Nonadiabatic Simulation of Exciton Dynamics in Organic Semiconductors Using Neural Network-Based Frenkel Hamiltonian and Gradients.

In this study, we present a multiscale method to simulate the propagation of Frenkel singlet excitons in organic semiconductors (OSCs). The approach uses neural network models to train a Frenkel-type Hamiltonian and its gradient, obtained by the long-range correction version of density functional tight-binding with self-consistent charges. Our models accurately predict site energies, excitonic couplings, and corresponding gradients, essential for the nonadiabatic molecular dynamics simulations. Combined with the fewest switches surface hopping algorithm, the method was applied to four representative OSCs: anthracene, pentacene, perylenediimide, and diindenoperylene. The simulated exciton diffusion constants align well with experimental and reported theoretical values and offer valuable insights into exciton dynamics in OSCs.

4-Year Follow-Up After Transcatheter Tricuspid Valve Replacement Using the EVOQUE System.

Transcatheter tricuspid valve replacement (TTVR) is an increasingly used treatment technique for patients with severe tricuspid regurgitation (TR). Currently, available data from international registries and randomized controlled trials provide outcome data until a maximum follow-up of 2 years after the procedure. This case report presents 4-year follow-up data for an 84-year-old woman who underwent TTVR for torrential TR in 2019. The patient experienced durable TR reduction, symptomatic improvement, right ventricular reverse remodeling, and substantial improvement in liver and kidney function.

Non-adiabatic molecular dynamics simulations provide new insights into the exciton transfer in the Fenna-Matthews-Olson complex.

A trajectory surface hopping approach, which uses machine learning to speed up the most time-consuming steps, has been adopted to investigate the exciton transfer in light-harvesting systems. The present neural networks achieve high accuracy in predicting both Coulomb couplings and excitation energies. The latter are predicted taking into account the environment of the pigments. Direct simulation of exciton dynamics through light-harvesting complexes on significant time scales is usually challenging due to the coupled motion of nuclear and electronic degrees of freedom in these rather large systems containing several relatively large pigments. In the present approach, however, we are able to evaluate a statistically significant number of non-adiabatic molecular dynamics trajectories with respect to exciton delocalization and exciton paths. The formalism is applied to the Fenna-Matthews-Olson complex of green sulfur bacteria, which transfers energy from the light-harvesting chlorosome to the reaction center with astonishing efficiency. The system has been studied experimentally and theoretically for decades. In total, we were able to simulate non-adiabatically more than 30 ns, sampling also the relevant space of parameters within their uncertainty. Our simulations show that the driving force supplied by the energy landscape resulting from electrostatic tuning is sufficient to funnel the energy towards site 3, from where it can be transferred to the reaction center. However, the high efficiency of transfer within a picosecond timescale can be attributed to the rather unusual properties of the BChl a molecules, resulting in very low inner and outer-sphere reorganization energies, not matched by any other organic molecule, e.g., used in organic electronics. A comparison with electron and exciton transfer in organic materials is particularly illuminating, suggesting a mechanism to explain the comparably high transfer efficiency.

Plastid phylogenomics reveals evolutionary relationships in the mycoheterotrophic orchid genus Dipodium and provides insights into plastid gene degeneration.

