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This paper is devoted to a theoretical and numerical investigation of Nash equilibria and Nash bargaining problems governed by bilinear (input-affine) differential models. These systems with a bilinear state-control structure arise in many applications in, e.g., biology, economics, physics, where competition between different species, agents, and forces needs to be modelled. For this purpose, the concept of Nash equilibria (NE) appears appropriate, and the building blocks of the resulting differential Nash games are different control functions associated with different players that pursue different non-cooperative objectives. In this framework, existence of Nash equilibria is proved and computed with a semi-smooth Newton scheme combined with a relaxation method. Further, a related Nash bargaining (NB) problem is discussed. This aims at determining an improvement of all players’ objectives with respect to the Nash equilibria. Results of numerical experiments successfully demonstrate the effectiveness of the proposed NE and NB computational framework.
Rag1\(^{−/−}\) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1\(^{−/−}\) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1\(^{null}\)IL2rg\(^{null}\) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1\(^{−/−}\) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1\(^{−/−}\) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1\(^{−/−}\) were comparable in number and function to those in WT mice. Rag1\(^{−/−}\) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.
Despite successful recanalization of large-vessel occlusions in acute ischemic stroke, individual patients profit to a varying degree. Dynamic susceptibility-weighted perfusion and dynamic T1-weighted contrast-enhanced blood-brain barrier permeability imaging may help to determine secondary stroke injury and predict clinical outcome. We prospectively performed perfusion and permeability imaging in 38 patients within 24 h after successful mechanical thrombectomy of an occlusion of the middle cerebral artery M1 segment. Perfusion alterations were evaluated on cerebral blood flow maps, blood-brain barrier disruption (BBBD) visually and quantitatively on ktrans maps and hemorrhagic transformation on susceptibility-weighted images. Visual BBBD within the DWI lesion corresponded to a median ktrans elevation (IQR) of 0.77 (0.41–1.4) min−1 and was found in all 7 cases of hypoperfusion (100%), in 10 of 16 cases of hyperperfusion (63%), and in only three of 13 cases with unaffected perfusion (23%). BBBD was significantly associated with hemorrhagic transformation (p < 0.001). While BBBD alone was not a predictor of clinical outcome at 3 months (positive predictive value (PPV) = 0.8 [0.56–0.94]), hypoperfusion occurred more often in patients with unfavorable clinical outcome (PPV = 0.43 [0.10–0.82]) compared to hyperperfusion (PPV = 0.93 [0.68–1.0]) or unaffected perfusion (PPV = 1.0 [0.75–1.0]). We show that combined perfusion and permeability imaging reveals distinct infarct signatures after recanalization, indicating the severity of prior ischemic damage. It assists in predicting clinical outcome and may identify patients at risk of stroke progression.
Metastatic pheochromocytoma and paraganglioma: signs and symptoms related to catecholamine secretion
(2021)
Background
The presence or future development of metastatic pheochromocytomas or paragangliomas (mPPGLs) can be difficult to diagnose or predict at initial presentation. Since production of catecholamines from mPPGLs is different from non-metastatic tumors (non-mPPGLs), this study aimed to clarify whether presenting catecholamine-related signs and symptoms (cSS) might also differ.
Methods
The study included 249 patients, 43 with mPPGL and 206 with non-mPPGL. Clinical data at the time of biochemical diagnosis (i.e. at entry into the study) were used to generate a cumulative score of cSS for each patient.
Results
Patients with mPPGL were significantly younger (43.3 ± 14 vs. 48.9 ± 16.1 years) and included a lower proportion of females (39.5% vs. 60.7%) than patients with non-mPPGLs. Frequencies of signs and symptoms did not differ between the two groups. Patients with mPPGLs had lower (P < 0.001) urinary excretion of epinephrine (3.5 (IQR, 1.9—6.5) µg/day) than those with non-mPPGLs (19.1 (IQR, 4.3—70.2) µg/day). There was no difference in urinary excretion of norepinephrine. In patients with mPPGLs a high cSS score was associated with high urinary excretion of norepinephrine and normetanephrine. In contrast, in patients with non-mPPGLs, a high cSS was associated with high urinary excretion of epinephrine and metanephrine.
Conclusion
Although presenting signs and symptoms were associated with production of norepinephrine in patients with mPPGLs and of epinephrine in patients with non-mPPGLs, there were no differences in signs and symptoms between the two groups. Therefore, consideration of signs and symptoms does not appear helpful for distinguishing patients with and without mPPGLs.
Despite the widespread application of landslide susceptibility analyses, there is hardly any information about whether or not the occurrence of recent landslide events was correctly predicted by the relevant susceptibility maps. Hence, the objective of this study is to evaluate four landslide susceptibility maps retrospectively in a landslide-prone area of the Swabian Alb (Germany). The predictive performance of each susceptibility map is evaluated based on a landslide event triggered by heavy rainfalls in the year 2013. The retrospective evaluation revealed significant variations in the predictive accuracy of the analyzed studies. Both completely erroneous as well as very precise predictions were observed. These differences are less attributed to the applied statistical method and more to the quality and comprehensiveness of the used input data. Furthermore, a literature review of 50 peer-reviewed articles showed that most landslide susceptibility analyses achieve very high validation scores. 73% of the analyzed studies achieved an area under curve (AUC) value of at least 80%. These high validation scores, however, do not reflect the high uncertainty in statistical susceptibility analysis. Thus, the quality assessment of landslide susceptibility maps should not only comprise an index-based, quantitative validation, but also an additional qualitative plausibility check considering local geomorphological characteristics and local landslide mechanisms. Finally, the proposed retrospective evaluation approach cannot only help to assess the quality of susceptibility maps and demonstrate the reliability of such statistical methods, but also identify issues that will enable the susceptibility maps to be improved in the future.
Background
Individuals’ physical and mental health, as well as their chances of returning to work after their ability to work is damaged, can be addressed by medical rehabilitation.
Aim
This study investigated the developmental trends of mental and physical health among patients in medical rehabilitation and the roles of self-efficacy and physical fitness in the development of mental and physical health.
Design
A longitudinal design that included four time-point measurements across 15 months.
