-SARS-CoV-2-spike IgG titers declined significantly with time after the second vaccination. Smoking and high age were associated with lower titers. Both recovered and vaccinated HCWs presented a predominantly good humoral immune response. Smoking and higher age limited the humoral SARS-CoV-2 immunity, adding to the risk of severe infections within this already health impaired collective.
Ó. Blasco and S. Pott showed that the supremum of operator norms over L\(^{2}\) of all bicommutators (with the same symbol) of one-parameter Haar multipliers dominates the biparameter dyadic product BMO norm of the symbol itself. In the present work we extend this result to the Bloom setting, and to any exponent 1 < p < ∞. The main tool is a new characterization in terms of paraproducts and two-weight John–Nirenberg inequalities for dyadic product BMO in the Bloom setting. We also extend our results to the whole scale of indexed spaces between little bmo and product BMO in the general multiparameter setting, with the appropriate iterated commutator in each case.
Xylem hydraulic safety and efficiency are key traits determining tree fitness in a warmer and drier world. While numerous plant hydraulic studies have focused on branches, our understanding of root hydraulic functioning remains limited, although roots control water uptake, influence stomatal regulation and have commonly been considered as the most vulnerable organ along the hydraulic pathway.
We investigated 11 traits related to xylem safety and efficiency along the hydraulic pathway in four temperate broad-leaved tree species.
Continuous vessel tapering from coarse roots to stems and branches caused considerable reduction in hydraulic efficiency. Wood density was always lowest in roots, but did not decline linearly along the flow path. In contrast, xylem embolism resistance (P50) did not differ significantly between roots and branches, except for one species. The limited variation in xylem safety between organs did not adequately reflect the corresponding reductions in vessel diameter (by ~70%) and hydraulic efficiency (by ~85%). Although we did not observe any trade-off between xylem safety and specific conductivity, vessel diameter, vessel lumen fraction and wood density were related to embolism resistance, both across and partly within organs.
We conclude that coarse roots are not highly vulnerable to xylem embolism as commonly believed, indicating that hydraulic failure during soil drying might be restricted to fine roots.
Earliest autobiographical memories mark a potential beginning of our life story. However, their meaning has hardly been investigated. Against this background, participants (N = 182) were asked to think about two kinds of meaning: the meaning that the remembered event might have had in the moment of experience and the meaning that the memory of the event has for their present life situation. With respect to the meaning in the moment of experience, participants most frequently referred to situational characteristics. The meaning for the present life situation was most frequently related to aspects of the memory that told something about the person beyond the immediate context of the remembered event. Moreover, these meanings were more frequently associated with continuity than with a contrast between then and now. Apart from these overarching commonalities, our data also show that the earliest autobiographical memories of different people can tell very different stories.
Candida auris was first described as a yeast pathogen in 2009. Since then, the species has emerged worldwide. In contrast to most other Candida spp., C. auris frequently exhibits multi-drug resistance and is readily transmitted in hospital settings. While most detections so far are from colonised patients, C. auris does cause superficial and life-threatening invasive infections. During management of the first documented C. auris transmission in a German hospital, experts from the National Reference Centers for Invasive Fungal Infections (NRZMyk) and the National Reference Center for Surveillance of Nosocomial Infections screened available literature and integrated available knowledge on infection prevention and C. auris epidemiology and biology to enable optimal containment. Relevant recommendations developed during this process are summarised in this guidance document, intended to assist in management of C. auris transmission and potential outbreak situations. Rapid and effective measures to contain C. auris spread require a multi-disciplinary approach that includes clinical specialists of the affected unit, nursing staff, hospital hygiene, diagnostic microbiology, cleaning staff, hospital management and experts in diagnostic mycology / fungal infections. Action should be initiated in a step-wise process and relevant interventions differ between management of singular C. auris colonised / infected patients and detection of potential C. auris transmission or nosocomial outbreaks.
Individual mobility and human patterns analyses is receiving increasing attention in numerous interdisciplinary studies and publications using the concept of time-geography but is largely unknown to the subdiscipline of sports geography. Meanwhile the visualization and evaluation of large data of individual patterns are still a major challenge. While a qualitative, microscale view on spatial-temporal topics is more common in today's pattern research using mostly 24h time intervals, this work examines a quantitative approach focusing on an extended period of life. This paper presents a combination of time-geographic approaches with 3D-geoinformation systems and demonstrates their value for analysing individual mobility by implementing a path-homogeneity factor (HPA). Using the example of professional athletes, it is shown which groups display greater similarities in their career paths. While a high homogeneity suggests that groups make similar decisions through socially influenced processes, low values allow the assumption that external processes provide stronger, independent individual structures.
Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) have been reported in patients with mitochondriopathies: most commonly encephalopathy, but also cardiomyopathy. Through a GWAS, we showed possible associations between mitochondrial valyl-tRNA synthetase (VARS2) dysregulations and non-ischemic cardiomyopathy. We aimed to investigate the possible consequences of VARS2 depletion in zebrafish and cultured HEK293A cells. Transient VARS2 loss-of-function was induced in zebrafish embryos using Morpholinos. The enzymatic activity of VARS2 was measured in VARS2-depleted cells via northern blot. Heterozygous VARS2 knockout was established in HEK293A cells using CRISPR/Cas9 technology. BN-PAGE and SDS-PAGE were used to investigate electron transport chain (ETC) complexes, and the oxygen consumption rate and extracellular acidification rate were measured using a Seahorse XFe96 Analyzer. The activation of the integrated stress response (ISR) and possible disruptions in mitochondrial fatty acid oxidation (FAO) were explored using RT-qPCR and western blot. Zebrafish embryos with transient VARS2 loss-of-function showed features of heart failure as well as indications of CNS and skeletal muscle involvements. The enzymatic activity of VARS2 was significantly reduced in VARS2-depleted cells. Heterozygous VARS2-knockout cells showed a rearrangement of ETC complexes in favor of complexes III\(_2\), III\(_2\) + IV, and supercomplexes without significant respiratory chain deficiencies. These cells also showed the enhanced activation of the ISR, as indicated by increased eIF-2α phosphorylation and a significant increase in the transcript levels of ATF4, ATF5, and DDIT3 (CHOP), as well as disruptions in FAO. The activation of the ISR and disruptions in mitochondrial FAO may underlie the adaptive changes in VARS2-depleted cells.
Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial bacterial metabolites, such as short-chain fatty acids. Evidence supports the beneficial effects of short-chain fatty acids in modulating inflammation and oxidative stress, which are implicated in CKD pathogenesis and progression. Therefore, this review will provide an overview of the current knowledge, based on pre-clinical and clinical evidence, on the effect of SCFAs on CKD-associated inflammation and oxidative stress.
Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O\(^6\)-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse.
The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.
Reversible protein phosphorylation is a posttranslational modification of regulatory proteins involved in cardiac signaling pathways. Here, we focus on the role of protein phosphatase 2A (PP2A) for cardiac gene expression and stress response using a transgenic mouse model with cardiac myocyte-specific overexpression of the catalytic subunit of PP2A (PP2A-TG). Gene and protein expression were assessed under basal conditions by gene chip analysis and Western blotting. Some cardiac genes related to the cell metabolism and to protein phosphorylation such as kinases and phosphatases were altered in PP2A-TG compared to wild type mice (WT). As cardiac stressors, a lipopolysaccharide (LPS)-induced sepsis in vivo and a global cardiac ischemia in vitro (stop-flow isolated perfused heart model) were examined. Whereas the basal cardiac function was reduced in PP2A-TG as studied by echocardiography or as studied in the isolated work-performing heart, the acute LPS- or ischemia-induced cardiac dysfunction deteriorated less in PP2A-TG compared to WT. From the data, we conclude that increased PP2A activity may influence the acute stress tolerance of cardiac myocytes.