The orchid genus Dipodium R.Br. (Epidendroideae) comprises leafy autotrophic and leafless mycoheterotrophic species, with the latter confined to sect. Dipodium. This study examined plastome degeneration in Dipodium in a phylogenomic and temporal context. Whole plastomes were reconstructed and annotated for 24 Dipodium samples representing 14 species and two putatively new species, encompassing over 80% of species diversity in sect. Dipodium. Phylogenomic analysis based on 68 plastid loci including a broad outgroup sampling across Orchidaceae found that sect. Leopardanthus is the sister lineage to sect. Dipodium. Dipodium ensifolium, the only leafy autotrophic species in sect. Dipodium, was found to be a sister to all leafless, mycoheterotrophic species, supporting a single evolutionary origin of mycoheterotrophy in the genus. Divergence-time estimations found that Dipodium arose ca. 33.3 Ma near the lower boundary of the Oligocene and that crown diversification commenced in the late Miocene, ca. 11.3 Ma. Mycoheterotrophy in the genus was estimated to have evolved in the late Miocene, ca. 7.3 Ma, in sect. Dipodium. The comparative assessment of plastome structure and gene degradation in Dipodium revealed that plastid ndh genes were pseudogenised or physically lost in all Dipodium species, including in leafy autotrophic species of both Dipodium sections. Levels of plastid ndh gene degradation were found to vary among species as well as within species, providing evidence of relaxed selection for retention of the NADH dehydrogenase complex within the genus. Dipodium exhibits an early stage of plastid genome degradation, as all species were found to have retained a full set of functional photosynthesis-related genes and housekeeping genes. This study provides important insights into plastid genome degradation along the transition from autotrophy to mycoheterotrophy in a phylogenomic and temporal context.

Multiple stressors affecting microbial decomposer and litter decomposition in restored urban streams: Assessing effects of salinization, increased temperature, and reduced flow velocity in a field mesocosm experiment.

A multitude of anthropogenic stressors impact biological communities and ecosystem processes in urban streams. Prominent among them are salinization, increased temperature, and altered flow regimes, all of which can affect microbial decomposer communities and litter decomposition, a fundamental ecosystem process in streams. Impairments caused by these stressors individually or in combination and recovery of communities and ecosystem processes after release from these stressors are not well understood. To improve our understanding of multiple stressors impacts we performed an outdoor stream mesocosm experiment with 64 experimental units to assess the response of microbial litter decomposers and decomposition. The three stressors we applied in a full-factorial design were increased salinity (NaCl addition, 0.53 mS cm-1 above ambient), elevated temperature (3.5 °C above ambient), and reduced flow velocity (3.5 vs 14.2 cm s-1). After two weeks of stressor exposure (first sampling) and two subsequent weeks of recovery (second sampling), we determined leaf-associated microbial respiration, fungal biomass, and the sporulation activity and community composition of aquatic hyphomycetes in addition to decomposition rates of black alder (Alnus glutinosa) leaves confined in fine-mesh litter bags. Microbial colonization of the litter was accompanied by significant mass loss in all mesocosms. However, there was little indication that mass loss, microbial respiration, fungal biomass, sporulation rate or community composition of aquatic hyphomycetes was strongly affected by either single stressors or their interactions. Two exceptions were temperature effects on sporulation and decomposition rate. Similarly, no notable differences among mesocosms were observed after the recovery phase. These results suggest that microbial decomposers and leaf litter decomposition are either barely impaired by exposure to the tested stressors at the levels applied in our experiment, or that communities in restored urban streams are well adapted to cope with these stressor levels.

Functional and compositional responses of stream microphytobenthic communities to multiple stressors increase and release in a mesocosm experiment.

Field observations form the basis of the majority of studies on microphytobenthic algal communities in freshwater ecosystems. Controlled mesocosm experiments data are comparatively uncommon. The few experimental mesocosm studies that have been conducted provide valuable insights into how multiple stressors affect the community structures and photosynthesis-related traits of benthic microalgae. The recovery process after the stressors have subsided, however, has received less attention in mesocosm studies. To close this gap, here we present the results of a riparian mesocosm experiment designed to investigate the effects of reduced flow velocity, increased salinity and increased temperature on microphytobenthic communities. We used a full factorial design with a semi-randomised distribution of treatments consisting of two levels of each stressor (2 × 2 × 2 treatments), with eight replicates making a total of 64 circular mesocosms, allowing a nuanced examination of their individual and combined influences. We aimed to elucidate the responses of microalgae communities seeded from stream water to the applied environmental stressors. Our results showed significant effects of reduced flow velocity and increased temperature on microphytobenthic communities. Recovery after stressor treatment led to a convergence in community composition, with priority effects (hypothesized to reflect competition for substrate between resident and newly arriving immigrant taxa) slowing down community shifts and biomass increase. Our study contributes to the growing body of literature on the ecological dynamics of microphytobenthos and emphasises the importance of rigorous experiments to validate hypotheses. These results encourage further investigation into the nuanced interactions between microphytobenthos and their environment and shed light on the complexity of ecological responses in benthic systems.