Setting
A medical rehabilitation center in Germany.
Population
Participants included 201 patients who were recruited from a medical rehabilitation center.
Methods
To objectively measure physical fitness (lung functioning), oxygen reabsorption at anaerobic threshold (VO2AT) was used, along with several self-report scales.
Results
We found a nonlinear change in mental health among medical rehabilitation patients. The results underscored the importance of medical rehabilitation for patients’ mental health over time. In addition, patients’ physical health was stable over time. The initial level of physical fitness (VO2AT) positively predicted their mental health and kept the trend more stable. Self-efficacy appeared to have a positive relationship with mental health after rehabilitation treatment.
Conclusions
This study revealed a nonlinear change in mental health among medical rehabilitation patients. Self-efficacy was positively related to mental health, and the initial level of physical fitness positively predicted the level of mental health after rehabilitation treatment.
Clinical Rehabilitation
More attention could be given to physical capacity and self-efficacy for improving and maintaining rehabilitants’ mental health.
In this study, we examined the conditional indirect and direct relations of pain-related cognitions to depression. Subjective helplessness was included as presumably mediating the relations of catastrophizing and thought suppression to depression due to motivational deficits. In addition, moderating effects of dispositional action versus state orientation were analyzed, whereby state orientation indicates volitional deficits in coping with distress. The study was based on self-report data from 536 patients with chronic non-specific low back pain at the beginning of inpatient rehabilitation. Moderated mediation analyses were performed. The indirect catastrophizing- and thought suppression-depression relations were (partially) mediated by subjective helplessness; and moderated by failure-related action versus state orientation. Moreover, action versus state orientation moderated the direct relation of thought suppression to depression. Results suggest that catastrophizing, thought suppression, and subjective helplessness do not lead to depression unless associated with self-regulatory inability (i.e., state orientation). In contrast, action-oriented patients more effectively self-regulate pain-related emotions, disengage from rumination, and distract from pain and thus better avoid the debilitating effects of negative pain-related cognitions on depression. Future research and treatment may more strongly focus on the role of motivational and volitional deficits underlying learned helplessness and depression in chronic pain.
Purpose
The subclassification of adrenal cancers according to the WHO classification in ordinary, myxoid, oncocytic, and sarcomatoid as well as pediatric types is well established, but the criteria for each subtype are not sufficiently determined and the relative frequency of the different types of adrenal cancers has not been studied in large cohorts. Therefore, our large collection of surgically removed adrenal cancers should be reviewed o establish the criteria for the subtypes and to find out the frequency of the various types.
Methods
In our series of 521 adrenal cancers the scoring systems of Weiss et al., Hough et al., van Slooten et al. and the new Helsinki score system were used for the ordinary type of cancer (97% of our series) and the myxoid type (0.8%). For oncocytic carcinomas (2%), the scoring system of Bisceglia et al. was applied.
Results
Discrepancies between benign and malignant diagnoses from the first thee classical scoring systems are not rare (22% in our series) and could be resolved by the Helsinki score especially by Ki-67 index (more than 8% unequivocally malignant). Since all our cancer cases are positive in the Helsinki score, this system can replace the three elder systems. For identification of sarcomatoid cancer as rarest type in our series (0.2%), the scoring systems are not practical but additional immunostainings used for soft tissue tumors and in special cases molecular pathology are necessary to differentiate these cancers from adrenal sarcomas. According to the relative frequencies of the different subtypes of adrenal cancers the main type is the far most frequent (97%) followed by the oncocytic type (2%), the myxoid type (0.8%) and the very rare sarcomatoid type (0.2%).
Conclusions
The Helsinki score is the best for differentiating adrenal carcinomas of the main, the oncocytic, and the myxoid type in routine work. Additional scoring systems for these carcinomas are generally not any longer necessary. Signs of proliferation (mitoses and Ki-67 index) and necroses are the most important criteria for diagnosis of malignancy.
Context
Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Besides its deleterious impact on cardiovascular target organ damage, PA is considered to cause osteoporosis.
Patients and methods
We assessed bone turnover in a subset of 36 postmenopausal women with PA. 18 patients had unilateral PA and were treated by adrenalectomy, whereas 18 patients had bilateral PA and received mineralocorticoid receptor antagonist (MRA) therapy respectively. 18 age- and BMI-matched females served as controls. To estimate bone remodeling, we measured the bone turnover markers intact procollagen 1 N-terminal propeptide, bone alkaline phosphatase, osteocalcin and tartrate resistant acid phosphatase 5b in plasma by chemiluminescent immunoassays at time of diagnosis and one year after initiation of treatment.
Study design
Observational longitudinal cohort study.
Setting
Tertiary care hospital.
Results
Compared with controls, patients with PA had mildly elevated osteocalcin at baseline (p = 0.013), while the other bone markers were comparable between both groups. There were no differences between the unilateral and the bilateral PA subgroup. One year after initiation of MRA treatment with spironolactone bone resorption and bone formation markers had significantly decreased in patients with bilateral PA. In contrast, patients adrenalectomized because of unilateral PA showed no significant change of bone turnover markers.
Conclusion
This study shows that aldosterone excess in postmenopausal women with PA is not associated with a relevant increase of bone turnover markers at baseline. However, we observed a significant decrease of bone markers in patients treated with spironolactone, but not in patients treated by adrenalectomy.
Purpose
Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors.
Design
A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics.
Methods
Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods.
Results
Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected.
Conclusions
Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.
Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis
(2021)
Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20–50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives.
Differences between immunotherapy-induced and primary hypophysitis—a multicenter retrospective study
(2022)
Objective
Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH)
Design
Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH.
Methods
All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected.
Results
Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 % of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002).
Conclusions
Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.
Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies
(2021)
Purpose
Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN.
Methods
Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated.
Results
Median age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found.
Conclusion
No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation.