Rac1 is a small Rho GTPase that is activated in platelets upon stimulation with various ligands, including collagen and thrombin, which are ligands for the glycoprotein VI (GPVI) receptor and the protease-activated receptors, respectively. Rac1-deficient murine platelets have impaired lamellipodia formation, aggregation, and reduced PLCγ2 activation, but not phosphorylation. The objective of our study is to investigate the role of Rac1 in GPVI-dependent human platelet activation and downstream signalling. Therefore, we used human platelets stimulated using GPVI agonists (collagen and collagen-related peptide) in the presence of the Rac1-specific inhibitor EHT1864 and analysed platelet activation, aggregation, spreading, protein phosphorylation, and GPVI clustering and shedding. We observed that in human platelets, the inhibition of Rac1 by EHT1864 had no significant effect on GPVI clustering on collagen fibres but decreased the ability of platelets to spread or aggregate in response to GPVI agonists. Additionally, in contrast to what was observed in murine Rac1-deficient platelets, EHT1864 enhanced GPVI shedding in platelets and reduced the phosphorylation levels of PLCγ2 following GPVI activation. In conclusion, Rac1 activity is required for both human and murine platelet activation in response to GPVI-ligands, but Rac1’s mode of action differs between the two species.
Melt electrowriting, a high-resolution additive manufacturing technique, is used in this study to process a magnetic polymer-based blend for the first time. Carbonyl iron (CI) particles homogenously distribute into poly(vinylidene fluoride) (PVDF) melts to result in well-defined, highly porous structures or scaffolds comprised of fibers ranging from 30 to 50 µm in diameter. This study observes that CI particle incorporation is possible up to 30 wt% without nozzle clogging, albeit that the highest concentration results in heterogeneous fiber morphologies. In contrast, the direct writing of homogeneous PVDF fibers with up to 15 wt% CI is possible. The fibers can be readily displaced using magnets at concentrations of 1 wt% and above. Combined with good viability of L929 CC1 cells using Live/Dead imaging on scaffolds for all CI concentrations indicates that these formulations have potential for the usage in stimuli-responsive applications such as 4D printing.
A facile and flexible approach for the integration of biomimetically branched microvasculature within bulk hydrogels is presented. For this, sacrificial scaffolds of thermoresponsive poly(2-cyclopropyl-2-oxazoline) (PcycloPrOx) are created using melt electrowriting (MEW) in an optimized and predictable way and subsequently placed into a customized bioreactor system, which is then filled with a hydrogel precursor solution. The aqueous environment above the lower critical solution temperature (LCST) of PcycloPrOx at 25 °C swells the polymer without dissolving it, resulting in fusion of filaments that are deposited onto each other (print-and-fuse approach). Accordingly, an adequate printing pathway design results in generating physiological-like branchings and channel volumes that approximate Murray's law in the geometrical ratio between parent and daughter vessels. After gel formation, a temperature decrease below the LCST produces interconnected microchannels with distinct inlet and outlet regions. Initial placement of the sacrificial scaffolds in the bioreactors in a pre-defined manner directly yields perfusable structures via leakage-free fluid connections in a reproducible one-step procedure. Using this approach, rapid formation of a tight and biologically functional endothelial layer, as assessed not only through fluorescent dye diffusion, but also by tumor necrosis factor alpha (TNF-α) stimulation, is obtained within three days.
In recent decades, hybrid characterization systems have become pillars in the study of cellular biomechanics. Especially, Atomic Force Microscopy (AFM) is combined with a variety of optical microscopy techniques to discover new aspects of cell adhesion. AFM, however, is limited to the early-stage of cell adhesion, so that the forces of mature cell contacts cannot be addressed. Even though the invention of Fluidic Force Microscopy (FluidFM) overcomes these limitations by combining the precise force-control of AFM with microfluidics, the correlative investigation of detachment forces arising from spread mammalian cells has been barely achieved. Here, a novel multifunctional device integrating Fluorescence Microscopy (FL) into FluidFM technology (FL-FluidFM) is introduced, enabling real-time optical tracking of entire cell detachment processes in parallel to the undisturbed acquisition of force-distance curves. This setup, thus, allows for entailing two pieces of information at once. As proof-of-principle experiment, this method is applied to fluorescently labeled rat embryonic fibroblast (REF52) cells, demonstrating a precise matching between identified force-jumps and visualized cellular unbinding steps. This study, thus, presents a novel characterization tool for the correlated evaluation of mature cell adhesion, which has great relevance, for instance, in the development of biomaterials or the fight against diseases such as cancer.
Melt electrowriting (MEW) is an additive manufacturing process that produces highly defined constructs with elements in the micrometer range. A specific configuration of MEW enables printing tubular constructs to create small-diameter tubular structures. The small pool of processable materials poses a bottleneck for wider application in biomedicine. To alleviate this obstacle, an acrylate-endcapped urethane-based polymer (AUP), using a poly(ε-caprolactone) (PCL) (molar mass: 20 000 g mol\(^{−1}\)) (AUP PCL20k) as backbone material, is synthesized and utilized for MEW. Spectroscopic analysis confirms the successful modification of the PCL backbone with photo-crosslinkable acrylate endgroups. Printing experiments of AUP PCL20k reveal limited printability but the photo-crosslinking ability is preserved post-printing. To improve printability and to tune the mechanical properties of printed constructs, the AUP-material is blended with commercially available PCL (AUP PCL20k:PCL in ratios 80:20, 60:40, 50:50). Print fidelity improves for 60:40 and 50:50 blends. Blending enables modification of the constructs' mechanical properties to approximate the range of blood vessels for transplantation surgeries. The crosslinking-ability of the material allows pure AUP to be manipulated post-printing and illustrates significant differences in mechanical properties of 80:20 blends after crosslinking. An in vitro cell compatibility assay using human umbilical vein endothelial cells also demonstrates the material's non-cytotoxicity.
Transcriptional and distributional profiling of microglia in retinal angiomatous proliferation
(2022)
Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors.
The platelet-activating collagen receptor GPVI represents the focus of clinical trials as an antiplatelet target for arterial thrombosis, and soluble GPVI is a plasma biomarker for several human diseases. A disintegrin and metalloproteinase 10 (ADAM10) acts as a ‘molecular scissor’ that cleaves the extracellular region from GPVI and many other substrates. ADAM10 interacts with six regulatory tetraspanin membrane proteins, Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33, which are collectively termed the TspanC8s. These are emerging as regulators of ADAM10 substrate specificity. Human platelets express Tspan14, Tspan15 and Tspan33, but which of these regulates GPVI cleavage remains unknown. To address this, CRISPR/Cas9 knockout human cell lines were generated to show that Tspan15 and Tspan33 enact compensatory roles in GPVI cleavage, with Tspan15 bearing the more important role. To investigate this mechanism, a series of Tspan15 and GPVI mutant expression constructs were designed. The Tspan15 extracellular region was found to be critical in promoting GPVI cleavage, and appeared to achieve this by enabling ADAM10 to access the cleavage site at a particular distance above the membrane. These findings bear implications for the regulation of cleavage of other ADAM10 substrates, and provide new insights into post-translational regulation of the clinically relevant GPVI protein.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject’s brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5\(^{-/-}\) mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5\(^{-/-}\) mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry.
