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The epigenome is thought to mediate between genes and the environment, particularly in response to adverse life experiences. Similar to other psychiatric diseases, the suicide liability of an individual appears to be influenced by many genetic factors of small effect size as well as by environmental stressors. To identify epigenetic marks associated with suicide, which is considered the endpoint of complex gene-environment interactions, we compared the cortex DNA methylation patterns of 6 suicide completers versus 6 non-psychiatric sudden-death controls, using Illumina 450K methylation arrays. Consistent with a multifactorial disease model, we found DNA methylation changes in a large number of genes, but no changes with large effects reaching genome-wide significance. Global methylation of all analyzed CpG sites was significantly (0.25 percentage point) lower in suicide than in control brains, whereas the vast majority (97%) of the top 1,000 differentially methylated regions (DMRs) were higher methylated (0.6 percentage point) in suicide brains. Annotation analysis of the top 1,000 DMRs revealed an enrichment of differentially methylated promoters in functional categories associated with transcription and expression in the brain. In addition, we performed a comprehensive literature research to identify suicide genes that have been replicated in independent genetic association, brain methylation and/or expression studies. Although, in general, there was no significant overlap between different published data sets or between our top 1,000 DMRs and published data sets, our methylation screen strengthens a number of candidate genes (APLP2, BDNF, HTR1A, NUAK1, PHACTR3, MSMP, SLC6A4, SYN2, and SYNE2) and supports a role for epigenetics in the pathophysiology of suicide.
Blazars like Markarian 421 or Markarian 501 are active galactic nuclei (AGN), with their jets orientated towards the observer. They are among the brightest objects in the very high energy (VHE) gamma ray regime (>100 GeV). Their emitted gamma-ray fluxes are extremely variable, with changing activity levels on timescales between minutes, months, and even years. Several questions are part of the current research, such as the question of the emission regions or the engine of the AGN and the particle acceleration. A dedicated longterm monitoring program is necessary to investigate the properties of blazars in detail. A densely sampled and unbiased light curve allows for observation of both high and low states of the sources, and the combination with multi-wavelength observation could contribute to the answer of several questions mentioned above. FACT (First G-APD Cherenkov Telescope) is the first operational telescope using silicon photomultiplier (SiPM, also known as Geigermode—Avalanche Photo Diode, G-APD) as photon detectors. SiPM have a very homogenous and stable longterm performance, and allow operation even during full moon without any filter, leading to a maximal duty cycle for an Imaging Air Cherenkov Telescope (IACT). Hence, FACT is an ideal device for such a longterm monitoring of bright blazars. A small set of sources (e.g., Markarian 421, Markarian 501, 1ES 1959+650, and 1ES 2344+51.4) is currently being monitored. In this contribution, the FACT telescope and the concept of longterm monitoring of bright blazars will be introduced. The results of the monitoring program will be shown, and the advantages of densely sampled and unbiased light curves will be discussed.
Salience bias and overwork
(2022)
In this study, we enrich a standard principal–agent model with hidden action by introducing salience-biased perception on the agent's side. The agent's misguided focus on salient payoffs, which leads the agent's and the principal's probability assessments to diverge, has two effects: First, the agent focuses too much on obtaining a bonus, which facilitates incentive provision. Second, the principal may exploit the diverging probability assessments to relax participation. We show that salience bias can reverse the nature of the inefficiency arising from moral hazard; i.e., the principal does not necessarily provide insufficient incentives that result in inefficiently low effort but instead may well provide excessive incentives that result in inefficiently high effort.