Strategies to Enhance Retention in a Cohort Study Among Adults of Turkish Descent Living in Berlin
(2022)
Retention is important for statistical power and external validity in long-term cohort studies. The aims of our study were to evaluate different retention strategies within a cohort study of adults of Turkish descent in Berlin, Germany, and to compare participants and non-participants. In 2011–2012, a population-based study was conducted among adults of Turkish descent to primarily examine recruitment strategies. 6 years later, the participants were re-contacted and invited to complete a self-report questionnaire regarding their health status, health care utilization, and satisfaction with medical services. The retention strategy comprised letters in both German and Turkish, phone calls, and home visits (by bilingual staff). We calculated the response rate and retention rate, using definitions of the American Association for Public Opinion Research, as well as the relative retention rate for each level of contact. Associations of baseline recruitment strategy, sociodemographic, migration-related and health-related factors with retention were investigated by logistic regression analysis. Of 557 persons contacted, 249 (44.7%) completed the questionnaire. This was 50.1% of those whose contact information was available. The relative retention rate was lowest for phone calls (8.9%) and highest for home visits (18.4%). Participants were more often non-smokers and German citizens than non-participants. For all remaining factors, no association with retention was found. In this study, among adults of Turkish descent, the retention rate increased considerably with every additional level of contact. Implementation of comprehensive retention strategies provided by culturally matched study personnel may lead to higher validity and statistical power in studies on migrant health issues.
Purpose
Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system.
Methods
Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system.
Results
Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia.
Conclusion
In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.
Amantadine: reappraisal of the timeless diamond—target updates and novel therapeutic potentials
(2021)
The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson’s disease symptoms and viral infections. Considering amantadine’s affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington’s disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine’s therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.
Mit der Entdeckung altersabhängiger epigenetischer Veränderungen, der DNA-Methylierung (DNAm), hat sich eine neue Möglichkeit aufgezeigt, das Alter eines Individuums zu schätzen. Die Methode wurde intensiv erforscht und ihre Anwendung in der forensischen Fallarbeit durch die Aktualisierung des § 81e der Strafprozessordnung (StPO) in Deutschland reguliert. Zur Untersuchung des DNAm-Grades müssen neue Techniken etabliert und validiert werden. Dies macht die Prüfung der Vergleichbarkeit von Messergebnissen aus verschiedenen forensischen Laboren erforderlich.
Hierzu führte die Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin (DGRM) im Winter 2019/2020 den 2. Ringversuch (RV) zur quantitativen DNAm-Analyse mithilfe der Mini- und der Pyrosequenzierung durch. Dieser basierte auf den Erfahrungen des 1. RV 2018/2019, dessen Ergebnisse in dieser Ausgabe ebenfalls vorgestellt werden. Die aktuelle Studie umfasst Analyseergebnisse aus 12 Laboren (ingesamt 14 teilnehmende Labore), von denen einige beide Methoden angewandt haben. Zusätzlich führten 4 Labore eine Altersschätzung an den RV-Proben mit eigenen Markerkombinationen und Modellen durch. Da diese auf unterschiedlichen Referenzdaten und Markerkombinationen beruhen, erfolgte kein qualitativer Vergleich der Modelle, sondern das grundsätzliche Potenzial der Methodik wurde verdeutlicht. Ziele des RV waren die Evaluierung der Vergleichbarkeit der DNAm-Messungen und die Bewertung möglicher Einflussfaktoren, wie Extraktionsmethode und verwendetes Gerät.
Die Ergebnisse zeigen, dass sich die gemessenen DNAm-Werte der untersuchten Marker sowohl zwischen Mini- und Pyrosequenzierung als auch innerhalb der jeweiligen Methode zwischen den Laboren unterscheiden können, sodass mit Schwankungen gerechnet werden muss.
Die quantitative Analyse der relativen DNA-Methylierung gilt als eine der vielversprechendsten Methoden der molekularen Altersschätzung. Viele Studien der letzten Jahre identifizierten geeignete Positionen im Genom, deren DNA-Methylierung sich altersabhängig verändert. Für den Einsatz dieser Methode in der Routine- bzw. Fallarbeit ist es von großer Bedeutung, angewandte Analysetechniken zu validieren. Als ein Teilaspekt dieser Validierung sollte die Vergleichbarkeit der Analyseergebnisse zur DNA-Methylierung mithilfe der Mini- und Pyrosequenzierung zwischen verschiedenen Laboren evaluiert werden. Die Arbeitsgruppe „Molekulare Altersschätzung“ der Deutschen Gesellschaft für Rechtsmedizin (DGRM) führte hierzu den ersten, technischen Ringversuch durch, der 4 Positionen in den Genen PDE4C, EDARADD, SST und KLF14 umfasste. Diese Marker waren in vorangegangenen Studien als altersabhängige Biomarker charakterisiert worden. Am Ringversuch nahmen 12 Labore teil, wobei jedes die Wahl zwischen der Minisequenzierung und/oder der Pyrosequenzierung für die quantitative Methylierungsanalyse hatte. Jedem teilnehmenden Labor wurden Blut- und Speichelproben von 3 Personen unterschiedlichen Alters übersandt. Die Wahl der Reagenzien für die Probenbearbeitung wurde den Teilnehmern freigestellt.
Die Ergebnisse der Minisequenzierung zeigten systematische Abweichungen zwischen den Laboren, die am ehesten auf die Verwendung unterschiedlicher Reagenzien und Analyseplattformen zurückzuführen sein können. Die Resultate der Pyrosequenzierung hingegen wiesen nicht auf systematische Abweichungen zwischen den Laboren hin, hier zeigte sich jedoch die Tendenz einer markerabhängigen Abweichung. Darüber hinaus konnten Unterschiede hinsichtlich technischer Probleme zwischen Laboren mit mehr Erfahrung in der jeweiligen Sequenzierungsmethode und Laboren mit weniger Erfahrung festgestellt werden. Sowohl die Beobachtung von systematischen als auch die von markerabhängigen Abweichungen lässt den Schluss zu, dass eine Übertragung von Analysemethoden zwischen Laboren grundsätzlich möglich ist, eine Anpassung des jeweiligen Modells zur Altersschätzung jedoch notwendig sein kann.