Osmotic stress can be detrimental to plants, whose survival relies heavily on proteomic plasticity. Protein ubiquitination is a central post-translational modification in osmotic-mediated stress. In this study, we used the K-Ɛ-GG antibody enrichment method integrated with high-resolution mass spectrometry to compile a list of 719 ubiquitinated lysine (K-Ub) residues from 450 Arabidopsis root membrane proteins (58% of which are transmembrane proteins), thereby adding to the database of ubiquitinated substrates in plants. Although no ubiquitin (Ub) motifs could be identified, the presence of acidic residues close to K-Ub was revealed. Our ubiquitinome analysis pointed to a broad role of ubiquitination in the internalization and sorting of cargo proteins. Moreover, the simultaneous proteome and ubiquitinome quantification showed that ubiquitination is mostly not involved in membrane protein degradation in response to short osmotic treatment but that it is putatively involved in protein internalization, as described for the aquaporin PIP2;1. Our in silico analysis of ubiquitinated proteins shows that two E2 Ub-conjugating enzymes, UBC32 and UBC34, putatively target membrane proteins under osmotic stress. Finally, we revealed a positive role for UBC32 and UBC34 in primary root growth under osmotic stress.
The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development of pharmacological phosphodiesterase inhibitors (PDE-I) to attenuate cAMP degradation. While there are many isotypes of PDE, a predominant role of PDE4 is to regulate fundamental functions, including endothelial and epithelial barrier stability, modulation of inflammatory responses and cognitive and/or mood functions. This makes the use of PDE4-I an interesting tool for various therapeutic approaches. However, due to the presence of PDE4 in many tissues, there is a significant danger for serious side effects. Based on this, the aim of this review is to provide a comprehensive overview of the approaches and effects of PDE4-I for different therapeutic applications. In summary, despite many obstacles to use of PDE4-I for different therapeutic approaches, the current data warrant future research to utilize the therapeutic potential of phosphodiesterase 4 inhibition.
Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2\(^{wt}\)) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood–brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP\(^{wt}\)) and its phosphorylation-deficient mutant RKIP\(^{S153A}\), known inhibitors of the ERK1/2 signaling cascade. RKIP\(^{wt}\) and RKIP\(^{S153A}\) attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.
V.2 Literarische Rezeption
(2022)
No abstract available.
No abstract available.
Understanding the pathways involved in the formation and stability of the core and shell regions of a platelet-rich arterial thrombus may result in new ways to treat arterial thrombosis. The distinguishing feature between these two regions is the absence of fibrin in the shell which indicates that in vitro flow-based assays over thrombogenic surfaces, in the absence of coagulation, can be used to resemble this region. In this study, we have investigated the contribution of Syk tyrosine kinase in the stability of platelet aggregates (or thrombi) formed on collagen or atherosclerotic plaque homogenate at arterial shear (1000 s\(^{−1}\)). We show that post-perfusion of the Syk inhibitor PRT-060318 over preformed thrombi on both surfaces enhances thrombus breakdown and platelet detachment. The resulting loss of thrombus stability led to a reduction in thrombus contractile score which could be detected as early as 3 min after perfusion of the Syk inhibitor. A similar loss of thrombus stability was observed with ticagrelor and indomethacin, inhibitors of platelet adenosine diphosphate (ADP) receptor and thromboxane A\(_2\) (TxA\(_2\)), respectively, and in the presence of the Src inhibitor, dasatinib. In contrast, the Btk inhibitor, ibrutinib, causes only a minor decrease in thrombus contractile score. Weak thrombus breakdown is also seen with the blocking GPVI nanobody, Nb21, which indicates, at best, a minor contribution of collagen to the stability of the platelet aggregate. These results show that Syk regulates thrombus stability in the absence of fibrin in human platelets under flow and provide evidence that this involves pathways additional to activation of GPVI by collagen.
Polymers sensitive to thermal degradation include poly(lactic-co-glycolic acid) (PLGA), which is not yet processed via melt electrowriting (MEW). After an initial period of instability where mean fiber diameters increase from 20.56 to 27.37 µm in 3.5 h, processing stabilizes through to 24 h. The jet speed, determined using critical translation speed measurements, also reduces slightly in this 3.5 h period from 500 to 433 mm min\(^{−1}\) but generally remains constant. Acetyl triethyl citrate (ATEC) as an additive decreases the glass transition temperature of PLGA from 49 to 4 °C, and the printed ATEC/PLGA fibers exhibits elastomeric behavior upon handling. Fiber bundles tested in cyclic mechanical testing display increased elasticity with increasing ATEC concentration. The processing temperature of PLGA also reduces from 165 to 143 °C with increase in ATEC concentration. This initial window of unstable direct writing seen with neat PLGA can also be impacted through the addition of 10-wt% ATEC, producing fiber diameters of 14.13 ± 1.69 µm for the first 3.5 h of heating. The investigation shows that the initial changes to the PLGA direct-writing outcomes seen in the first 3.5 h are temporary and that longer times result in a more stable MEW process.
Mucin, a high molecular mass hydrophilic glycoprotein, is the main component of mucus that coats every wet epithelium in animals. It is thus intrinsically biocompatible, and with its protein backbone and the o-glycosidic bound oligosaccharides, it contains a plethora of functional groups which can be used for further chemical modifications. Here, chain-growth and step-growth (thiol-ene) free-radical cross-linked hydrogels prepared from commercially available pig gastric mucin (PGM) are introduced and compared as cost-efficient and easily accessible alternative to the more broadly applied bovine submaxillary gland mucin. For this, PGM is functionalized with photoreactive acrylate groups or allyl ether moieties, respectively. Whereas homopolymerization of acrylate-functionalized polymers is performed, for thiol-ene cross-linking, the allyl-ether-functionalized PGM is cross-linked with thiol-functionalized hyaluronic acid. Morphology, mechanical properties, and cell compatibility of both kinds of PGM hydrogels are characterized and compared. Furthermore, the biocompatibility of these hydrogels can be evaluated in cell culture experiments.
Diagnosis and therapy of Mycobacterium marinum: a single-center 21-year retrospective analysis
(2022)
Background and Objectives
In Europe, infections with Mycobacterium (M.) marinum are rare. We conducted a retrospective single-center study to assess the clinical spectrum of M. marinum infection and its diagnosis, treatment and outcome under real-world conditions.
Patients and Methods
Eighteen patients presenting with M. marinum infections between 1998 and 2018 were identified in the data warehouse of the University Hospital Würzburg and considered for detailed analysis.
Results
Twelve patients reported aquatic exposure. In 16/18 cases the upper extremities were affected. No invasive infections were detected. Mean time to diagnosis was 15 weeks. Histology revealed granulomatous inflammation in 14 patients while mycobacterial cultures were positive for M. marinum in 16 cases. Most patients received antibiotic monotherapy (14/18) while combination therapy was administered in four cases. Treatment (with a median duration of 10 weeks) was successful in 13 patients. Five patients were lost to follow-up.
Conclusions
Our retrospective analysis of M. marinum infections at a German tertiary referral center revealed a considerable diagnostic delay and the relevance of microbiological culture, PCR and histology for diagnosis. Monotherapy with clarithromycin (rather than doxycycline) appeared as a reasonable treatment option while immunosuppressed or -compromised patients and those with extended disease received combination therapy.
There is a lack of standardized treatment recommendations for orofacial granulomatosis, a chronic inflammatory condition aetiologically related to Crohn disease. To assess clinical baseline parameters and treatment strategies, we retrospectively analysed 61 consecutive cases from our institutional database. Disease-related functional/psychological impairment and long-term outcomes were descriptively evaluated using a standardized self-reporting questionnaire. The median age of patients was 45 (7–77) years. Oral steroids were given in 41.0% of cases, but only produced short-term disease control, while response to steroid-sparing agents was inconsistent. Only a minority of patients reported relevant disease-related functional impairment in eating (21.7%) or speaking (4.3%), but the majority perceived psychological distress due to the cosmetic aspects of the disease (69.6%), comments from others (65.2%) and/or general anxiety/insecurity (73.9%). Regardless of the initial treatment, long-term outcomes after 71 months (range 7–304 months) were beneficial, with most patients being in complete remission (52.2%) or reporting only mild residual swelling (43.5%).
