γ-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics.

Sequence variants of the microglial expressed TREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease. TREM2 requires a stable interaction with DAP12 in the membrane to initiate signaling, which is terminated by TREM2 ectodomain shedding and subsequent intramembrane cleavage by γ-secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of the TREM2 transmembrane helix (TMH). Caused by the presence of a charged amino acid in the membrane region, the TREM2-TMH adopts a kinked structure with increased flexibility. Charge removal leads to TMH stabilization and reduced dynamics, similar to its structure in complex with DAP12. Strikingly, these dynamical features match with the site of the initial γ-secretase cleavage event. These data suggest an unprecedented cleavage mechanism by γ-secretase where flexible TMH regions act as key determinants of substrate cleavage specificity.

Non-patient-related SARS-CoV-2 exposure from colleagues and household members poses the highest infection risk for hospital employees in a German university hospital: follow-up of the prospective Co-HCW seroprevalence study.

PURPOSE: The Co-HCW study is a prospective, longitudinal, single-center observational study that aims to assess the SARS-CoV-2 seroprevalence and infection status in staff members of Jena University Hospital (JUH) in Jena, Germany. METHODS: This follow-up study covers the observation period from 19th May 2020 to 22nd June 2021. At each of the three voluntary study visits, participants filled out a questionnaire regarding their SARS-CoV-2 exposure and provided serum samples to detect specific SARS-CoV-2 antibodies. Participants who were tested positive for antibodies against nucleocapsid and/or spike protein without previous vaccination and/or reported a positive SARS-CoV-2 PCR test were regarded to have been infected with SARS-CoV-2. Multivariable logistic regression modeling was applied to identify potential risk factors for infected compared to non-infected participants. RESULTS: Out of 660 participants that were included during the first study visit, 406 participants (61.5%) were eligible for the final analysis as their COVID-19 risk area (high-risk n = 76; intermediate-risk n = 198; low-risk n = 132) did not change during the study. Forty-four participants [10.8%, 95% confidence interval (95%CI) 8.0-14.3%] had evidence of a current or past SARS-CoV-2 infection detected by serology (n = 40) and/or PCR (n = 28). No association between SARS-CoV-2 infection and the COVID-19 risk group according to working place was detected. However, exposure to a SARS-CoV-2 positive household member [adjusted OR (AOR) 4.46, 95% CI 2.06-9.65] or colleague (AOR 2.30, 95%CI 1.10-4.79) was found to significantly increase the risk of a SARS-CoV-2 infection. CONCLUSION: Our results demonstrate that non-patient-related SARS-CoV-2 exposure posed the highest infection risk for hospital staff members of JUH.

Transcriptome-wide association study of coronary artery disease identifies novel susceptibility genes.

The majority of risk loci identified by genome-wide association studies (GWAS) are in non-coding regions, hampering their functional interpretation. Instead, transcriptome-wide association studies (TWAS) identify gene-trait associations, which can be used to prioritize candidate genes in disease-relevant tissue(s). Here, we aimed to systematically identify susceptibility genes for coronary artery disease (CAD) by TWAS. We trained prediction models of nine CAD-relevant tissues using EpiXcan based on two genetics-of-gene-expression panels, the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and the Genotype-Tissue Expression (GTEx). Based on these prediction models, we imputed gene expression of respective tissues from individual-level genotype data on 37,997 CAD cases and 42,854 controls for the subsequent gene-trait association analysis. Transcriptome-wide significant association (i.e. P < 3.85e-6) was observed for 114 genes. Of these, 96 resided within previously identified GWAS risk loci and 18 were novel. Stepwise analyses were performed to study their plausibility, biological function, and pathogenicity in CAD, including analyses for colocalization, damaging mutations, pathway enrichment, phenome-wide associations with human data and expression-traits correlations using mouse data. Finally, CRISPR/Cas9-based gene knockdown of two newly identified TWAS genes, RGS19 and KPTN, in a human hepatocyte cell line resulted in reduced secretion of APOB100 and lipids in the cell culture medium. Our CAD TWAS work (i) prioritized candidate causal genes at known GWAS loci, (ii) identified 18 novel genes to be associated with CAD, and iii) suggested potential tissues and pathways of action for these TWAS CAD genes.

Double Tropopauses and the Tropical Belt Connected to ENSO.