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
The mechanisms behind carbon dioxide (CO2) dependency in non-autotrophic bacterial isolates are unclear. Here we show that the Staphylococcus aureus mpsAB operon, known to play a role in membrane potential generation, is crucial for growth at atmospheric CO2 levels. The genes mpsAB can complement an Escherichia coli carbonic anhydrase (CA) mutant, and CA from E. coli can complement the S. aureus delta-mpsABC mutant. In comparison with the wild type, S. aureus mps mutants produce less hemolytic toxin and are less virulent in animal models of infection. Homologs of mpsA and mpsB are widespread among bacteria and are often found adjacent to each other on the genome. We propose that MpsAB represents a dissolved inorganic carbon transporter, or bicarbonate concentrating system, possibly acting as a sodium bicarbonate cotransporter.
Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection. Re-adaptation of spinal stumps supports formation of a tissue bridge, glial and vascular cell invasion, motor axon regeneration and myelination, resulting in partial recovery of motor-evoked potentials and a thus far unmet improvement of locomotor behaviour. The recovery lasts for at least 5 months. Despite a late partial decline, motor recovery remains significantly superior to controls. Our findings demonstrate that microsystem technology can foster long-lasting functional improvement after complete spinal injury, providing a new and effective tool for combinatorial therapies.
The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.
Meiotic chromosomes undergo rapid prophase movements, which are thought to facilitate the formation of inter-homologue recombination intermediates that underlie synapsis, crossing over and segregation. The meiotic telomere complex (MAJIN, TERB1, TERB2) tethers telomere ends to the nuclear envelope and transmits cytoskeletal forces via the LINC complex to drive these rapid movements. Here, we report the molecular architecture of the meiotic telomere complex through the crystal structure of MAJIN-TERB2, together with light and X-ray scattering studies of wider complexes. The MAJIN-TERB2 2:2 hetero-tetramer binds strongly to DNA and is tethered through long flexible linkers to the inner nuclear membrane and two TRF1-binding 1:1 TERB2-TERB1 complexes. Our complementary structured illumination microscopy studies and biochemical findings reveal a telomere attachment mechanism in which MAJIN-TERB2-TERB1 recruits telomere-bound TRF1, which is then displaced during pachytene, allowing MAJIN-TERB2-TERB1 to bind telomeric DNA and form a mature attachment plate.
Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7−/− mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7−/− mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.
Natural light harvesting as well as optoelectronic and photovoltaic devices depend on efficient transport of energy following photoexcitation. Using common spectroscopic methods, however, it is challenging to discriminate one-exciton dynamics from multi-exciton interactions that arise when more than one excitation is present in the system. Here we introduce a coherent two-dimensional spectroscopic method that provides a signal only in case that the presence of one exciton influences the behavior of another one. Exemplarily, we monitor exciton diffusion by annihilation in a perylene bisimide-based J-aggregate. We determine quantitatively the exciton diffusion constant from exciton–exciton-interaction 2D spectra and reconstruct the annihilation-free dynamics for large pump powers. The latter enables for ultrafast spectroscopy at much higher intensities than conventionally possible and thus improves signal-to-noise ratios for multichromophore systems; the former recovers spatio–temporal dynamics for a broad range of phenomena in which exciton interactions are present.
Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Auxin is a key regulator of plant growth and development, but the causal relationship between hormone transport and root responses remains unresolved. Here we describe auxin uptake, together with early steps in signaling, in Arabidopsis root hairs. Using intracellular microelectrodes we show membrane depolarization, in response to IAA in a concentration- and pH-dependent manner. This depolarization is strongly impaired in aux1 mutants, indicating that AUX1 is the major transporter for auxin uptake in root hairs. Local intracellular auxin application triggers Ca2+ signals that propagate as long-distance waves between root cells and modulate their auxin responses. AUX1-mediated IAA transport, as well as IAA- triggered calcium signals, are blocked by treatment with the SCFTIR1/AFB - inhibitor auxinole. Further, they are strongly reduced in the tir1afb2afb3 and the cngc14 mutant. Our study reveals that the AUX1 transporter, the SCFTIR1/AFB receptor and the CNGC14 Ca2+ channel, mediate fast auxin signaling in roots.
Surgical extrusion is a recognised treatment option for teeth that have insufficient coronal tooth structure remaining due to deep caries, resorption or traumatic injury. However, the technique has not been widely adopted, arguably because extraction of a severely compromised tooth may be difficult to achieve in a gentle and predictable way. In this paper, we present our novel approach to surgical extrusion and subsequent management of teeth using a vertical extraction system (Benex), which has become the method of choice in the authors' practice for many teeth that would otherwise be deemed unrestorable. We describe the clinical procedure in detail and discuss the advantages and disadvantages compared to alternative approaches, including surgical crown lengthening and orthodontic extrusion.
C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS.
Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
Animals must slow or halt locomotion to integrate sensory inputs or to change direction. In Caenorhabditis elegans, the GABAergic and peptidergic neuron RIS mediates developmentally timed quiescence. Here, we show RIS functions additionally as a locomotion stop neuron. RIS optogenetic stimulation caused acute and persistent inhibition of locomotion and pharyngeal pumping, phenotypes requiring FLP-11 neuropeptides and GABA. RIS photoactivation allows the animal to maintain its body posture by sustaining muscle tone, yet inactivating motor neuron oscillatory activity. During locomotion, RIS axonal Ca2+ signals revealed functional compartmentalization: Activity in the nerve ring process correlated with locomotion stop, while activity in a branch correlated with induced reversals. GABA was required to induce, and FLP-11 neuropeptides were required to sustain locomotion stop. RIS attenuates neuronal activity and inhibits movement, possibly enabling sensory integration and decision making, and exemplifies dual use of one cell across development in a compact nervous system.
Obdach, Speisung und Heilung. Zur Geschichte des Seelhauses an der Juliuspromenade in Würzburg
(2023)
Das 1379 gestiftete Seelhaus befindet sich seit 1587 an der heutigen Juliuspromenade in Würzburg. Ursprünglich zur Beherbergung bedürftiger Reisender eingerichtet, entwickelte es sich seit dem 17. Jahrhundert zum Alterssitz für Mägde und Hausangestellte, bevor es im 19. Jahrhundert ganz aufgelöst wurde. Durch den Kauf der Hausnummern 9-11 durch die Oberzeller Schwestern 1927 erlebte sein karitativer Auftrag bis zur Zerstörung am 16. März 1945 eine Wiederbelebung.