Background and objectives
Bullous pemphigoid (BP) is associated with neuropsychiatric disorders. Other comorbid diseases are discussed controversially. We evaluated the prevalence of comorbidity in BP patients in a representative area of Germany.
Patients and methods
Medical files of all BP patients treated at the Department of Dermatology, University Hospital Würzburg, Germany, between June 2002 and May 2013 were retrospectively reviewed. Bullous pemphigoid was diagnosed based on established criteria. For each patient, two controls were individually matched. Records were evaluated for age, sex, laboratory values, concomitant medication and comorbidity. Conditional logistic regression, multivariable regression analysis and complex regression models were performed to compare results.
Results
300 BP patients were identified and compared to 583 controls. Bullous pemphigoid was associated with neuropsychiatric disorders as well as laboratory abnormalities including leukocytosis and eosinophilia. Importantly, a highly significant association of BP with anemia (OR 2.127; 95 % CI 1.532–2.953) and renal impairment (OR 2.218; 95 % CI 1.643–2.993) was identified. No association was found with malignancy and arterial hypertension.
Conclusions
Our data revealed an increased frequency of anemia and renal impairment in BP patients. In accordance with previous studies the strong association for neuropsychiatric disorders was confirmed (p < 0.0005).
Herein, we report the facile synthesis of a three-dimensional (3D) inorganic analogue of 9,10-diazido-9,10-dihydrodiboraantracene, which turned out to be a monomer in both the solid and solution state, and thermally stable up to 230 °C, representing a rare example of azido borane with boosted Lewis acidity and stability in one. Apart from the classical acid-base and Staudinger reactions, E−H bond activation (E=B, Si, Ge) was investigated. While the reaction with B−H (9-borabicyclo[3.3.1]nonane) led directly to the 1,1-addition on N\(_{α}\) upon N\(_{2}\) elimination, the Si−H (Et\(_{3}\)SiH, PhMe\(_{2}\)SiH) activation proceeded stepwise via 1,2-addition, with the key intermediates 5\(_{int}\) and 6\(_{int}\) being isolated and characterized. In contrast, the cooperative Ge−H was reversible and stayed at the 1,2-addition step.
Herein, the copper-catalyzed borylation of readily available acyl chlorides with bis(pinacolato)diboron, (B\(_{2}\)pin\(_{2}\)) or bis(neopentane glycolato)diboron (B\(_{2}\)neop\(_{2}\)) is reported, which provides stable potassium acyltrifluoroborates (KATs) in good yields from the acylboronate esters. A variety of functional groups are tolerated under the mild reaction conditions (room temperature) and substrates containing different carbon-skeletons, such as aryl, heteroaryl and primary, secondary, tertiary alkyl are applicable. Acyl N-methyliminodiacetic acid (MIDA) boronates can also been accessed by modification of the workup procedures. This process is scalable and also amenable to the late-stage conversion of carboxylic acid-containing drugs into their acylboron analogues, which have been challenging to prepare previously. A catalytic mechanism is proposed based on in situ monitoring of the reaction between p-toluoyl chloride and an NHC-copper(I) boryl complex as well as the isolation of an unusual lithium acylBpinOBpin compound as a key intermediate.
Ten thiosemicarbazone ligands obtained by condensation of pyridine-2-carbaldehyde, quinoline-2-carbaldehyde, 2-acetylpyridine, 2-acetylquinoline, or corresponding 2-pyridyl ketones with thiosemicarbazides RNHC(S)NHNH\(_{2}\) and R=CH\(_{3}\), C\(_{6}\)H\(_{5}\) were prepared in good yield. The reaction of [PdCl\(_{2}\)(cod)] with cod=1,5-cyclooctadiene or K\(_{2}\)[PtCl\(_{4}\)] resulted in a total of 17 Pd(II) and Pt(II) complexes isolated in excellent purity, as demonstrated by \(^{1}\)H, \(^{13}\)C, and, where applicable, \(^{195\)Pt NMR spectroscopy combined with CHNS analysis. The cytotoxicity of the title compounds was studied on four human glioblastoma cell lines (GaMG, U87, U138, and U343). The most active compound, with a Pd(II) metal centre, a 2-quinolinyl ring, and methyl groups on both the proximal C and distal N atoms exhibited an EC\(_{50}\) value of 2.1 μM on the GaMG cell lines, thus being slightly more active than cisplatin (EC\(_{50}\) 3.4 μM) and significantly more potent than temozolomide (EC\(_{50}\) 67.1 μM). Surprisingly, the EC\(_{50}\) values were inversely correlated with the lipophilicity, as determined with the “shake-flask method”, and decreased with the length of the alkyl substituents (C\(_{1}\)>C\(_{8}\)>C\(_{10}\)). Correlation with the different structural motifs showed that for the most promising anticancer activity, a maximum of two aromatic rings (either quinolinyl or pyridyl plus phenyl) combined with one methyl group are favoured and the Pd(II) complexes are slightly more potent than their Pt(II) analogues.
A convenient route for the synthesis of the cAAC\(^{Me}\) (cAAC=cyclic (alkyl)(amino)carbene, cAAC\(^{Me}\)=1-(2,6-di-iso-propylphenyl)-3,3,5,5-tetramethyl-pyrrolidin-2-ylidene) and cAAC\(^{Cy}\) (cAAC\(^{Cy}\)=2-azaspiro[4.5]dec-2-(2,6-diisopropylphenyl)-3,3-dimethyl-1-ylidene) stabilized stibinidenes cAAC\(^{Me}\)⋅SbMes (2a) (Mes=2,4,6-trimethylphenyl) and cAAC\(^{Cy}\)⋅SbMes (2b) is reported. A mechanism for the formation of [cAAC\(^{R}\)Cl][SbCl\(_{3}\)Mes] 1 and cAAC\(^{R}\)⋅SbMes 2 from the reaction of cAAC with the antimony(III) precursor SbCl\(_{2}\)Mes, which proceeds via the isolable intermediate [cAAC\(^{R}\)SbClMes][SbCl\(_{3}\)Mes] (3), is proposed.
A series of unprecedently air-stable (tricyanoboryl)plumbate anions was obtained by the reaction of the boron-centered nucleophile B(CN)\(_{3}\)\(^{2-}\) with triorganyllead halides. Salts of the anions [R\(_{3}\)PbB(CN)\(_{3}\)]\(^{-}\) (R=Ph, Et) were isolated and found to be stable in air at room temperature. In the case of Me\(_{3}\)PbHal (Hal=Cl, Br), a mixture of the anions [Me\(_{4-n}\)Pb{B(CN)\(_{3}\)}\(_{n}\)]\(^{n-}\) (n=1, 2) was obtained. The [Et\(_{3}\)PbB(CN)\(_{3}\)]− ion undergoes stepwise dismutation in aqueous solution to yield the plumbate anions [Et4\(_{4-n}\)Pb{B(CN)\(_{3}\)}\(_{n}\)]\(^{n-}\) (n=1–4) and PbEt\(_{4}\) as by-product. The reaction rate increases with decreasing pH value of the aqueous solution or by bubbling O\(_{2}\) through the reaction mixture. Adjustment of the conditions allowed the selective formation and isolation of salts of all anions of the series [Et\(_{4-n}\)Pb{B(CN)\(_{3}\)}\(_{n}\)]\(^{n-}\) (n=2–4) including the homoleptic tetraanion [Pb{B(CN)\(_{3}\)}\(_{4}\)]\(^{4-}\).