Carbon Dioxide Targets in Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome.

Target values for arterial carbon dioxide tension (PaCO2) in extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) are unknown. We hypothesized that lower PaCO2 values on ECMO would be associated with lighter sedation. We used data from two independent patient cohorts with ARDS spending 1,177 days (discovery cohort, 69 patients) and 516 days (validation cohort, 70 patients) on ECMO and evaluated the associations between daily PaCO2, pH, and bicarbonate (HCO3) with sedation. Median PaCO2 was 41 (interquartile range [IQR] = 37-46) mm Hg and 41 (IQR = 37-45) mm Hg in the discovery and the validation cohort, respectively. Lower PaCO2 and higher pH but not bicarbonate (HCO3) served as significant predictors for reaching a Richmond Agitation Sedation Scale (RASS) target range of -2 to +1 (lightly sedated to restless). After multivariable adjustment for mortality, tracheostomy, prone positioning, vasoactive inotropic score, Simplified Acute Physiology Score (SAPS) II or Sequential Organ Failure Assessment (SOFA) Score and day on ECMO, only PaCO2 remained significantly associated with the RASS target range (adjusted odds ratio 1.1 [95% confidence interval (CI) = 1.01-1.21], p = 0.032 and 1.29 [95% CI = 1.1-1.51], p = 0.001 per mm Hg decrease in PaCO2 for the discovery and the validation cohort, respectively). A PaCO2 ≤40 mm Hg, as determined by the concordance probability method, was associated with a significantly increased probability of a sedation level within the RASS target range in both patient cohorts (adjusted odds ratio = 2.92 [95% CI = 1.17-7.24], p = 0.021 and 6.82 [95% CI = 1.50-31.0], p = 0.013 for the discovery and the validation cohort, respectively).

Immunofilaments Are Well Tolerated after Local or Systemic Administration in Mice.

The invention of nanosized biomaterials has paved the way for novel therapeutics that can manipulate cells on a nanoscale. Nanosized immunofilaments (IFs) are synthetic filamentous polymers consisting out of polyisocyanopeptides, which have been recently established as a powerful platform to activate specific immune cells in vivo such that they raise an antitumor immune response. However, toxicological effects or immunogenicity toward the IFs have not yet been investigated. In this study, we evaluated potential toxic or immunogenic effects in C57BL/6 mice upon intravenous or subcutaneous injection of nonfunctionalized IFs or immunostimulatory IFs over 30 days. We here present a detailed analysis of the gross pathology, hematological parameters, blood biochemistry, histology, and antibody-response against the IF backbone. Our results demonstrate that IFs do not induce severe acute or chronic toxicity in mice. After 30 days, we only found elevated IgG-titers in intravenously injected but not subcutaneously injected mice. In summary, we demonstrate that IFs can be administered into a living organism without adverse side effects, thereby establishing the safety of IFs as a therapeutic intervention.

Right ventricular to pulmonary artery coupling in patients with different types of aortic stenosis undergoing TAVI.

BACKGROUND: Right ventricular (RV) dysfunction in patients undergoing transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) has long been disregarded. We aimed to assess the predictive value of RV to pulmonary artery coupling (RV/PAc), defined as tricuspid annular plane systolic excursion to systolic pulmonary artery pressure, on mortality in different flow types of AS after TAVI. METHODS: All patients undergoing TAVI for AS at our centre between 2018 and 2020 were assessed; 862 patients were analysed. The cohort was dichotomized using a ROC analysis (cut-off 0.512 mm/mmHg), into 429 patients with preserved and 433 patients with reduced RV/PAc. RESULTS: Reduced RV/PAc was associated with male sex and a higher rate of comorbidities. Short-term VARC-3 endpoints and NYHA classes at follow-up were comparable. Reduced RV/PAc was associated with higher 2-year all-cause mortality (35.0% [30.3-39.3%] vs. 15.4% [11.9-18.7%], hazard ratio 2.5 [1.9-3.4], p < 0.001). Cardiovascular mortality was almost tripled. Results were consistent after statistical adjustment and in a multivariate model. Sub-analyses of AS flow types revealed lower RV/PAc in classical and paradoxical low-flow low-gradient AS, with the majority having reduced RV/PAc (74% and 59%). RV/PAc retained its predictive value in these subgroups. CONCLUSIONS: RV dysfunction defined by low RV/PAc is a strong mortality predictor after TAVI independent of flow group. It should be incorporated in future TAVI risk assessment.