Post-synthetic shaping of porosity and crystal structure of Ln-Bipy-MOFs by thermal treatment
(2015)
The reaction of anhydrous lanthanide chlorides together with 4,4'-bipyridine yields the MOFs \(^{2}\)\(_{∞}\)[Ln\(_{2}\)Cl\(_{6}\)(bipy)\(_{3}\)]*2bipy, with Ln = Pr-Yb, bipy = 4,4'-bipyridine, and \(^{3}\)\(_{∞}\)[La\(_{2}\)Cl\(_{6}\)(bipy)\(_{5}\)]*4bipy. Post-synthetic thermal treatment in combination with different vacuum conditions was successfully used to shape the porosity of the MOFs. In addition to the MOFs microporosity, a tuneable mesoporosity can be implemented depending on the treatment conditions as a surface morphological modification. Furthermore, thermal treatment without vacuum results in several identifiable crystalline high-temperature phases. Instead of collapse of the frameworks upon heating, further aggregation under release of bipy is observed. \(^{3}\)\(_{∞}\)[LaCl\(_{3}\)(bipy)] and \(^{2}\)\(_{∞}\)[Ln\(_{3}\)Cl\(_{9}\)(bipy)\(_{3}\)], with Ln = La, Pr, Sm, and \(^{1}\)\(_{∞}\)[Ho\(_{2}\)Cl\(_{6}\)(bipy)\(_{2}\)] were identified and characterized, which can also exhibit luminescence. Besides being released upon heating, the linker 4,4'-bipyridine can undergo activation of C-C bonding in ortho-position leading to the in-situ formation of 4,4':2',2 '':4 '',4'''-quaterpyridine (qtpy). qtpy can thereby function as linker itself, as shown for the formation of the network \(^{2}\)\(_{∞}\)[Gd\(_{2}\)Cl\(_{6}\)(qtpy)\(_{2}\)(bipy)\(_{2}\)]*bipy. Altogether, the manuscript elaborates the influence of thermal treatment beyond the usual activation procedures reported for MOFs.
Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69–0.82) vs 0.69 (95% CI: 0.61–0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P = 0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.
Background:
The interaction of eukaryotic host and prokaryotic pathogen cells is linked to specific changes in the cellular proteome, and consequently to infection-related gene expression patterns of the involved cells. To simultaneously assess the transcriptomes of both organisms during their interaction we developed dual 3'Seq, a tag-based sequencing protocol that allows for exact quantification of differentially expressed transcripts in interacting pro-and eukaryotic cells without prior fixation or physical disruption of the interaction.
Results:
Human epithelial cells were infected with Salmonella enterica Typhimurium as a model system for invasion of the intestinal epithelium, and the transcriptional response of the infected host cells together with the differential expression of invading and intracellular pathogen cells was determined by dual 3'Seq coupled with the next-generation sequencing-based transcriptome profiling technique deepSuperSAGE (deep Serial Analysis of Gene Expression). Annotation to reference transcriptomes comprising the operon structure of the employed S. enterica Typhimurium strain allowed for in silico separation of the interacting cells including quantification of polycistronic RNAs. Eighty-nine percent of the known loci are found to be transcribed in prokaryotic cells prior or subsequent to infection of the host, while 75% of all protein-coding loci are represented in the polyadenylated transcriptomes of human host cells.
Conclusions:
Dual 3'Seq was alternatively coupled to MACE (Massive Analysis of cDNA ends) to assess the advantages and drawbacks of a library preparation procedure that allows for sequencing of longer fragments. Additionally, the identified expression patterns of both organisms were validated by qRT-PCR using three independent biological replicates, which confirmed that RELB along with NFKB1 and NFKB2 are involved in the initial immune response of epithelial cells after infection with S. enterica Typhimurium.
This evidence‐based clinical guideline provides consensus‐recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus‐based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non‐infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG‐replacement therapy. Summary and consensus‐recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG‐replacement therapy. Special aspects of concomitant impaired T‐cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA‐4‐, and LRBA‐deficiency).
The biomedical consequences of allogeneic blood transfusions and the possible pathomechanisms of transfusion-related morbidity and mortality are still not entirely understood. In retrospective studies, allogeneic transfusion was associated with increased rates of cancer recurrence, metastasis and death in patients with colorectal cancer. However, correlation does not imply causation. The purpose of this study was to elucidate this empirical observation further in order to address insecurity among patients and clinicians. We focused on the in vitro effect of microparticles derived from red blood cell units (RMPs). We incubated different colon carcinoma cells with RMPs and analyzed their effects on growth, invasion, migration and tumor marker expression. Furthermore, effects on Wnt, Akt and ERK signaling were explored. Our results show RMPs do not seem to affect functional and phenotypic characteristics of different colon carcinoma cells and did not induce or inhibit Wnt, Akt or ERK signaling, albeit in cell culture models lacking tumor microenvironment. Allogeneic blood transfusions are associated with poor prognosis, but RMPs do not seem to convey tumor-enhancing effects. Most likely, the circumstances that necessitate the transfusion, such as preoperative anemia, tumor stage, perioperative blood loss and extension of surgery, take center stage.
Purpose
The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study’s aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD.
Methods
We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified.
Results
Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15–65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27–33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66–147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49–54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17–8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13–10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68–1.93, p = 0.611).
Conclusion
The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2.