Designing highly efficient purely organic phosphors at room temperature remains a challenge because of fast non-radiative processes and slow intersystem crossing (ISC) rates. The majority of them emit only single component phosphorescence. Herein, we have prepared 3 isomers (o, m, p-bromophenyl)-bis(2,6-dimethylphenyl)boranes. Among the 3 isomers (o-, m- and p-BrTAB) synthesized, the ortho-one is the only one which shows dual phosphorescence, with a short lifetime of 0.8 ms and a long lifetime of 234 ms in the crystalline state at room temperature. Based on theoretical calculations and crystal structure analysis of o-BrTAB, the short lifetime component is ascribed to the T\(^M_1\) state of the monomer which emits the higher energy phosphorescence. The long-lived, lower energy phosphorescence emission is attributed to the T\(^A_1\) state of an aggregate, with multiple intermolecular interactions existing in crystalline o-BrTAB inhibiting nonradiative decay and stabilizing the triplet states efficiently.
Boric acid (BA) has been used as a transparent glass matrix for optical materials for over 100 years. However, recently, apparent room-temperature phosphorescence (RTP) from BA (crystalline and powder states) was reported (Zheng et al., Angew. Chem. Int. Ed. 2021, 60, 9500) when irradiated at 280 nm under ambient conditions. We suspected that RTP from their BA sample was induced by an unidentified impurity. Our experimental results show that pure BA synthesized from B(OMe)\(_{3}\) does not luminesce in the solid state when irradiated at 250–400 nm, while commercial BA indeed (faintly) luminesces. Our theoretical calculations show that neither individual BA molecules nor aggregates would absorb light at >175 nm, and we observe no absorption of solid pure BA experimentally at >200 nm. Therefore, it is not possible for pure BA to be excited at >250 nm even in the solid state. Thus, pure BA does not display RTP, whereas trace impurities can induce RTP.
Defunctionalization of readily available feedstocks to provide alkenes for the synthesis of multifunctional molecules represents an extremely useful process in organic synthesis. Herein, we describe a transition metal-free, simple and efficient strategy to access alkyl 1,2-bis(boronate esters) via regio- and diastereoselective diboration of secondary and tertiary alkyl halides (Br, Cl, I), tosylates, and alcohols. Control experiments demonstrated that the key to this high reactivity and selectivity is the addition of a combination of potassium iodide and N,N-dimethylacetamide (DMA). The practicality and industrial potential of this transformation are demonstrated by its operational simplicity, wide functional group tolerance, and the late-stage modification of complex molecules. From a drug discovery perspective, this synthetic method offers control of the position of diversification and diastereoselectivity in complex ring scaffolds, which would be especially useful in a lead optimization program.
Anaemia is a risk factor for several adverse postoperative outcomes. Detailed data about the prevalence of anaemia are not available over a long time-period in Germany. In this retrospective, observational, multicentre study, patients undergoing surgery in March in 2007, 2012, 2015, 2017 and 2019 were studied. The primary objective was the prevalence of anaemia at hospital admission. The secondary objectives were the association between anaemia and the number of units of red blood cells transfused, length of hospital stay and in-hospital mortality. A total of 23,836 patients were included from eight centres. The prevalence of pre-operative anaemia in patients aged ≥ 18 years decreased slightly from 37% in 2007 to 32.5% in 2019 (p = 0.01) and increased in patients aged ≤ 18 years from 18.8% in 2007 to 26.4% in 2019 (p > 0.001). The total amount of blood administered per 1000 patients decreased from 671.2 units in 2007 to 289.0 units in 2019. Transfusion rates in anaemic patients declined from 33.8% in 2007 to 19.1% in 2019 (p < 0.001) and in non-anaemic patients from 8.4% in 2007 to 3.4% in 2019 (p < 0.001). Overall, the mortality rate remained constant over the years: 2.9% in 2007, 2.1% in 2012, 2.5% in 2015, 1.9% in 2017 and 2.5% in 2019. In the presence of anaemia, mortality was significantly increased compared with patients without anaemia (OR 5.27 (95%CI 4.13–6.77); p < 0.001). Red blood cell transfusion was associated with an increased risk of mortality (OR 14.98 (95%CI 11.83–19.03); p < 0.001). Using multivariable linear regression analysis with fixed effects, we found that pre-operative anaemia (OR 2.08 (95%CI 1.42–3.05); p < 0.001) and red blood cell transfusion (OR 4.29 (95%CI 3.09–5.94); p < 0.001) were predictors of mortality but not length of stay (0.99 (95%CI 0.98–1.00) days; p = 0.12) and analysed years (2007 vs. 2019: OR 1.49 (95%CI 0.86–2.69); p = 0.07). Pre-operative anaemia affects more than 30% of surgical patients in Germany and multidisciplinary action is urgently required to reduce adverse outcomes.
Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.
Background
Complex regional pain syndrome (CRPS) is an orphan disease occurring as a complication after trauma. Due to its acute onset and the typical clinical presentation of the inflammatory and autonomous signs, it is an eye-catching chronic pain disease affecting also young and working people. In social media and the internet, high pain severity and the unfavourable prognosis are often empathized.
Methods
Here, we compared epidemiological, pain and lifestyle factors of 223 CPRS patients from the “ncRNAPain” cohort with 255 patients with chronic musculoskeletal pain (MSK). MSK patients were recruited at the beginning of a multimodal pain therapy programme. We searched for factors predicting pain intensity.
Results
Both chronic pain diseases affected women in middle age. Patients with MSK were more obese, drank more alcohol, and were less educated (Pearson chi-square Test or Mann–Whitney/U-Test). Both groups smoked more than healthy people in the OECD (Organization for Economic Cooperation and Development). Mann–Whitney/U-Test confirmed that CRPS patients did not have more severe pain and did not suffer more from pain-related disability than patients with MSK. CRPS patients also had less psychiatric comorbidities. Multiple linear regression analysis revealed that group assignment, depressive characteristics, body mass index, average alcohol consumption and smoking predicted higher pain ratings, while disease duration, anxiety symptoms or gender had no influence on pain intensity.
Conclusion
In summary, our study supports a more optimistic view on pain in CRPS patients in comparison to MSK and identifies lifestyle factors that might contribute to the pathophysiology like smoking and drinking. Important next steps are the identification of CRPS patients at risk for chronification or—vice versa—with protective factors for pain resolution.
Significance
This study compares complex regional pain syndrome (CRPS) and chronic musculoskeletal pain and questions previously reported pain, disability and lifestyle factors associated with CRPS.
Stalk cell polar ion transport provide for bladder‐based salinity tolerance in Chenopodium quinoa
(2022)
Chenopodium quinoa uses epidermal bladder cells (EBCs) to sequester excess salt. Each EBC complex consists of a leaf epidermal cell, a stalk cell, and the bladder.
Under salt stress, sodium (Na\(^{+}\)), chloride (Cl\(^{−}\)), potassium (K\(^{+}\)) and various metabolites are shuttled from the leaf lamina to the bladders. Stalk cells operate as both a selectivity filter and a flux controller.
In line with the nature of a transfer cell, advanced transmission electron tomography, electrophysiology, and fluorescent tracer flux studies revealed the stalk cell’s polar organization and bladder‐directed solute flow.
RNA sequencing and cluster analysis revealed the gene expression profiles of the stalk cells. Among the stalk cell enriched genes, ion channels and carriers as well as sugar transporters were most pronounced. Based on their electrophysiological fingerprint and thermodynamic considerations, a model for stalk cell transcellular transport was derived.
