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Abstract Archaea are vital components of the human microbiome, yet their study within the gastrointestinal tract (GIT) is limited by the scarcity of cultured representatives. Our study presents a method for the targeted enrichment and isolation of methanogenic archaea from human fecal samples. The procedure combines methane breath testing, in silico metabolic modeling, media optimization, FACS, dilution series, and genomic sequencing through Nanopore technology. Additional analyzes include the co-cultured bacteriome, comparative genomics of archaeal genomes, functional comparisons, and structure-based protein function prediction of unknown differential traits. Successful establishment of stable archaeal cultures from 14 out of 16 fecal samples yielded nine previously uncultivated strains, eight of which are absent from a recent archaeome genome catalog. Comparative genomic and functional assessments of Methanobrevibacter smithii and Candidatus Methanobrevibacter intestini strains from individual donors revealed features potentially associated with gastrointestinal diseases. Our work broadens available archaeal representatives for GIT studies, and offers insights into Candidatus Methanobrevibacter intestini genomes’ adaptability in critical microbiome contexts.

Abstract In the last few decades, the field of ancient DNA has taken a new direction towards using sedimentary ancient DNA (sedaDNA) for studying human and mammalian population dynamics as well as past ecosystems. However, the screening of numerous sediment samples from archaeological sites remains a time-consuming and costly endeavor, particularly when targeting hominin DNA. Here, we present a novel high-throughput method that facilitates the fast and efficient analysis of sediment samples by applying a pooled testing approach. This method combines multiple extracts, enabling early parallelization of laboratory procedures and effective aDNA screening. Pooled samples with detectable aDNA signals undergo detailed analysis, while empty pools are discarded. We have successfully applied our method to multiple sediment samples from Middle and Upper Paleolithic sites in Europe, Asia, and Africa. Notably, our results reveal that an aDNA signal remains discernible even when pooled with four negative samples. We also demonstrate that the DNA yield of double-stranded libraries increases significantly when reducing the extract input, potentially mitigating the effects of inhibition. By embracing this innovative approach, researchers can analyze large numbers of sediment samples for aDNA preservation, achieving significant cost reductions of up to 70% and reducing hands-on laboratory time to one-fifth.

Abstract Purpose Blood-flow restriction (BFR) endurance training may increase endurance performance and muscle strength similar to traditional endurance training while requiring a lower training intensity. We aimed to compare acute cardiorespiratory responses to low-intensity interval exercise under BFR with moderate-intensity traditional interval exercise (TRA). Methods We conducted a randomized crossover study. The protocol involved three cycling intervals interspersed with 1 min resting periods. With a 48-h washout period, individuals performed the protocol twice in random order: once as BFR-50 (i.e., 50% incremental peak power output [IPPO] and 50% limb occlusion pressure [LOP]) and once as TRA-65 (65% IPPO without occlusion). TRA-65 intervals lasted 2 min, and time-matched BFR-50 lasted 2 min and 18 s. Respiratory parameters were collected by breath-by-breath analysis. The ratings of perceived breathing and leg exertion (RPE, 0 to 10) were assessed. Linear mixed models were used for analysis. Results Out of the 28 participants initially enrolled in the study, 24 healthy individuals (18 males and 6 females) completed both measurements. Compared with TRA-65, BFR-50 elicited lower minute ventilation (VE, primary outcome) (-3.1 l/min [-4.4 to -1.7]), oxygen consumption (-0.22 l/min [-0.28 to -0.16]), carbon dioxide production (-0.25 l/min [-0.29 to -0.20]) and RPE breathing (-0.9 [-1.2 to -0.6]). RPE leg was significantly greater in the BFR-50 group (1.3 [1.0 to 1.7]). Conclusion BFR endurance exercise at 50% IPPO and 50% LOP resulted in lower cardiorespiratory work and perceived breathing effort compared to TRA at 65% IPPO. BFR-50 could be an attractive alternative for TRA-65, eliciting less respiratory work and perceived breathing effort while augmenting perceived leg muscle effort. Trial registration NCT05163600; December 20, 2021.