Residual tricuspid regurgitation after tricuspid transcatheter edge-to-edge repair: Insights into the EuroTR registry.

AIMS: Data on the prognostic impact of residual tricuspid regurgitation (TR) after tricuspid transcatheter edge-to-edge repair (T-TEER) are scarce. The aim of this analysis was to evaluate 2-year survival and symptomatic outcomes of patients in relation to residual TR after T-TEER. METHODS AND RESULTS: Using the large European Registry of Transcatheter Repair for Tricuspid Regurgitation (EuroTR registry) we investigated the impact of residual TR on 2-year all-cause mortality and New York Heart Association (NYHA) functional class at follow-up. The study further identified predictors for residual TR ≥3+ using a logistic regression model. The study included a total of 1286 T-TEER patients (mean age 78.0 ± 8.9 years, 53.6% female). TR was successfully reduced to ≤1+ in 42.4%, 2+ in 40.0% and 3+ in 14.9% of patients at discharge, while 2.8% remained with TR ≥4+ after the procedure. Residual TR ≥3+ was an independent multivariable predictor of 2-year all-cause mortality (hazard ratio 2.06, 95% confidence interval 1.30-3.26, p = 0.002). The prevalence of residual TR ≥3+ was four times higher in patients with higher baseline TR (vena contracta >11.1 mm) and more severe tricuspid valve tenting (tenting area >1.92 cm2). Of note, no survival difference was observed in patients with residual TR ≤1+ versus 2+ (76.2% vs. 73.1%, p = 0.461). The rate of NYHA functional class ≥III at follow-up was significantly higher in patients with residual TR ≥3+ (52.4% vs. 40.5%, p < 0.001). Of note, the degree of TR reduction significantly correlated with the extent of symptomatic improvement (p = 0.012). CONCLUSIONS: T-TEER effectively reduced TR severity in the majority of patients. While residual TR ≥3+ was associated with worse outcomes, no differences were observed for residual TR 1+ versus 2+. Symptomatic improvement correlated with the degree of TR reduction.

[COVID-19 in the intensive care unit]. / Intensivmedizinische Therapie von COVID-19.

The acute respiratory failure as well as ARDS (acute respiratory distress syndrome) have challenged clinicians since the initial description over 50 years ago. Various causes can lead to ARDS and therapeutic approaches for ARDS/ARF are limited to the support or replacement of organ functions and the prevention of therapy-induced consequences. In recent years, triggered by the SARS-CoV-2 pathogen, numerous cases of acute lung failure (C-ARDS) have emerged. The pathophysiological processes of classical ARDS and C-ARDS are essentially similar. In their final stages of inflammation, both lead to a disruption of the blood-air barrier. Treatment strategies for C-ARDS, like classical ARDS, focus on supporting or replacing organ functions and preventing consequential damage. This article summarizes the treatment strategies in the intensive care unit.

Peristromal niches protect lung cancers from targeted therapies through a combined effect of multiple molecular mediators.