Purpose
Fungal biomarkers support early diagnosis of invasive fungal infections. In this study, we evaluated the impact of a recent update to the manufacturer‐recommended cut‐off for beta‐1,3‐D‐glucan (BDG) testing (Fujifilm Wako BDG assay) on sensitivity and specificity for the detection of candidemia. Additionally, we compared the performance with tests for Candida antigen (Ag by Serion ELISA antigen Candida, Virion\Serion) and anti‐mannan antibodies (Ab by Hemkit Candida IHA, Ravo Diagnostika).
Methods
Sera of 82 patients with candidemia, which were sampled with a maximum distance of ±14 days from the date of sampling of the corresponding positive blood cultures, were retrospectively analysed for BDG, Ag and Ab. Results of BDG testing were compared with results from sera of 129 patients with candidemia from a different hospital.
Results
Sensitivity of BDG testing (47%) was higher than for Ag (17%) or Ab (20%). By combining Ag and Ab testing, sensitivity was raised to 32%. Lowering the cut‐off of BDG from 11 pg/ml to the newly recommended cut‐off of 7 pg/ml resulted in a significant increase in sensitivity (47% vs 58%, p = .01 and 63% vs 71% p < .01). At both centres, the increase was significant in NAC but not in C. albicans candidemia. No significant effects on specificity were observed.
Conclusion
BDG testing outperformed Ag and Ab testing and its combination. Lowering the BDG cut‐off had no significant impact on specificity. The increase in sensitivity can be mainly attributed to a gain in sensitivity for non‐albicans Candida species bloodstream infections.
Aseptic loosening of total hip and knee joint replacements is the most common indication for revision surgery after primary hip and knee arthroplasty. Research suggests that exposure and uptake of wear by mesenchymal stromal cells (MSC) and macrophages results in the secretion of proinflammatory cytokines and local osteolysis, but also impaired cell viability and regenerative capacity of MSC. Therefore, this in vitro study compared the regenerative and differentiation capacity of MSC derived from patients undergoing primary total hip arthroplasty (MSCprim) to MSC derived from patients undergoing revision surgery after aseptic loosening of total hip and knee joint implants (MSCrev). Regenerative capacity was examined by measuring the cumulative population doubling (CPD) in addition to the number of passages until cells stopped proliferating. Osteogenesis and adipogenesis in monolayer cultures were assessed using histological stainings. Furthermore, RT‐PCR was performed to evaluate the relative expression of osteogenic and adipogenic marker genes as well as the expression of markers for a senescence‐associated secretory phenotype (SASP). MSCrev possessed a limited regenerative capacity in comparison to MSCprim. Interestingly, MSCrev also showed an impaired osteogenic and adipogenic differentiation capacity compared to MSCprim and displayed a SASP early after isolation. Whether this is the cause or the consequence of the aseptic loosening of total joint implants remains unclear. Future research should focus on the identification of specific cell markers on MSCprim, which may influence complication rates such as aseptic loosening of total joint arthroplasty to further individualize and optimize total joint arthroplasty.
Activating Organic Phosphorescence via Heavy Metal–π Interaction Induced Intersystem Crossing
(2022)
Heavy‐atom‐containing clusters, nanocrystals, and other semiconductors can sensitize the triplet states of their surface‐bonded chromophores, but the energy loss, such as nonradiative deactivation, often prevents the synergistic light emission in their solid‐state coassemblies. Cocrystallization allows new combinations of molecules with complementary properties for achieving functionalities not available in single components. Here, the cocrystal formation that employs platinum(II) acetylacetonate (Pt(acac)\(_{2}\)) as a triplet sensitizer and electron‐deficient 1,4,5,8‐naphthalene diimides (NDIs) as organic phosphors is reported. The hybrid cocrystals exhibit room‐temperature phosphorescence confined in the low‐lying, long‐lived triplet state of NDIs with photoluminescence (PL) quantum yield (Φ\(_{PL}\)) exceeding 25% and a phosphorescence lifetime (τ\(_{Ph}\)) of 156 µs. This remarkable PL property benefits from the noncovalent electronic and spin–orbital coupling between the constituents.
Green plants are equipped with photoreceptors that are capable of sensing radiation in the ultraviolet‐to‐blue and the red‐to‐far‐red parts of the light spectrum. However, plant cells are not particularly sensitive to green light (GL), and light which lies within this part of the spectrum does not efficiently trigger the opening of stomatal pores. Here, we discuss the current knowledge of stomatal responses to light, which are either provoked via photosynthetically active radiation or by specific blue light (BL) signaling pathways. The limited impact of GL on stomatal movements provides a unique option to use this light quality to control optogenetic tools. Recently, several of these tools have been optimized for use in plant biological research, either to control gene expression, or to provoke ion fluxes. Initial studies with the BL‐activated potassium channel BLINK1 showed that this tool can speed up stomatal movements. Moreover, the GL‐sensitive anion channel GtACR1 can induce stomatal closure, even at conditions that provoke stomatal opening in wild‐type plants. Given that crop plants in controlled‐environment agriculture and horticulture are often cultivated with artificial light sources (i.e. a combination of blue and red light from light‐emitting diodes), GL signals can be used as a remote‐control signal that controls stomatal transpiration and water consumption.
Objective
Global challenges such as climate change or the COVID‐19 pandemic have drawn public attention to conspiracy theories and citizens' non‐compliance to science‐based behavioral guidelines. We focus on individuals' worldviews about how one can and should construct reality (epistemic beliefs) to explain the endorsement of conspiracy theories and behavior during the COVID‐19 pandemic and propose the Dark Factor of Personality (D) as an antecedent of post‐truth epistemic beliefs.
Method and Results
This model is tested in four pre‐registered studies. In Study 1 (N = 321), we found first evidence for a positive association between D and post‐truth epistemic beliefs (Faith in Intuition for Facts, Need for Evidence, Truth is Political). In Study 2 (N = 453), we tested the model proper by further showing that post‐truth epistemic beliefs predict the endorsement of COVID‐19 conspiracies and disregarding COVID‐19 behavioral guidelines. Study 3 (N = 923) largely replicated these results at a later stage of the pandemic. Finally, in Study 4 (N = 513), we replicated the results in a German sample, corroborating their cross‐cultural validity. Interactions with political orientation were observed.
Conclusion
Our research highlights that epistemic beliefs need to be taken into account when addressing major challenges to humankind.
Aim
This study evaluated the oral health status of adult patients with hypophosphatasia (HPP).
Materials and Methods
Parameters of oral health assessment comprised decayed/missing/filled teeth (DMFT) index, probing pocket depth and clinical attachment level (CAL) as well as documentation of tooth loss and periodontal health status according to CCD/AAP criteria. Findings were compared with national reference data (DMS V survey) reporting oral health status in age‐related controls. Within‐group comparisons were made between the HPP patients harbouring one versus two alkaline phosphatase liver/bone/kidney type (ALPL) gene variants.
Results
Of 80 HPP patients (64 female) with a mean age of 46.4 years (range 24–78) and one (n = 55) or two (n = 18) variants (n = 7 lacking testing) within the ALPL gene, those with two variants displayed substantially higher tooth loss rate (14.0 ± 9.3) than those affected by only one ALPL variant (4.1 ± 5.4), who did not differ substantially from healthy DMS V controls. While DMFT score and severe periodontal diseases (PDs) of HPP patients with one variant only increased with progressing age, the two‐variant sub‐cohort age independently exhibited increased DMFT scores and a higher rate of severe PDs.
Conclusions
HPP patients affected by two variants of the ALPL gene exhibited a higher risk of periodontitis and tooth loss than the general population, while patients with one variant developed clinically relevant oral disease symptoms with progressing ageing.