A detailed analysis of double tropopause (DT) occurrences requires vertically well resolved, accurate, and globally distributed information on the troposphere-stratosphere transition zone. Here, we use radio occultation observations from 2001 to 2018 with such properties. We establish a connection between El Niño-Southern Oscillation (ENSO) phases and the distribution of DTs by analyzing the global and seasonal DT characteristics. The seasonal distribution of DTs reveals several hotspot locations, such as near the subtropical jet stream and over high mountain ranges, where DTs occur particularly often. In this study, we detect a higher number of DTs during the cold La Niña state while warmer El Niño events result in lower DT rates, affecting the structure of the tropopause region. Close to the Niño 3 region, this relates to a much lower first lapse rate tropopause altitude during La Niña and corresponds to an apparent narrowing of the tropical belt there.

Morphological diversity of integumentary traits in fowl domestication: Insights from disparity analysis and embryonic development.

The domestication of the fowl resulted in a large diversity of integumental structures in chicken breeds. Several integumental traits have been investigated from a developmental genetics perspective. However, their distribution among breeds and their developmental morphology remain unexplored. We constructed a discrete trait-breed matrix and conducted a disparity analysis to investigate the variation of these structures in chicken breeds; 20 integumental traits of 72 chicken breeds and the red junglefowl were assessed. The analyses resulted in slight groupings of breed types comparable to standard breed classification based on artificial selection and chicken type use. The red junglefowl groups together with bantams and European breeds. We provide new data on the red junglefowl and four chicken breeds, demonstrating where and when variation arises during embryonic development. We document variation in developmental timing of the egg tooth and feather formation, as well as other kinds of developmental patterning as in the anlagen of different type of combs. Changes in epithelial-mesenchymal signaling interactions may drive the highly diverse integument in chickens. Experimental and comparative work has revealed that the cranial neural crest mesenchyme mediates its interactions with the overlying epithelium and is the likely source of patterning that generates diversity in integumental structures.

Quantifying Stratospheric Temperature Signals and Climate Imprints From Post-2000 Volcanic Eruptions.

Small volcanic eruptions and their effects have recently come into research focus. While large eruptions are known to strongly affect stratospheric temperature, the impacts of smaller eruptions are hard to quantify because their signals are masked by natural variability. Here, we quantify the temperature signals from small volcanic eruptions between 2002 and 2016 using new vertically resolved aerosol data and precise temperature observations from radio occultation. We find characteristic space-time signals that can be associated with specific eruptions. In the lower stratosphere, robust warming signals are observed, while in the midstratosphere also cooling signals of some eruptions appear. We find that the volcanic contribution to the temperature trend is up to 20%, depending on latitude and altitude. We conclude that detailed knowledge of the vertical structure of volcanic temperature impacts is crucial for comprehensive trend analysis in order to separate natural from anthropogenic temperature changes.

Dependence of Present and Future European Temperature Extremes on the Location of Atmospheric Blocking.

The impact of atmospheric blocking on European heat waves (HWs) and cold spells (CSs) is investigated for present and future conditions . A 50-member ensemble of the second generation Canadian Earth System Model is used to quantify the role of internal variability in the response to blocking. We find that the present blocking-extreme temperature link is well represented compared to ERA-Interim, despite a significant underestimation of blocking frequency in most ensemble members. Our results show a strong correlation of blocking with northern European HWs in summer, spring, and fall. However, we also find a strong anticorrelation between blocking and HW occurrence in southern Europe in all seasons. Blocking increases the CS frequency particularly in southern Europe in fall, winter, and spring but reduces it in summer. For the future we find that blocking will continue to play an important role in the development of both CSs and HWs in all seasons.

Revisiting the mystery of recent stratospheric temperature trends.