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes a significant burden on Westernized regions. The Western diet, high in salt intake, significantly contributes to disease development. However, there are a lack of data on salt literacy and salt intake among MASLD patients in Germany. Our study aims to analyze daily salt intake and salt-intake-related behavior in MASLD patients. Methods: 234 MASLD patients were prospectively included. Daily salt intake and salt-intake-related behavior were assessed via a food frequency questionnaire (FFQ—DEGS) and a salt questionnaire (SINU). Statistical analyses were performed using SPSS. Results: Mean daily salt intake was higher in men than in women (7.3 ± 5 g/d vs. 5.3 ± 4 g/d; p < 0.001). There was significant agreement between increased daily salt intake (6 g/d) and the behavioral salt index (SI) (p < 0.001). Men exhibited higher SI scores compared to women, indicating lower awareness of salt in everyday life. Multivariate analysis identified specific salt-intake-related behaviors impacting daily salt consumption. Conclusions: Our study reveals a strong link between daily salt intake and salt-intake-related behavior, highlighting sex-specific differences in an MASLD cohort. To enhance patient care in high-cardiovascular-risk populations, specific behavioral approaches may be considered, including salt awareness, to improve adherence to lifestyle changes, particularly in male patients.
To define frailty in older cancer patients, the aim of this study was to assess the geriatric status and quality of life (QoL) aspects in patients suffering from recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC) under palliative treatment. A comprehensive geriatric assessment (CGA) was performed on 21 r/m HNSCC patients at two defined assessments, and the QoL aspects and the impact of descriptive data were evaluated. The Kolmogorov–Smirnov test, Spearman’s rho correlation, and two-way mixed ANOVA were used for statistical analysis. All patients were found to be “frail”. Pain, fatigue, and the burden of illness were the highest-rated symptoms. Oral function and orofacial appearance were highly impaired. A significant impact of descriptive data on the CGA and QoL results was found (all p ≤ 0.05). Thus, the CGA results revealed high frailty, severe comorbidities, and high impairments in QoL aspects. The CGA and QoL results were negatively affected by the primary HNSCC treatment approach, the need for prosthetic treatment, and worse oral functional capacity. Therefore, frailty in r/m HNSCC patients seems to be multidimensional. The evaluation of the CGA and QoL aspects in r/m HNSCC patients can be recommended to detect special needs, organize aftercare, and improve the support for frail and vulnerable cancer patients to create a multidisciplinary treatment approach.
Sufficiently disordered metals display systematic deviations from the behavior predicted by semi-classical Boltzmann transport theory. Here the scattering events from impurities or thermal excitations can no longer be considered as additive-independent processes, as asserted by Matthiessen’s rule following from this picture. In the intermediate region between the regime of good conduction and that of insulation, one typically finds a change of sign of the temperature coefficient of resistivity, even at elevated temperature spanning ambient conditions, a phenomenology that was first identified by Mooij in 1973. Traditional weak coupling approaches to identify relevant corrections to the Boltzmann picture focused on long-distance interference effects such as “weak localization”, which are especially important in low dimensions (1D and 2D) and close to the zero-temperature limit. Here we formulate a strong-coupling approach to tackle the interplay of strong disorder and lattice deformations (phonons) in bulk three-dimensional metals at high temperatures. We identify a polaronic mechanism of strong disorder renormalization, which describes how a lattice locally responds to the relevant impurity potential. This mechanism, which quantitatively captures the Mooij regime, is physically distinct and unrelated to Anderson localization, but realizes early seminal ideas of Anderson himself, concerning the interplay of disorder and lattice deformations.
AbstractWater oxidation catalysis is a key step for sustainable fuel production by water splitting into hydrogen and oxygen. The synthesis of a novel coordination oligomer based on four Ru(bda) (bda = 2,2′‐bipyridine‐6,6′‐dicarboxylate) centers, three 4,4′‐bipyridine (4,4′‐bpy) linkers, and two 4‐picoline (4‐pic) end caps is reported. The monodispersity of this tetranuclear compound is characterized by NMR techniques. Heterogeneous electrochemical water oxidation after immobilization on multi‐walled carbon nanotubes (MWCNTs) shows catalytic performance unprecedented for this compound class, with a turnover frequency (TOF) of 133 s\(^{−1}\) and a turnover number (TON) of 4.89 × 10\(^6\), at a current density of 43.8 mA cm\(^{−2}\) and a potential of 1.45 V versus normal hydrogen electrode (NHE).
Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a thus far unknown cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the lytic-latent switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily drugable master regulator of the herpesvirus lytic-latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.
The Essential Climate Variable (ECV) Permafrost is currently undergoing strong changes due to rising ground and air temperatures. Surface movement, forming characteristic landforms such as rock glaciers, is one key indicator for mountain permafrost. Monitoring this movement can indicate ongoing changes in permafrost; therefore, rock glacier velocity (RGV) has recently been added as an ECV product. Despite the increased understanding of rock glacier dynamics in recent years, most observations are either limited in terms of the spatial coverage or temporal resolution. According to recent studies, Sentinel-1 (C-band) Differential SAR Interferometry (DInSAR) has potential for monitoring RGVs at high spatial and temporal resolutions. However, the suitability of DInSAR for the detection of heterogeneous small-scale spatial patterns of rock glacier velocities was never at the center of these studies. We address this shortcoming by generating and analyzing Sentinel-1 DInSAR time series over five years to detect small-scale displacement patterns of five high alpine permafrost environments located in the Central European Alps on a weekly basis at a range of a few millimeters. Our approach is based on a semi-automated procedure using open-source programs (SNAP, pyrate) and provides East-West displacement and elevation change with a ground sampling distance of 5 m. Comparison with annual movement derived from orthophotos and unpiloted aerial vehicle (UAV) data shows that DInSAR covers about one third of the total movement, which represents the proportion of the year suited for DInSAR, and shows good spatial agreement (Pearson R: 0.42–0.74, RMSE: 4.7–11.6 cm/a) except for areas with phase unwrapping errors. Moreover, the DInSAR time series unveils spatio-temporal variations and distinct seasonal movement dynamics related to different drivers and processes as well as internal structures. Combining our approach with in situ observations could help to achieve a more holistic understanding of rock glacier dynamics and to assess the future evolution of permafrost under changing climatic conditions.