Targeted therapies directed against oncogenic signaling addictions, such as inhibitors of ALK in ALK+ NSCLC often induce strong and durable clinical responses. However, they are not curative in metastatic cancers, as some tumor cells persist through therapy, eventually developing resistance. Therapy sensitivity can reflect not only cell-intrinsic mechanisms but also inputs from stromal microenvironment. Yet, the contribution of tumor stroma to therapeutic responses in vivo remains poorly defined. To address this gap of knowledge, we assessed the contribution of stroma-mediated resistance to therapeutic responses to the frontline ALK inhibitor alectinib in xenograft models of ALK+ NSCLC. We found that stroma-proximal tumor cells are partially protected against cytostatic effects of alectinib. This effect is observed not only in remission, but also during relapse, indicating the strong contribution of stroma-mediated resistance to both persistence and resistance. This therapy-protective effect of the stromal niche reflects a combined action of multiple mechanisms, including growth factors and extracellular matrix components. Consequently, despite improving alectinib responses, suppression of any individual resistance mechanism was insufficient to fully overcome the protective effect of stroma. Focusing on shared collateral sensitivity of persisters offered a superior therapeutic benefit, especially when using an antibody-drug conjugate with bystander effect to limit therapeutic escape. These findings indicate that stroma-mediated resistance might be the major contributor to both residual and progressing disease and highlight the limitation of focusing on suppressing a single resistance mechanism at a time.

External Validation of the PREdiction of Survival on Extracorporeal Membrane Oxygenation Therapy (PRESET) Score: A Single Center Cohort Experience.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition affecting >10% of intensive care unit (ICU) patients worldwide with a mortality of up to 59% depending on severity. Extracorporeal membrane oxygenation (ECMO) is a potentially life-saving procedure in severe ARDS but is technically and financially challenging. In recent years, various scoring systems have been proposed to select patients most likely to benefit from ECMO, with the PREdiction of Survival on ECMO Therapy (PRESET) score being one of the most used. We collected data from 283 patients with ARDS of various etiology who underwent veno-venous (V-V) ECMO therapy at a German tertiary care ICU from January 2012 to December 2022. Median age in the cohort was 56 years, and 64.31% were males. The in-hospital mortality rate was 50.88% (n = 144). The median (25%; 75% quartile) severity scores were 38 (31; 49) for Simplified Acute Physiology Score (SAPS) II, 12 (10; 13) for Sequential Organ Failure Assessment (SOFA) and 7 (5; 8) for PRESET. Simplified Acute Physiology Score-II displayed the best prognostic value (area under the receiver operating characteristic [AUROC]: 0.665 [confidence interval (CI): 0.574-0.756; p = 0.046]). Prediction performance was weak in all analyzed scores despite good calibration. Simplified Acute Physiology Score-II had the best discrimination after adjustment of our original cohort. The use of scores explored in this study for patient selection for eligibility for V-V ECMO is not recommendable.

Copper Catalyzed Borylation of Alkynes: An Experimental Mechanistic Study.

The copper catalyzed hydroboration of alkynes with B2pin2 was studied by in detail studies of individual relevant steps along the catalytic pathway. A number of reaction steps were retraced by in situ NMR spectroscopy as well as central intermediates and side-products were isolated and comprehensively characterized. A copper boryl complex is central to the catalytic process by inserting the terminal alkyne substrate into the B-Cu bond. The selectivity of this step - depending on the NHC auxiliary ligand - determines the α/ß selectivity observed in the product. The latter complex is protonated by the auxiliary alcohol reagent resulting in hydroboration product formation and formation of a Cu alkoxido complex. Reaction of the latter with B2pin2 results in the regeneration of the central copper boryl complex. This alcoholysis step depends on the acidity of the alcohol, in particular on the relative acidity of the alcohol vs. the alkyne substrate. A number of side reactions leading to the hydrogenation product of the alkyne substrate and a bis hydroborated product were identified and studied in some detail. It is concluded that the performance of a particular catalytic system depends crucially on the relative acidities of the reagents and generalizations may be difficult.

CD20-bispecific antibodies improve response to CD19-CAR T-cells in lymphoma in-vitro and CLL in-vivo models.