Simulated stratospheric temperatures over the period 1979-2016 in models from the Chemistry-Climate Model Initiative (CCMI) are compared with recently updated and extended satellite observations. The multi-model mean global temperature trends over 1979- 2005 are -0.88 ± 0.23, -0.70 ± 0.16, and -0.50 ± 0.12 K decade-1 for the Stratospheric Sounding Unit (SSU) channels 3 (~40-50 km), 2 (~35-45 km), and 1 (~25-35 km), respectively. These are within the uncertainty bounds of the observed temperature trends from two reprocessed satellite datasets. In the lower stratosphere, the multi-model mean trend in global temperature for the Microwave Sounding Unit channel 4 (~13-22 km) is -0.25 ± 0.12 K decade-1 over 1979-2005, consistent with estimates from three versions of this satellite record. The simulated stratospheric temperature trends in CCMI models over 1979-2005 agree with the previous generation of chemistry-climate models. The models and an extended satellite dataset of SSU with the Advanced Microwave Sounding Unit-A show weaker global stratospheric cooling over 1998-2016 compared to the period of intensive ozone depletion (1979-1997). This is due to the reduction in ozone-induced cooling from the slow-down of ozone trends and the onset of ozone recovery since the late 1990s. In summary, the results show much better consistency between simulated and satellite observed stratospheric temperature trends than was reported by Thompson et al. (2012) for the previous versions of the SSU record and chemistry-climate models. The improved agreement mainly comes from updates to the satellite records; the range of simulated trends is comparable to the previous generation of models.

Tetramers are the activation-competent species of the HOCl-specific transcription factor HypT.

Hypochlorous acid (HOCl) is an important component of the immune system and is produced by neutrophils to kill invading microorganisms. The transcription factor HypT is specifically activated by HOCl by methionine oxidation and protects Escherichia coli cells from the detrimental effects of HOCl. HypT forms dodecameric ring-like oligomers. Binding of HypT to DNA induces dissociation of the dodecamers into dimers and tetramers, thus forming the DNA-binding species. To dissect HypT dissociation, binding to DNA, and activation, we aimed to dissociate the dodecamers independently of DNA and to analyze HOCl-dependent activation in vitro. We found that HypT dodecamers dissociated into tetramers in the presence of l-arginine and NaCl, which was reversible upon dilution of the additive. Making use of the reversible dissociation, we generated mixed assemblies consisting of wild-type and mutant HypT subunits and determined that mutant subunits with reduced thermal stability were stabilized by wild-type HypT in the mixed assembly. HypT tetramers, as present at high NaCl concentrations, were stabilized against thermal unfolding and aggregation triggered by high HOCl concentrations. Importantly, in vitro activation by HOCl of HypT tetramers was completed within 1 min, whereas activation of dodecamers required 1 h for completion. Furthermore, activation of HypT tetramers required stoichiometric amounts of HOCl instead of an excess of HOCl, as observed for dodecamers. This supports the idea that small HypT oligomers are the activation-competent species, whereas the dodecamers are a storage form. Our study reveals the importance of the dynamic oligomeric state for HypT activation by HOCl.

Deriving dynamics from GPS radio occultation: Three-dimensional wind fields for monitoring the climate.

Global Positioning System (GPS) radio occultation (RO) measurements are proven highly useful for observing the thermal structure of the troposphere and stratosphere. Here we use RO data for the first time to derive climatological wind fields from sampling error-corrected geopotential height fields on isobaric surfaces from about 800 hPa to 3 hPa. We find monthly mean RO geostrophic wind and gradient wind fields (2007 to 2012, about 500 km horizontal resolution, outside tropics) to clearly capture all main wind features, with differences to atmospheric analysis winds being, in general, smaller than 2 m/s. Larger differences (up to 10 m/s) occur close to the subtropical jet where RO winds underestimate actual winds. Such biases are caused by the geostrophic and gradient wind approximations, while RO retrieval errors introduce negligible effect. These results demonstrate that RO wind fields are of high quality and can provide new information on troposphere-stratosphere dynamics, for the benefit of monitoring the climate from weekly to decadal scales.

BAG-1 diversely affects steroid receptor activity.