The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.
Background and objectives: Cartilage surgery constitutes a standard intervention in foot and ankle procedures. Currently, there is a lack of epidemiological data on its frequency, age distribution, and surgical options for cartilage surgery. This study aimed to investigate the current landscape of cartilage surgery in Germany and identify the most common procedures from an epidemiological standpoint. Materials and methods: Medical billing and reporting data from the Federal Statistical Office of Germany, encompassing the period 2006–2020, was examined, including all foot and ankle cartilage surgical procedures (summarized under OPS codes 5-812 and 5-801). The dataset incorporated information on the affected joint, patient age and sex, and surgery type. Each surgical procedure was categorized as “debridement”, “regeneration” or “refixation”. Linear and nonlinear regression analyses were employed, with a statistical significance threshold of 0.05. Results: From the total of 136,501 procedures conducted during the study period, the most frequently performed interventions were microfracture (58,252) and chondroplasty (56,135), and thus, debridement procedures were in the leading position. The use of acellular membranes was the most used regenerative technique (n = 11,414). At the ankle joint, interventions were mostly arthroscopic and in men, while foot cartilage surgeries were preferably performed via open surgery and mostly in women. Age distribution analysis revealed two primary peaks: the first in the 20–25-year-old group (ankle and foot) and the second in the 45–50-year-old group (ankle) and 55–60-year-old group (foot). Refixation and regenerative procedures were more frequent among younger individuals, while debriding procedures were more frequent among older individuals. Regenerative procedures, particularly in the ankle, significantly increased over time. Conclusions: Cartilage surgery of the foot and ankle was common, with two primary age groups predominantly affected. Notably, recent years have witnessed a considerable rise in cartilage regenerative procedures.
The use of bone-cement-enforced osteosynthesis is a growing topic in trauma surgery. In this context, drillability is a desirable feature for cements that can improve fracture stability, which most of the available cement systems lack. Therefore, in this study, we evaluated a resorbable and drillable magnesium-phosphate (MgP)-based cement paste considering degradation behavior and biocompatibility in vivo. Two different magnesium-phosphate-based cement (MPC) pastes with different amounts of phytic acid (IP 6) as setting retarder (MPC 22.5 and MPC 25) were implanted in an orthotopic defect model of the lateral femoral condyle of New Zealand white rabbits for 6 weeks. After explantation, their resorption behavior and material characteristics were evaluated by means of X-ray diffraction (XRD), porosimetry measurement, histological staining, peripheral quantitative computed tomography (pQCT), cone-beam computed tomography (CBCT) and biomechanical load-to-failure tests. Both cement pastes displayed comparable results in mechanical strength and resorption kinetics. Bone-contact biocompatibility was excellent without any signs of inflammation. Initial resorption and bone remodeling could be observed. MPC pastes with IP 6 as setting retardant have the potential to be a valuable alternative in distinct fracture patterns. Drillability, promising resorption potential and high mechanical strength confirm their suitability for use in clinical routine.
Innerhalb der Juvenilen Idiopathischen Arthritis (JIA) bilden Patienten mit Antinukleären Antikörpern (ANA) Subgruppen-übergreifend eine klinisch homogene Erkrankungsgruppe. Ob diesen klinischen Gemeinsamkeiten jedoch auch eine einheitliche Pathogenese zugrunde liegt, ist bisher unbekannt. Sogenannte periphere T-Helferzellen (TPH) spielen im Kontext zahlreicher Autoimmunerkrankungen eine entscheidende Rolle bei der Aktivierung autoreaktiver B-Zellen. Ziel dieser Arbeit war daher die phänotypische und funktionelle Analyse von PD-1hiCXCR5-CD4+ TPH-Zellen, sowie deren Verteilung in der Synovialflüssigkeit von Patienten unterschiedlicher Subgruppen der JIA.
Hierzu wurden Phänotyp und Zytokinprofil von PD-1hiCD4+ T-Zellen durchflusszytometrisch analysiert. Der funktionelle Einfluss von PD-1hiCD4+ T-Zellen auf die B-Zell-Differenzierung wurde mittels in vitro Kokulturen FACS-sortierter TPH-Zellen der Synovialflüssigkeit untersucht.
IL-21- und IL-17-produzierende T-Gedächtniszellen der Synovialflüssigkeit zeigten eine negative Korrelation zueinander. Die IL-21-Produktion ging besonders von PD-1hiCXCR5-HLA-DR+CD4+ T-Zellen aus, welche besonders in den Gelenken ANA-positiver JIA-Patienten akkumulierten. Diese Population zeigte phänotypische Ähnlichkeit mit TPH-Zellen und leistete in vitro effiziente B-Zell-Hilfe zu Plasmazelldifferenzierung und Immunglobulinsekretion, induzierte jedoch zudem einen CD21lo/-CD11c+T-bet+ Phänotyp in B-Zellen. Passend hierzu bestand auch ex vivo eine signifikante Korrelation zwischen TPH und CD21lo/-CD11c+T-bet+ doppelt-negativen B-Zellen (BDN).
Es konnte also die Expansion einer spezifischen T-Zellpopulation mit phänotypischen und funktionellen Charakteristika von TPH-Zellen beobachtet und deren funktioneller Zusammenhang mit CD21lo/-CD11c+T-bet+ BDN in der Synovialflüssigkeit von JIA-Patienten aufgezeigt werden. Dies könnte die Autoimmunantwort auf ubiquitäre Autoantigene innerhalb betroffener Gelenke ANA-positiver JIA-Patienten widerspiegeln.
Helically Twisted Graphene Nanoribbons: Bottom-up Stereospecific Synthesis and Characterization
(2024)
Over the past decade, substantial progress has been made in synthesizing atomically precise carbon nanostructures, with a focus on graphene nanoribbons (NRs) through advanced synthetic techniques. Despite these advancements, precise control over the stereochemistry of twisted NRs remains challenging. This thesis introduces a strategic approach to achieve absolute control over the single-handed helical conformation in a cove-edged NR, utilizing enantiopure [n]helicenes as a molecular wrench to intricately dictate the overall conformation of the NR.