Anti-CD19 chimeric antigen receptor T-cells (CD19-CAR) represent an effective treatment for relapsed/refractory B-cell malignancies but incomplete responses often result in early disease progression. We here assessed potential benefits of co-administering CD20-targeting bispecific antibodies (CD20-BsAb) with CD19-CAR, aiming to enhance immunotherapeutic efficacy. Addition of CD20-BsAb to co-cultures of CD19-CAR and primary samples of B-cell malignancies, comprising malignant B- and endogenous T-cells, significantly improved killing of malignant cells alongside enhanced expansion of both endogenous T-cells and CD19-CAR. CD20-BsAb induced an increase in proliferation and activation of endogenous T-cells and CD19-CAR. In an immunocompetent mouse model of CLL, relapse after initial treatment response frequently occurred after CD19-CAR monotherapy. Combination with injections of CD20-BsAb significantly enhanced treatment response and resulted in improved eradication of malignant cells. Higher efficacy was accompanied by improved T-cell expansion upon CD20-BsAb administration and resulted in longer survival, with 80% of mice being cured with no detectable malignant cell population within eight weeks of therapy initiation. Collectively, our in-vitro and in-vivo data demonstrate enhanced therapeutic efficacy of CD19-CAR when combined with CD20-BsAb in B-cell malignancies. Activation and proliferation of both infused CAR T-cells as well as endogenous T-cells may contribute to improved disease control.

Paradox of disproportionate atrial functional mitral regurgitation and survival after transcatheter edge-to-edge repair.

AIMS: This study aims to assess the applicability of the mitral regurgitation (MR) proportionality concept in patients with atrial functional mitral regurgitation (aFMR) treated with transcatheter edge-to-edge repair (M-TEER). We hypothesized that patients with disproportionate MR (higher MR relative to left ventricular size) would exhibit different outcomes compared to those with proportionate MR, despite undergoing M-TEER. METHODS AND RESULTS: We retrospectively analysed 98 patients with aFMR from the EuroSMR registry who underwent M-TEER between 2008 and 2019. Patients met criteria for aFMR (normal indexed left ventricular end-diastolic volume [LVEDV], preserved left ventricular ejection fraction [LVEF] ≥ 50% without regional wall motion abnormalities, and structurally normal mitral valves). We excluded patients with missing effective regurgitant orifice area (EROA) or LVEDV data. The primary endpoint was 2-year mortality, with an EROA/LVEDV ratio employed to differentiate disproportionate from proportionate MR. Procedural success and baseline characteristics were analysed, and multivariate Cox proportional hazards models were used to identify mortality predictors. The mean patient age was 79 ± 7.3 years, with 68.8% female, and 79% had a history of atrial fibrillation. The mean EROA was 0.27 ± 0.14 cm2, and LVEDV was 95.6 ± 33.7 mL. Disproportionate MR was identified with an EROA/LVEDV ratio >0.339 cm2/100 mL. While procedural success was similar in both groups, disproportionate MR was associated with a numerically higher estimate of systolic pulmonary artery pressures (sPAP) and rates of NYHA ≥III and TR ≥ 3+. Disproportionate MR had a significant association with increased 2-year mortality (P < 0.001). The EROA/LVEDV ratio and tricuspid annular plane systolic excursion (TAPSE) were independent predictors of 2-year mortality (EROA/LVEDV: HR: 1.35, P = 0.010; TAPSE: HR: 0.85, P = 0.020). CONCLUSIONS: This analysis introduces the MR proportionality concept in aFMR patients and its potential prognostic value. Paradoxically, disproportionate MR in aFMR was linked to a 1.35-fold increase in 2-year mortality post-M-TEER, emphasizing the importance of accurate preprocedural FMR characterization. Our findings in patients with disproportionate MR indicate that a high degree of aFMR with high regurgitant volumes may lead to aggravated symptoms, which is a known contributor to increased mortality following M-TEER. These results underline the need for further research into the pathophysiology of aFMR to inform potential preventative and therapeutic strategies, ensuring optimal patient outcomes.

SARS-CoV-2 Transmission during High-Altitude Field Studies.