Studying the role of doctors in the institution of a military-virile norm provides a better understanding of the role of medicine in the relationships of domination, subordination and marginalisation between different masculinities in France during the Napoleonic Empire. One of the aims of Napoleon’s regime was to inculcate military virility, seen as a resource for organising the reproduction of a hierarchical, militaristic society. The army’s medical staff played a specific role in this process. Their interventions helped to save wounded soldiers and prevent certain simulations, while at the same time maintaining the formation of masculinities subordinated to a valid wounded masculinity. Soldiers who had been treated and were severely disabled were still assigned the role of welfare recipients, while wounded soldiers who were still able-bodied enjoyed promotions and decorations. In both cases, medical expertise is used to fuel these promotion and pension systems by scientifically objectifying the traces of these men’s sacrifice.

Abstract Addressing the global disparity in cancer care necessitates the development of rapid and affordable nucleic acid (NA) testing technologies. This need is particularly critical for cervical cancer, where molecular detection of human papillomavirus (HPV) has emerged as an accurate screening method. However, implementing this transition in low- and middle-income countries has been challenging due to the high costs and centralized facilities required for current NA tests. Here, we present CreDiT (CRISPR Enhanced Digital Testing) for on-site NA detection. The CreDiT platform integrates i) a one-pot CRISPR strategy that simultaneously amplifies both target NAs and analytical signals and ii) a robust fluorescent detection based on digital communication (encoding/decoding) technology. These features enable a rapid assay (

Abstract Background Ethanol shock significantly affects expression of over 1200 genes in Streptomyces venezuelae NRRL B-65,442, including those involved in secondary metabolite biosynthesis and a cryptic gene pepX, which encodes a 19-amino acid peptide with an unknown function. Results To establish a possible correlation between the PepX peptide and secondary metabolism in S. venezuelae, its gene was deleted, followed by analyses of the transcriptome and secondary metabolome of the mutant. Although the secondary metabolome of the pepX mutant was not strongly affected, pepX deletion, similar to ethanol shock, mostly resulted in downregulated expression of secondary metabolite biosynthesis gene clusters (BGCs). At the same time, there was a reverse correlation between the expression of certain extracytoplasmic function sigma factors (ECFs) and several BGCs. Individual deletions of three selected ECF-coding genes conserved in Streptomyces that were upregulated upon both pepX deletion and ethanol shock, had a profound positive effect on the expression of BGCs, which also correlated with the overproduction of specific secondary metabolites. Deletion of one such ECF-coding gene in a marine sponge-derived Streptomyces sp. also significantly altered the secondary metabolite profile, suggesting an important role of this ECF in the regulation of secondary metabolism. Conclusions These findings pave the way for the activation or upregulation of BGCs in Streptomyces bacteria harboring genes for ECFs homologous to those identified in this study, hereby assisting in the discovery of novel bioactive secondary metabolites.

Abstract Spontaneous symmetry breaking and emergent polar order are each of fundamental importance to a range of scientific disciplines, as well as generating rich phase behaviour in liquid crystals (LCs). Here, we show the union of these phenomena to lead to two previously undiscovered polar liquid states of matter. Both phases have a lamellar structure with an inherent polar ordering of their constituent molecules. The first of these phases is characterised by polar order and a local tilted structure; the tilt direction processes about a helix orthogonal to the layer normal, the period of which is such that we observe selective reflection of light. The second new phase type is anti-ferroelectric, with the constituent molecules aligning orthogonally to the layer normal. This has led us to term the phases the $${{{{{\rm{Sm}}}}}}{{{{{{\rm{C}}}}}}}_{{{{{{\rm{P}}}}}}}^{{{{{{\rm{H}}}}}}}$$ Sm C P H and SmAAF phases, respectively. Further to this, we obtain room temperature ferroelectric nematic (NF) and $${{{{{\rm{Sm}}}}}}{{{{{{\rm{C}}}}}}}_{{{{{{\rm{P}}}}}}}^{{{{{{\rm{H}}}}}}}$$ Sm C P H phases via binary mixture formulation of the novel materials described here with a standard NF compound (DIO), with the resultant materials having melting points (and/or glass transitions) which are significantly below ambient temperature. The new soft matter phase types discovered herein can be considered as electrical analogues of topological structures of magnetic spins in hard matter.