Enantiopure [7]helicenes were stitched to the terminal K-regions of a conjugated pyrene NR using a stereospecific and site-selective palladium(II)-catalyzed annulative π-extension (APEX) reaction, resulting in a helically twisted NR with an end-to-end twist of 171°, the second-largest twist reported so far in the literature for twistacenes. The helical end-to-end twist increases with each addition of benzene ring to the central acene core, suggesting that the extra strain induced by the terminal [7]helicenes maintains such a high level of twist.
The quantum chemical calculations were conducted to investigate the impact of twisting on the conformational population. At room temperature, the central backbone of the nanoribbon adopts the twisted helicity opposite to that of the attached [7]helicene, constituting around 99% of the molecular population. For instance, (P)-[7]helicenes produce a left-handed helical nanoribbon, while (M)-[7]helicenes produce a right-handed helical nanoribbon. In the presence of helicenes of opposite chirality, the nanoribbon adopts a waggling conformation. The helically twisted nanoribbons are conformationally robust, as variable temperature chiroptical measurements showed no change in CD and CPL spectra. The proposed strategy, involving the late-stage addition of [n]helicene units through the APEX reaction, appears promising for streamlining the synthesis of diverse cove edge NR variants with desired conformations.
In addition to single-handed helically twisted nanoribbons, the symmetry-based functional properties of C2 and C1 symmetric pyrene-fused single and double [n]helicene compounds were studied. Owing to its higher structural rigidity, the C1 symmetric heptagonal ring-containing molecules exhibited exceptional configurational stability along with remarkable chiroptical properties compared to their C2 symmetric as well as pristine helicene congeners.
Sprech- und Stimmstörungen sind häufige Symptome der Idiopathischen Parkinson Erkrankung (IPS), wobei bis zu 89% der Patienten im Verlauf der Krankheit unter einer Dysarthrie leiden. Die Tiefenhirnstimulation des Nucleus subthalamicus (STN-DBS) ist eine etablierte Behandlung für die motorischen Symptome des IPS (Allert et al., 2004). Während STN-DBS positive Effekte auf einige Teilfunktionsbereiche der Dysarthrie zu haben scheint, berichten die meisten Studien entweder über keine Verbesserung oder eine Verschlechterung der Sprech- und Stimmfunktionen nach Implantation der STN-DBS (Tsuboi et al., 2015; Wang et al., 2003; Wertheimer et al., 2014). Klinische Erfahrungswerte sowie Fallberichte und Studien lassen vermuten, dass diese sprachtherapeutisch relevanten Nebenwirkungen unabhängig von der therapeutischen Wirksamkeit der STN-DBS sind und daher als unerwünschte, aber nicht therapieimmanente Interferenzfaktoren anzusehen sind (Bouthour et al., 2018), die es genauer zu untersuchen gilt, da die Lebensqualität von IPS-Erkrankten als stark einschränkend wahrgenommen wird (Hariz et al., 2010). Eine aufwendige und methodisch fundierte Klassifizierung wurde von Tsuboi und Kollegen vorgenommen, die im Zusammenhang mit STN-DBS fünf Cluster von Sprech- und Stimmstörungen identifizierten (Tanaka et al., 2020; Tsuboi et al., 2015, 2017). Dazu zählten die Phänotypen „spastische Dysarthrie“, „Stottern“, „rigid-hypokinetischer Typ“, „behauchte Stimme“ und „gepresste Stimme“.
Erste Hinweise lassen darauf schließen, dass die Nebenwirkungen von STN-DBS auf die Stimulation spezifischer Gehirnkreise zurückzuführen sein könnte (Fox et al., 2014). In dieser Arbeit wird eine retrospektive Studie mit STN-DBS stimulierten IPS Erkrankten vorgestellt, die sprachtherapeutisch relevante Sprech- und Stimmstörungen unter zwei Bedingungen bewertet (ein- und ausgeschaltete Stimulation) sowie eine prospektive Studie mit den beiden gleichen Bedingungen. Beide Studien haben das Ziel einer Replizierbarkeit der Ergebnisse von Tsuboi et al. (2015, 2017). Die zweite prospektive Studie bezieht außerdem konnektombasierte Daten ein.
Die Ergebnisse beider Studien lassen quantitativ keine Signifikanzen hinsichtlich der o.g. dysarthrischen Phänotypen zu, quantitativ lassen sich jedoch deutliche Tendenzen ähnlich der Ausgangsstudie erkennen. Zudem wurden das Cluster „Stottern“ in der retrospektiven Studie als weiteres möglicherweise STN-DBS immantentes Cluster identifiziert. In der prospektiven Studie wurde ein Cluster hinzugefügt, da in den Beurteilungen zusätzlich die Symptomatik „hasty speech“ oder auch „hastiges Sprechen“ beobachtet wurde.
The goal of this thesis was to investigate the influence of rotational restriction between individual parts and of the varying electron density in the bridging unit of D B A systems on the exchange interaction 2J, and thus the electronic coupling between a donor state and an acceptor state. A better understanding of how to influence the underlaying spin dynamics in such donor acceptor systems can open up the door to new technologies, such as modern molecular electronics or optoelectronic devices.
Therefore, three series of molecules consisting of a TAA electron donor, a TTC or ATC bridging unit and a PDI electron acceptor were studied. To investigate the influence of rotational restriction on 2J and the electronic coupling, a series of four rotationally hindered triads (chapter 6) was synthesised. The dihedral angle between the TAA and the TTC as well as between the TTC and the PDI was restricted by ortho methyl groups at the phenylene linkers of the connecting ends to the TTC bridge, producing a twist around the linking single bond which minimises the π overlap. The triads exhibit varying numbers of ortho methyl groups and therefore different degrees of rotational restriction. In order to shine light on the influence of varying electron density on 2J and the electronic coupling, a series of four substituted triptycene triads (chapter 7) was synthesised. The electron density in the TTC bridging unit was varied by electron donating and electron withdrawing groups in 12,13 position of the TTC bridging unit and thus varying its HOMO/LUMO energy. The last series of two anthracene bridge triads (chapter 8) connected both approaches by restricting the rotation with ortho methyl groups and simultaneously by varying the bridge energies.