Recent reports on insect decline have highlighted the need for long‐term data on insect communities towards identifying their trends and drivers.
With the launch of many new insect monitoring schemes to investigate insect communities over large spatial and temporal scales, Malaise traps have become one of the most important tools due to the broad spectrum of species collected and reduced capture bias through passive sampling of insects day and night. However, Malaise traps can vary in size, shape, and colour, and it is unknown how these differences affect biomass, species richness, and composition of trap catch, making it difficult to compare results between studies.
We compared five Malaise trap types (three variations of the Townes and two variations of the Bartak Malaise trap) to determine their effects on biomass and species richness as identified by metabarcoding.
Insect biomass varied by 20%–55%, not strictly following trap size but varying with trap type. Total species richness was 20%–38% higher in the three Townes trap models compared to the Bartak traps. Bartak traps captured lower richness of highly mobile taxa but increased richness of ground‐dwelling taxa. The white roofed Townes trap captured a higher richness of pollinators.
We find that biomass, total richness, and taxa group specific richness are all sensitive to Malaise trap type. Trap type should be carefully considered and aligned to match monitoring and research questions. Additionally, our estimates of trap type effects can be used to adjust results to facilitate comparisons across studies.
Increase in lower limb strength after multimodal pain management in patients with low back pain
(2022)
Background and Objectives: The aim of the present study was to evaluate the efficacy of a multimodal pain therapy (MPM) regarding the objective parameter muscle strength of segment-dependent lower limb muscle groups before and after such a treatment. Materials and Methods: 52 patients with a history of low back pain and/or leg pain received standardized multimodal pain management. Strength of segment indicating lower limb muscles were assessed for each patient before and after ten days of treatment by handheld dynamometry. Results: Overall strength increased significantly from 23.6 kg ± 6.6 prior to treatment to 25.4 ± 7.3 after treatment, p ≤ 0.001. All muscle groups significantly increased in strength with exception of great toe extensors. Conclusions: Despite lower basic strength values at the beginning of treatment, all investigated muscle groups, except for the great toe extensors, showed a significant increase of overall strength after completion of the multimodal pain management concept. Increased overall strength could help with avoiding further need of medical care by supporting patients’ autonomy in daily life activities, as well as maintaining working abilities. Thus, our study is the first to show a significant positive influence on lower limb strength in patients with low back pain after a conservative MPM program.
The exponential increase in the human population in tandem with increased food demand has caused agriculture to be the global‐dominant form of land use. Afrotropical drylands are currently facing the loss of natural savannah habitats and agricultural intensification with largely unknown consequences for bees. Here we investigate the effects of agricultural intensification on bee assemblages in the Afrotropical drylands of northern Tanzania. We disentangled the direct effects of agricultural intensification and temperature on bee richness from indirect effects mediated by changes in floral resources.
We collected data from 24 study sites representing three levels of management intensity (natural savannah, moderate intensive and highly intensive agriculture) spanning an extensive gradient of mean annual temperature (MAT) in northern Tanzania. We used ordinary linear models and path analysis to test the effects of agricultural intensity and MAT on bee species richness, bee species composition and body‐size variation of bee communities.
We found that bee species richness increased with agricultural intensity and with increasing temperature. The effects of agricultural intensity and temperature on bee species richness were mediated by the positive effects of agriculture and temperature on the richness of floral resources used by bees. During the off‐growing season, agricultural land was characterized by an extensive period of fallow land holding a very high density of flowering plants with unique bee species composition. The increase in bee diversity in agricultural habitats paralleled an increasing variation of bee body sizes with agricultural intensification that, however, diminished in environments with higher temperatures.
Synthesis and applications. Our study reveals that bee assemblages in Afrotropical drylands benefit from agricultural intensification in the way it is currently practiced. However, further land‐use intensification, including year‐round irrigated crop monocultures and excessive use of agrochemicals, is likely to exert a negative impact on bee diversity and pollination services, as reported in temperate regions. Moreover, several bee species were restricted to natural savannah habitats. To conserve bee communities and guarantee pollination services in the region, a mixture of savannah and agriculture, with long periods of fallow land should be maintained.
The mechanisms by which climatic changes influence ecosystem functions, that is, by a direct climatic control of ecosystem processes or by modifying richness and trait compositions of species communities, remain unresolved.
This study is a contribution to this discourse by elucidating the linkages between climate, land use, biodiversity, body size and ecosystem functions.
We disentangled direct climatic from biodiversity‐mediated effects by using dung removal by dung beetles as a model system and by combining correlative field data and exclosure experiments along an extensive elevational gradient on Mt. Kilimanjaro, Tanzania.
Dung removal declined with increasing elevation, being associated with a strong reduction in the richness and body size traits of dung beetle communities. Climate influenced dung removal rates by modifying biodiversity rather than by direct effects. The biodiversity–ecosystem effect was driven by a change in the mean body size of dung beetles. Dung removal rates were strongly reduced when large dung beetles were experimentally excluded.
This study underscores that climate influences ecosystem functions mainly by modifying biodiversity and underpins the important role of body size for dung removal.
Bivariate copula monitoring
(2022)
The assumption of multivariate normality underlying the Hotelling T\(^{2}\) chart is often violated for process data. The multivariate dependency structure can be separated from marginals with the help of copula theory, which permits to model association structures beyond the covariance matrix. Copula‐based estimation and testing routines have reached maturity regarding a variety of practical applications. We have constructed a rich design matrix for the comparison of the Hotelling T\(^{2}\) chart with the copula test by Verdier and the copula test by Vuong, which allows for weighting the observations adaptively. Based on the design matrix, we have conducted a large and computationally intensive simulation study. The results show that the copula test by Verdier performs better than Hotelling T\(^{2}\) in a large variety of out‐of‐control cases, whereas the weighted Vuong scheme often fails to provide an improvement.
We quantify the contemporaneous relationships among stock markets in the euro area, the United States, and a group of emerging economies over the period from 2008 to 2017. Exploiting the heteroskedasticity in the stock market data, we identify shocks that originated in the respective domestic markets and shocks that are common to all markets. Our results underline the leading role of the United States in international equity markets, but also point to the importance of indirect spillovers for all economies. Variance decompositions show that while domestic shocks explain the bigger part of the variation in each stock market, a substantial part of the variation in the euro area and the emerging economies can be attributed to foreign shocks. A comparison with a sample covering the pre‐crisis period from 1999 to 2007 suggests a strengthening of the linkages among global stock markets in recent years. In particular, the spillovers from advanced to emerging economies have become more pronounced.