Abstract The distance conjecture diagnoses viable low-energy effective realisations of consistent theories of quantum gravity by examining their breakdown at infinite distance in their parameter space. At the same time, infinite distance points in parameter space are naturally intertwined with string dualities. We explore the implications of the distance conjecture when T-duality is applied to curved compact manifolds and in presence of (non-)geometric fluxes. We provide evidence of how divergent potentials signal pathological infinite distance points in the scalar field space where towers of light states cannot be sustained by the curved background. This leads us to suggest an extension to the current statement of the Swampland distance conjecture in curved spaces or in presence of non-trivial fluxes supporting the background.

Abstract Background A significant proportion of the global population has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at some point since the onset of the pandemic. Although most individuals who develop coronavirus disease 2019 (COVID-19) recover without complications, about 6% have persistent symptoms, referred to as post-COVID-19 condition (PCC). Intervention studies investigating treatments that potentially alleviate PCC-related symptoms and thus aim to mitigate the global public health burden and healthcare costs linked to PCC are desperately needed. The PYCNOVID trial investigates the effects of Pycnogenol®, a French maritime pine bark extract with anti-inflammatory and antioxidative properties, versus placebo on patient-reported health status in people with PCC. Methods This is a single-center, placebo-controlled, quadruple blind, randomized trial. We aim to randomly assign 150 individuals with PCC (1:1 ratio) to receive either 200 mg Pycnogenol® or placebo daily for 12 weeks. Randomization is stratified for duration of PCC symptoms (≤ 6 months versus > 6 months) and presence of symptomatic chronic disease(s). The primary endpoint is perceived health status at 12 weeks (EuroQol—Visual Analogue Scale) adjusted for baseline values and stratification factors. Secondary endpoints include change in self-reported PCC symptoms, health-related quality of life, symptoms of depression and anxiety, cognitive function, functional exercise capacity, physical activity measured with accelerometry, and blood biomarkers for endothelial health, inflammation, coagulation, platelet function, and oxidative stress. Investigators, study participants, outcome assessors, and data analysts are blinded regarding the intervention assignment. Individuals with PCC were involved in the design of this study. Discussion This is the first trial to investigate the effects of Pycnogenol® versus placebo on patient-reported health status in people with PCC. Should the trial proof clinical effectiveness, Pycnogenol® may serve as a therapeutic approach to mitigate symptoms associated with PCC. Trial registration The study is registered at ClinicalTrials.gov. :NCT05890534, June 6, 2023.

Resting is an integral component of animal behavior, contributing to one’s fitness through careful optimization strategies. In large herbivores, resting periods are driven by availability of food, presence of predators, and thermoregulation. A combination of these drivers leads to high variability in resting behaviors and their time allocation throughout the day. However, these drivers are rarely evaluated in the wild. Megaherbivores, including giraffe (Giraffa spp.), adopt social resting strategies, which enable them to optimize the cost–benefit ratio, with rest and vigilance varying with group size and composition. We investigated resting behavior of the West African giraffe (G. camelopardalis peralta) living in a human-populated landscape dominated by agropastoralism activities in Niger. Through direct observation, we evaluated the influence of group size and composition, and presence of livestock and humans on giraffe resting behavior. We concluded that giraffe increased their resting time with shorter distance to other giraffe and livestock. Livestock did not negatively impact giraffe behavior; rather, they provided a kind of “safe environment”. Human presence resulted in only minor changes in vigilance of giraffe and did not significantly affect their resting time. Our findings highlight a positive instance of human–giraffe coexistence in a human-dominated landscape, attributed to the long-term benefits of conservation efforts.