In order to obtain the electronic properties, steady state absorption and emission spectra of all triads were investigated (chapter 4). Here, all triads show spectral features associated with the separate absorption bands of TAA and the PDI moiety. The reduced QYs, compared to the unsubstituted PDI acceptor, indicate a non radiative quenching mechanism in all triads. The CV data (chapter 5) were used to calculate the energies of possible CSSs and those results were used to assign the CR dynamics into the different Marcus regions. fs TA measurements reveal that all triads form a CSS upon excitation of the PDI moiety. The lifetimes of the involved states and the rate constants were determined by global exponential fits and global target analysis. The CR dynamics upon depopulation of the CSSs were investigated using external magnetic field dependent ns TA spectroscopy. The ns TA maps show that all triads recombine via CRT pathway populating the local 3PDI state in toluene and provided the respective lifetimes. The approximate QYs of triplet formation were determined using actinometry. The magnetic field dependent ns TA data reveal the exchange interaction 2J between singlet and triplet CSS for each triad. Those magnetic field dependent ns TA data in toluene were furthermore treated using a quantum mechanical simulation (done by U.E. Steiner) to extract the rate constants kT and kS for CRT and CRS, respectively. However, the error margins of kS were rather wide. Finally, the electronic couplings between the donor and the acceptor states were obtained by combining the aforementioned experimental results of the rate constants and applying the Bixon Jortner theoretical description of diabatic ET and Andersons perturbative theory of the exchange coupling. Therefore, the experimentally determined values of 2J and the calculated values of kCS and kT were used. The rate constant kS was calculated based on the electronic coupling V1CSS 1S0.
The rotationally hindered triads (chapter 6) show a strong influence of the degree of rotational restriction on the lifetimes and rate constants of the CS processes. The rate constants of CS are increasing with increasing rotational freedom. The magnetic field dependent decay data show that the exchange interactions increase with increasing rotational freedom. Based on the CR dynamics, the calculated electronic couplings of the ET processes reflect the same trend along the series. Here, only singlet couplings turned out to be strongly influenced while the triplet couplings are not. Therefore, this series shows that the ET dynamics of donor acceptor systems can strongly be influenced by restricting the rotational freedom.
In the substituted triptycene triads (chapter 7), decreasing electron density in the bridging unit causes a decrease of the CS rate constants. The magnetic field dependent decay data show that with decreasing electron density in the bridge the exchange interaction decreases. The CR dynamics-based rate constants and the electronic couplings follow the same trend as the exchange interaction. This series shows that varying the HOMO/LUMO levels of the connecting bridge between donor and acceptor strongly influences the ET processes.
In the anthracene bridge triads (chapter 8), the CS process is slow in both triads. The CR was fast in the anthracene triad and is slowed down in the methoxy substituted anthracene bridge triad. The increase of the exchange interaction with increasing electron density in the bridge was more pronounced than in the substituted triptycene triads. Thus, the variation of electron density in the bridge strongly influences the ET processes even though the rotation is restricted.
In this thesis, it was shown that the influence of the rotational hindrance as well as the electron density in a connecting bridge have strong influence on all ET processes and the electronic coupling in donor acceptor systems. These approaches can therefore be used to modify magnetic properties of new materials.
In a world of constant change, uncertainty has become a daily challenge for businesses. Rapidly shifting market conditions highlight the need for flexible responses to unforeseen events. Operations Management (OM) is crucial for optimizing business processes, including site planning, production control, and inventory management. Traditionally, companies have relied on theoretical models from microeconomics, game theory, optimization, and simulation. However, advancements in machine learning and mathematical optimization have led to a new research field: data-driven OM.
Data-driven OM uses real data, especially time series data, to create more realistic models that better capture decision-making complexities. Despite the promise of this new research area, a significant challenge remains: the availability of extensive historical training data. Synthetic data, which mimics real data, has been used to address this issue in other machine learning applications.
Therefore, this dissertation explores how synthetic data can be leveraged to improve decisions for data-driven inventory management, focusing on the single-period newsvendor problem, a classic stochastic optimization problem in inventory management.
The first article, "A Meta Analysis of Data-Driven Newsvendor Approaches", presents a standardized evaluation framework for data-driven prescriptive approaches, tested through a numerical study. Findings suggest model performance is not robust, emphasizing the need for a standardized evaluation process.
The second article, "Application of Generative Adversarial Networks in Inventory Management", examines using synthetic data generated by Generative Adversarial Networks (GANs) for the newsvendor problem. This study shows GANs can model complex demand relationships, offering a promising alternative to traditional methods.
The third article, "Combining Synthetic Data and Transfer Learning for Deep Reinforcement Learning in Inventory Management", proposes a method using Deep Reinforcement Learning (DRL) with synthetic and real data through transfer learning. This approach trains a generative model to learn demand distributions, generates synthetic data, and fine-tunes a DRL agent on a smaller real dataset. This method outperforms traditional approaches in controlled and practical settings, though further research is needed to generalize these findings.
In heart failure and atrial fibrillation, a persistent Na\(^+\) current (I\(_{NaL}\)) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na\(_V\)1.8 contributes to arrhythmogenesis by inducing a I\(_{NaL}\). Genome-wide association studies indicate that mutations in the SCN10A gene (Na\(_V\)1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na\(_V\)1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I\(_{NaL}\) and action potential duration. Ca\(^{2+}\) measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca\(^{2+}\) leak. The I\(_{NaL}\) was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na\(_V\)1.8. No effects on atrial APD\(_{90}\) were detected in any groups. Both SCN10A KO and specific blockers of Na\(_V\)1.8 led to decreased Ca\(^{2+}\) spark frequency and a significant reduction of arrhythmogenic Ca\(^{2+}\) waves. Our experiments demonstrate that Na\(_V\)1.8 contributes to I\(_{NaL}\) formation in human atrial CMs and that Na\(_V\)1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na\(_V\)1.8 could be a new target for antiarrhythmic strategies.