Part of the cellular and physiological functions of BAG-1 (Bcl-2-associated athanogene 1) has been ascribed to the ability of this hsp70 (heat-shock protein 70) co-chaperone to regulate steroid receptor activity. BAG-1 has been reported to inhibit the GR (glucocorticoid receptor) and stimulate the androgen receptor, but to leave the activity of the MR (mineralocorticoid receptor) unchanged. Given the high homology between the MR and GR, this disparity in the actions of BAG-1 is surprising. In the present study, we analysed the effect of BAG-1 on the activity of the closely related PR (progesterone receptor). Similarly to the GR, the transcriptional activity of the PR is inhibited by the long and middle isoforms of BAG-1, BAG-1L and BAG-1M, but not by the short isoform, BAG-1S. We found this inhibition to require the hsp70-binding domain of BAG-1. To shed light on the mechanisms that could explain BAG-1's differential actions on steroid receptors, we tested the binding of BAG-1M to the PR. Mutational analyses of the PR and BAG-1M revealed that the mode of interaction and BAG-1M-mediated inhibition of the PR differs from the reported scenario for the GR. Surprisingly, we also found binding of BAG-1M to the MR. In addition, BAG-1M was able to inhibit the transcriptional activity of the MR. These data entail a reappraisal of the physiological actions of BAG-1M on steroid receptor activity.

Resolving the 21st century temperature trends of the upper troposphere-lower stratosphere with satellite observations.

Historically, observational information about atmospheric temperature has been limited due to a lack of suitable measurements. Recent advances in satellite observations provide new insight into the fine structure of the free atmosphere, with the upper troposphere and lower stratosphere comprising essential components of the climate system. This is a prerequisite for understanding the complex processes of this part of the atmosphere, which is also known to have a large impact on surface climate. With unprecedented resolution, latest climate observations reveal a dramatic warming of the atmosphere. The tropical upper troposphere has already warmed about 1 K during the first two decades of the 21st century. The tropospheric warming extends into the lower stratosphere in the tropics and southern hemisphere mid-latitudes, forming a prominent hemispheric asymmetry in the temperature trend structure. Together with seasonal trend patterns in the stratosphere, this indicates a possible change in stratospheric circulation.

Burnout status of healthcare workers in the world during the peak period of the COVID-19 pandemic.

During the COVID-19 pandemic, healthcare workers have a high workload and have been exposed to various psychosocial stressors. This study aimed to evaluate health workers during the COVID-19 pandemic in the world. The method used in this research is qualitative with a literature review approach. The data sources in this study were taken from the Scopus database using the keywords "health workers," "burnout," AND "coronavirus" from the time range of 2020 to April 25, 2022. From the determination of the time range, 150 documents emerged. This study revealed that the Pearson correlation between total burnout scale scores on healthcare workers, professionals, exhaustion, mental, stress, personal, depression, symptoms, emergency, system, job, and impact indicated that overall burnout scores were associated with depression and anxiety. Stress symptoms had correlation values ranging from 0.84 to 0.73. Job burnout had a significant relationship with exhaustion at 0.89; depression r = 0.73), impacting a score of 0.66. At the same time, the fulfillment of professional and interpersonal disengagement showed a Pearson correlation between the total burnout scale scores on health workers, professionals, exhaustion, mental, stress, personal, depression, symptoms, emergency, system, job, and impact. Overall, the participants in health care workers worldwide experienced high levels of psychological distress. We also found that health workers dealing with COVID-19 pandemic patients were more likely to experience depression, stress, and burnout than health staff who were not personally involved in medical work. Furthermore, this study will be a follow-up study using the Work Ability Index (WAI) to measure work ability and work satisfaction.

Seasonal Influenza Vaccination at a German University Hospital: Distinguishing Barriers Between Occupational Groups.

The annual influenza vaccination has been officially recommended for medical staff in Germany since 1988. Nevertheless, the vaccination rate among medical staff is still low. The present study deals with the influenza vaccination rate of staff at a German University hospital over time as well as with the reasons that led to a positive vaccination decision and the barriers to acceptance of vaccination. For this purpose, the staff members received questionnaires in which they were asked about influenza vaccination and the reasons for or against vaccination. In addition, the questionnaire contains information on gender, age group, occupational group and presence of a chronic co-morbidity. Logistic regression analysis was used to investigate which of these predictors most strongly influenced the vaccination decision. It was shown that the reasons for or against vaccination differ significantly between the occupational groups and that the occupational group affiliation has the greatest influence on the vaccination decision in the comparison of the investigated predictors. In order to achieve a positive influence on vaccination acceptance, future measures should focus on increasing confidence in vaccination and on increasing the perception of risk from influenza illness. The findings may contribute to future targeted strategies to increase vaccination rates and suggest occupational group-specific interventions.

Prospective surveillance study in a 1,400-bed university hospital: COVID-19 exposure at home was the main risk factor for SARS-CoV-2 point seroprevalence among hospital staff.