Objective We aimed to assess health-related quality of life (HRQOL) in a cohort of very preterm born children and adolescents (aged 5–16), and to compare it with their fullterm born siblings and the general population. We also explored correlates of HRQOL among the very preterm born.Design Cross-sectional survey.Patients Children born

Spt4 and Spt5 form the DRB sensitivity inducing factor (DSIF) complex that regulates transcription elongation at multiple steps including promotor-proximal pausing, processivity and termination. Although this implicated a general role in transcription, several studies pointed to smaller sets of target genes and indicated a more specific requirement in certain cellular contexts. To unravel common or distinct functions of Spt4 and Spt5 in vivo, we generated knock-out alleles for both genes in Drosophila melanogaster. Using the development of the mushroom bodies as a model, we provided evidence for two common functions of Spt4 and Spt5 during mushroom body development, namely control of cell proliferation of neural progenitor cells and remodeling of axonal projections of certain mushroom body neurons. This latter function is not due to a general requirement of Spt4 and Spt5 for axon pathfinding of mushroom body neurons, but due to distinct effects on the expression of genes controlling remodeling.

Abstract Background The Red Cross and Red Crescent Movement (RCRC) utilizes specialized Emergency Response Units (ERUs) for international disaster response. However, data collection and reporting within ERUs have been time-consuming and paper-based. The Red Cross Red Crescent Health Information System (RCHIS) was developed to improve clinical documentation and reporting, ensuring accuracy and ease of use while increasing compliance with reporting standards. Case presentation RCHIS is an Electronic Medical Record (EMR) and Health Information System (HIS) designed for RCRC ERUs. It can be accessed on Android tablets or Windows laptops, both online and offline. The system securely stores data on Microsoft Azure cloud, with synchronization facilitated through a local ERU server. The functional architecture covers all clinical functions of ERU clinics and hospitals, incorporating user-friendly features. A pilot study was conducted with the Portuguese Red Cross (PRC) during a large-scale event. Thirteen super users were trained and subsequently trained the staff. During the four-day pilot, 77 user accounts were created, and 243 patient files were documented. Feedback indicated that RCHIS was easy to use, requiring minimal training time, and had sufficient training for full utilization. Real-time reporting facilitated coordination with the civil defense authority. Conclusions The development and pilot use of RCHIS demonstrated its feasibility and efficacy within RCRC ERUs. The system addressed the need for an EMR and HIS solution, enabling comprehensive clinical documentation and supporting administrative reporting functions. The pilot study validated the training of trainers’ approach and paved the way for further domestic use of RCHIS. RCHIS has the potential to improve patient safety, quality of care, and reporting efficiency within ERUs. Automated reporting reduces the burden on ERU leadership, while electronic compilation enhances record completeness and correctness. Ongoing feedback collection and feature development continue to enhance RCHIS’s functionality. Further trainings took place in 2023 and preparations for international deployments are under way. RCHIS represents a significant step toward improved emergency medical care and coordination within the RCRC and has implications for similar systems in other Emergency Medical Teams.

Background: Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin. Methods: Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors. Results: We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004). Conclusions: Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. Funding: LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). Clinical trial number: NCT04359654.

ObjectivesAlthough the Perceval sutureless aortic valve bioprosthesis presents a feasible alternative to conventional aortic valve prostheses, the extent of its applicability with respect to technical considerations for a real-world patient collective is still under debate.MethodsOne hundred patients received the Perceval prosthesis [males: 59; age: 72.5 (7.3–79) years] between December 2015 and February 2023 [EuroSCORE II: 2.8 (1.7–5.4)] for an aortic valve replacement (AVR), with additional concomitant procedures, for underlying severe aortic valve stenosis [n = 93 (93)], endocarditis [n = 5 (5)], and redo AVR [n = 7 (7)] including a prior surgical AVR [n = 4 (4)] and a failed transcatheter aortic valve implantation [n = 3 (3)]. Surgery was conducted primarily by median sternotomy [n = 71 (71)] and, alternatively, by the upper hemisternotomy approach [n = 29 (29)].ResultsOver a median follow-up time of 36.5 (16.5–53) months, eight patients (8%) underwent postoperative pacemaker implantation, with five (5%) due to high-grade atrioventricular block, while nine patients experienced a stroke (9%). The median values of maximum and mean gradients across all valve sizes were 22 (18–27.5) mmHg and 10 (13–18) mmHg, respectively. Two patients (2%) had moderate and one (1%) had severe paravalvular leakage, with the latter presenting the only case of underlying valve migration and induced redo AVR with valve explantation 2 days following initial surgery. Thirty-day mortality (and overall mortality) was 5% and 26%, respectively.ConclusionThe implantation of the Perceval bioprosthesis is feasible for a variety of indications, with excellent hemodynamic results and low complication rates in a real-world high-risk patient collective.