Grimm, Mirjam, Lucie Ziegler, Annina Seglias, Maamed Mademilov, Kamila Magdieva, Gulzada Mirzalieva, Aijan Taalaibekova, Simone Suter, Simon R. Schneider, Fiona Zoller, Vera Bissig, Lukas Reinhard, Meret Bauer, Julian Müller, Tanja L. Ulrich, Arcangelo F. Carta, Patrick R. Bader, Konstantinos Bitos, Aurelia E. Reiser, Benoit Champigneulle, Damira Ashyralieva, Philipp M. Scheiwiller, Silvia Ulrich, Talant M. Sooronbaev, Michael Furian, and Konrad E. Bloch. SARS-CoV-2 Transmission during High-Altitude Field Studies. High Alt Med Biol. 00:00-00, 2024. Background: Throughout the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, virus transmission during clinical research was of concern. Therefore, during high-altitude field studies performed in 2021, we took specific COVID-19 precautions and investigated the occurrence of SARS-CoV-2 infection. Methods: From May to September 2021, we performed studies in patients with chronic obstructive pulmonary disease (COPD) and in healthy school-age children in Kyrgyzstan in high-altitude facilities at 3,100 m and 3,250 m and at 760 m. The various implemented COVID-19 safety measures included systematic SARS-CoV-2 rapid antigen testing (RAT). Main outcomes were SARS-CoV-2-RAT-positive rate among participants and staff at initial presentation (prevalence) and SARS-CoV-2-RAT-positive conversion during and within 10 days after studies (incidence). Results: Among 338 participants and staff, SARS-CoV-2-RAT-positive prevalence was 15 (4.4%). During mean ± SD duration of individual study participation of 3.1 ± 1.0 day and within 10 days, RAT-positive conversion occurred in 1/237(0.4%) participants. Among staff working in studies for 31.5 ± 29.3 days, SARS-CoV-2-RAT-positive conversion was 11/101(10.9%). In all 338 individuals involved in the studies over the course of 15.6 weeks, the median SARS-CoV-2-RAT-positive incidence was 0.00%/week (quartiles 0.00; 0.64). Over the same period, the median background incidence among the total Kyrgyz population of 6,636 million was 0.06%/week (0.03; 0.11), p = 0.013 (Wilcoxon rank sum test). Conclusions: Taking precautions by implementing specific safety measures, SARS-CoV-2 transmission during clinical studies was very rare, and the SARS-CoV-2 incidence among participants and staff was lower than that in the general population during the same period. The results are reassuring and may help in decision-making on the conduct of clinical research in similar settings.

Standardizing Substrate Selection: A Strategy toward Unbiased Evaluation of Reaction Generality.

With over 10,000 new reaction protocols arising every year, only a handful of these procedures transition from academia to application. A major reason for this gap stems from the lack of comprehensive knowledge about a reaction's scope, i.e., to which substrates the protocol can or cannot be applied. Even though chemists invest substantial effort to assess the scope of new protocols, the resulting scope tables involve significant biases, reducing their expressiveness. Herein we report a standardized substrate selection strategy designed to mitigate these biases and evaluate the applicability, as well as the limits, of any chemical reaction. Unsupervised learning is utilized to map the chemical space of industrially relevant molecules. Subsequently, potential substrate candidates are projected onto this universal map, enabling the selection of a structurally diverse set of substrates with optimal relevance and coverage. By testing our methodology on different chemical reactions, we were able to demonstrate its effectiveness in finding general reactivity trends by using a few highly representative examples. The developed methodology empowers chemists to showcase the unbiased applicability of novel methodologies, facilitating their practical applications. We hope that this work will trigger interdisciplinary discussions about biases in synthetic chemistry, leading to improved data quality.

T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia.

The T-box transcription factor T-bet is known as a master regulator of T-cell response but its role in malignant B cells is not sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with genetic knockout of TBX21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity induced by inflammatory signals provided by the microenvironment, triggered T-bet expression which impacted on promoter proximal and distal chromatin co-accessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling, and a negative control of proliferation by T-bet. In line, we showed that T-bet represses cell cycling and is associated with longer overall survival of CLL patients. Our study uncovers a novel tumor suppressive role of T-bet in malignant B cells via its regulation of inflammatory processes and cell cycling which has implications for stratification and therapy of CLL patients. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in inflammatory signaling pathways in CLL.