The Co-HCW study is a prospective cohort study among hospital staff, including healthcare workers (HCWs) and administration staff, at the Jena University Hospital (JUH), Germany. The objectives of this study were to assess SARS-CoV-2 IgG seroprevalence, individual exposure risk factors and compliance of HCWs to wear personal protective equipment (PPE). After the first nosocomial COVID-19 outbreak at JUH, mandatory masking was implemented on 20th March 2020. We evaluated point seroprevalence using two IgG detecting immunoassays and issued a questionnaire to assess COVID-19 exposure, clinical symptoms and compliance to wear PPE. Antibody retesting was offered to participants with a divergent result of both immunoassays 5-10 weeks after the first test. Between 19th May and 19th June 2020, we analysed 660 participants [out of 3,228; 20.4%]. Among them, 212 participants (32.1%) had received a previous COVID-19 test. Four of them (1.9%) reported a positive test result. After recruitment, 18 participants (2.7%) had SARS-CoV-2 antibodies in at least one immunoassay. Overall, 21 participants (3.2%) had any evidence of a past or current SARS-CoV-2 infection. Among them, 13 (61.9%) were not aware of direct COVID-19 exposure and 9 (42.9%) did not report any clinical symptoms. COVID-19 exposure at home (adjusted OR (aOR) with 95% CI: 47.82 (5.49, 416.62)) was associated with SARS-CoV-2 seroprevalence. We observed no evidence for an association between seroprevalence and exposure at work (aOR 0.48 (0.13, 1.70)) or with COVID-19 risk area according to the working place (aOR for intermediate-risk vs. high-risk: 1.97 (0.42, 9.22), aOR for low-risk versus high-risk: 2.10 (0.40, 11.06); p = .655). Reported compliance of HCWs to wear PPE differed (p < .001) between working in high-risk (98.3%) and in intermediate-risk areas (69.8%). In conclusion, compared to administration staff, we observed no additional risk to acquire SARS-CoV-2 infections by patient care, probably due to high compliance to wear PPE.

A novel SARS-CoV-2 IgG line-blot for evaluating discrepant IgG test results - Observations in pre-pandemic and follow-up samples of five patients.

To confirm discrepant SARS-CoV-2-IgG results in four standard assays we applied for the first time a prototype of a coronavirus IgG-line-blot which employs antigens from seasonal coronaviruses, SARS-1 and SARS-CoV-2 combined with avidity testing as a confirmatory tool in a follow-up of five cases including pre-pandemic samples.

Observing the climate impact of large wildfires on stratospheric temperature.

Wildfires are expected to become more frequent and intense in the future. They not only pose a serious threat to humans and ecosystems, but also affect Earth's atmosphere. Wildfire plumes can reach into the stratosphere, but little is known about their climate impact. Here, we reveal observational evidence that major wildfires can have a severe impact on the atmospheric temperature structure and short-term climate in the stratosphere. Using advanced satellite observation, we find substantial warming of up to 10 K of the lower stratosphere within the wildfire plumes during their early development. The short-term climate signal in the lower stratosphere lasts several months and amounts to 1 K for the Northern American wildfires in 2017, and up to striking 3.5 K for the Australian wildfires in 2020. This is stronger than any signal from recent volcanic eruptions. Such extreme events affect atmospheric composition and climate trends, underpinning their importance for future climate.

Continuous rise of the tropopause in the Northern Hemisphere over 1980-2020.

Tropopause height (H) is a sensitive diagnostic for anthropogenic climate change. Previous studies showed increases in H over 1980­2000 but were inconsistent in projecting H trends after 2000. While H generally responds to temperature changes in the troposphere and stratosphere, the relative importance of these two contributions is uncertain. Here, we use radiosonde balloon observations in the Northern Hemisphere (NH) over 20°N to 80°N to reveal a continuous rise of H over 1980­2020. Over 2001­2020, H increases at 50 to 60 m/decade, which is comparable to the trend over 1980­2000. The GPS radio occultation measurements from satellites and homogenized radiosonde records are in good agreement with those results. The continuous rise of the tropopause in the NH after 2000 results primarily from tropospheric warming. A large trend in H remains after major natural forcings for H are removed, providing further observational evidence for anthropogenic climate change.