A study on the reactivity of N‐heterocyclic carbenes (NHCs) and the cyclic (alkyl)(amino)carbene cAAC\(^{Me}\) with selected germanium(IV) and tin(IV) chlorides and organyl chlorides is presented. The reactions of the NHCs Me\(_{2}\)Im\(^{Me}\), iPr\(_{2}\)Im\(^{Me}\) and Dipp2Im with the methyl chlorides ECl\(_{2}\)Me\(_{2}\) afforded the adducts NHC ⋅ ECl\(_{2}\)Me\(_{2}\) (E=Ge (1), Sn (2)), NHC=Me\(_{2}\)Im\(^{Me}\) (a), iPr\(_{2}\)Im\(^{Me}\) (b), Dipp\(_{2}\)Im (c)). The reaction of Me2Im\(^{Me}\) with GeCl\(_{4}\) led to isolation of Me\(_{2}\)Im\(^{Me}\) ⋅ GeCl\(_{4}\) (3), the reaction of iPr\(_{2}\)Im\(^{Me}\) with SnCl\(_{4}\) in THF afforded the THF adduct iPr\(_{2}\)Im\(^{Me}\) ⋅ SnCl\(_{4}\) ⋅ THF (4). Dipp\(_{2}\)Im ⋅ GeCl\(_{2}\)Me\(_{2}\) (1 c) isomerized into the backbone coordinated imidazolium salt [aDipp\(_{2}\)Im ⋅ GeClMe\(_{2}\)][Cl] (5) upon thermal treatment. The reactions of cAAC\(^{Me}\) with (i) ECl\(_{2}\)R\(_{2}\) (E=Ge, Sn) gave the adducts cAAC\(^{Me}\) ⋅ ECl\(_{2}\)R\(_{2}\) (R=Me: E=Ge (6); Sn (7); Ph: E=Ge (8)), with (ii) GeClMe\(_{3}\) and GeCl\(_{4}\) the salts [cAAC\(^{Me}\) ⋅ GeMe\(_{3}\)][Cl] (9) and [cAACMeCl][GeCl\(_{3}\)] (10), and (iii) with SnCl\(_{4}\) the salt [cAACMeCl][SnCl\(_{3}\)] (11) and the adduct cAAC\(^{Me}\) ⋅ SnCl\(_{4}\) (12). Reduction of 2 a with KC\(_{8}\) afforded the NHC‐stabilized stannylene Me\(_{2}\)Im\(^{Me}\) ⋅ SnMe\(_{2}\) 13, reduction of 7 with either KC8 or 1,4‐bis‐(trimethylsilyl)‐1,4‐dihydropyrazin in the presence of SnCl\(_{2}\)Me\(_{2}\) yielded cAAC\(^{Me}\) ⋅ SnMe\(_{2}\) ⋅ SnMe\(_{2}\)Cl\(_{2}\) (14).
A series of five new homoleptic, linear nickel d\(^{9}\)‐complexes of the type [Ni\(^{I}\)(NHC)\(_{2}\)]\(^{+}\) is reported. Starting from the literature known Ni(0) complexes [Ni(Mes\(_{2}\)Im)\(_{2}\)] 1, [Ni(Mes\(_{2}\)Im\(^{H2}\))2] 2, [Ni(Dipp\(_{2}\)Im)\(_{2}\)] 3, [Ni(Dipp\(_{2}\)Im\(^{H2}\))\(_{2}\)] 4 and [Ni(cAAC\(^{Me}\))\(_{2}\)] 5 (Mes\(_{2}\)Im=1,3‐bis(2,4,6‐trimethylphenyl)‐imidazolin‐2‐ylidene, Mes\(_{2}\)Im\(^{H2}\)=1,3‐bis(2,4,6‐trimethylphenyl)‐imidazolidin‐2‐ylidene, Dipp\(_{2}\)Im=1,3‐bis(2,6‐diisopropylphenyl)‐imidazolin‐2‐ylidene, Dipp\(_{2}\)Im\(^{H2}\)=1,3‐bis(2,6‐diisopropylphenyl)‐imidazolidin‐2‐ylidene, cAAC\(^{Me}\)=1‐(2,6‐diisopropylphenyl)‐3,3,5,5‐tetramethylpyrrolidin‐2‐yliden), their oxidized Ni(I) analogues [Ni\(^{I}\)(Mes\(_{2}\)Im)\(_{2}\)][BPh\(_{4}\)] 1\(^{+}\), [Ni\(^{I}\)(Mes\(_{2}\)Im\(^{H2}\))\(_{2}\)][BPh\(_{4}\)] 2\(^{+}\), [Ni\(^{I}\)(Dipp\(_{2}\)Im)\(_{2}\)][BPh\(_{4}\)] 3\(^{+}\), [Ni\(^{I}\)(Dipp\(_{2}\)Im\(^{H2}\))\(_{2}\)][BPh\(_{4}\)] 4\(^{+}\) and [Ni\(^{I}\)(cAAC\(^{Me}\))\(_{2}\)][BPh\(_{4}\)] 5\(^{+}\) were synthesized by one‐electron oxidation with ferrocenium tetraphenyl‐borate. The complexes 1\(^{+}\)–5\(^{+}\) were fully characterized including X‐ray structure analysis. The complex cations reveal linear geometries in the solid state and NMR spectra with extremely broad, paramagnetically shifted resonances. DFT calculations predicted an orbitally degenerate ground state leading to large magnetic anisotropy, which was verified by EPR measurements in solution and on solid samples. The magnetic anisotropy of the complexes is highly dependent from the steric protection of the metal atom, which results in a noticeable decrease of the g‐tensor anisotropy for the N‐Mes substituted complexes 1\(^{+}\) and 2\(^{+}\) in solution due to the formation of T‐shaped THF adducts.
The development of two conventional dendritic cells (DC) subsets (cDC1 and cDC2) and the plasmacytoid DC (pDC) in vivo and in cultures of bone marrow (BM) cells is mediated by the growth factor Flt3L. However, little is known about the factors that direct the development of the individual DC subsets. Here, we describe the selective in vitro generation of murine ESAM\(^{low}\) CD103\(^{-}\) XCR1\(^{-}\) CD172a\(^{+}\) CD11b\(^{+}\) cDC2 from BM by treatment with a combination of Flt3L, LIF, and IL‐10 (collectively named as FL10). FL10 promotes common dendritic cell progenitors (CDP) proliferation in the cultures, similar to Flt3L and CDP sorted and cultured in FL10 generate exclusively cDC2. These cDC2 express the transcription factors Irf4, Klf4, and Notch2, and their growth is reduced using BM from Irf4\(^{-/-}\) mice, but the expression of Batf3 and Tcf4 is low. Functionally they respond to TLR3, TLR4, and TLR9 signals by upregulation of the surface maturation markers MHC II, CD80, CD86, and CD40, while they poorly secrete proinflammatory cytokines. Peptide presentation to TCR transgenic OT‐II cells induced proliferation and IFN‐γ production that was similar to GM‐CSF‐generated BM‐DC and higher than Flt3L‐generated DC. Together, our data support that FL10 culture of BM cells selectively promotes CDP‐derived ESAM\(^{low}\) cDC2 (cDC2B) development and survival in vitro.
Environmental gradients generate and maintain biodiversity on Earth. Mountain slopes are among the most pronounced terrestrial environmental gradients, and the elevational structure of species and their interactions can provide unique insight into the processes that govern community assembly and function in mountain ecosystems. We recorded bumble bee–flower interactions over 3 years along a 1400‐m elevational gradient in the German Alps. Using nonlinear modeling techniques, we analyzed elevational patterns at the levels of abundance, species richness, species β‐diversity, and interaction β‐diversity. Though floral richness exhibited a midelevation peak, bumble bee richness increased with elevation before leveling off at the highest sites, demonstrating the exceptional adaptation of these bees to cold temperatures and short growing seasons. In terms of abundance, though, bumble bees exhibited divergent species‐level responses to elevation, with a clear separation between species preferring low versus high elevations. Overall interaction β‐diversity was mainly caused by strong turnover in the floral community, which exhibited a well‐defined threshold of β‐diversity rate at the tree line ecotone. Interaction β‐diversity increased sharply at the upper extreme of the elevation gradient (1800–2000 m), an interval over which we also saw steep decline in floral richness and abundance. Turnover of bumble bees along the elevation gradient was modest, with the highest rate of β‐diversity occurring over the interval from low‐ to mid‐elevation sites. The contrast between the relative robustness bumble bee communities and sensitivity of plant communities to the elevational gradient in our study suggests that the strongest effects of climate change on mountain bumble bees may be indirect effects mediated by the responses of their floral hosts, though bumble bee species that specialize in high‐elevation habitats may also experience significant direct effects of warming.