BackgroundBy March 2023, the COVID-19 illness had caused over 6.8 million deaths globally. Countries restricted disease spread through non-pharmaceutical interventions (NPIs; e.g. social distancing). More severe “lockdowns” were also required to manage disease spread. Although lockdowns effectively reduce virus transmission, they substantially disrupt economies and individual well-being. Fortunately, the availability of vaccines provides alternative approaches to manage disease spread. Yet, vaccination programs take several months to implement fully, require further time for individuals to develop immunity following inoculation, may not have complete coverage and/or may be imperfectly efficacious against the virus. Given these aspects of a vaccination programme, it is important to understand how NPIs (such as lockdowns) can be used in conjunction with vaccination to achieve public health goals.MethodsWe use mathematical methods to, investigate optimal approaches for vaccination under varying lockdown lengths and/or severities to prevent COVID-19-related deaths exceeding critical thresholds.ResultsWe find that increases in vaccination rate cause a disproportionate decrease in the length and severity lockdowns to keep mortality levels below a critical threshold. With vaccination, severe lockdowns can further reduce infections by up to 89%. Notably, we include simple demographics, modelling three groups: vulnerable, front-line workers, and non-vulnerable. We investigate the sequence of vaccination. One counter-intuitive finding is that even though the vulnerable group is high risk, demographically, this is a small group and critically, per person, vaccination therefore occurs more slowly. Hence vaccinating this group first achieves limited gains in overall disease control.DiscussionImportantly, we conclude that improved disease control may be best achieved by vaccinating the non-vulnerable group coupled with longer and/or more severe NPIs.

The observation of photosynthetic biofilms growing on the Fine Residue Deposit (FRD) kimberlite produced by the Venetia Diamond Mine, Limpopo, South Africa suggests that processed kimberlite supports bacterial growth. The presence of this biofilm may aid in the acceleration of weathering of this ultra-mafic host material – a process that can sequester CO2 via carbon mineralization. Laboratory and field trial experiments were undertaken to understand the microbe–mineral interactions occurring in these systems, and how these interactions impact geochemical cycling and carbonate precipitation. At laboratory scale it was discovered that using kimberlite as a growth supplement increased biomass production (up to 25-fold) and promoted microbiome diversity, while the inoculation of FRD systems aided in the aggregation, settling, and dewatering of kimberlitic slurries. Field trial studies combining photosynthetic biofilms (cultured in 3 × 1,000 L bioreactors) with FRD material were initiated to better understand microbially enhanced mineral carbonation across different depths, and under field environmental conditions. Over the 15-month experiment the microbial populations shifted with the kimberlitic environmental pressure, with the control and inoculated systems converging. The natural endogenous biosphere (control) and the inoculum accelerated carbonate precipitation across the entire 40 cm bioreactor depth, producing average 15-month carbonation rates of 0.57 wt.% and 1.17 wt.%, respectively. This corresponds to an annual CO2e mine offset of ~4.48% and ~ 9.2%, respectively. Millimetre-centimetre scale secondary carbonate that formed in the inoculated bioreactors was determined to be biogenic in nature (i.e., possessing microbial fossils) and took the form of radiating colloform precipitates with the addition of new, mineralized colonies. Surficial conditions resulted in the largest production of secondary carbonate, consistent with a ca. 12% mine site CO2e annual offset after a 15-month incubation period.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

ABSTRACT Sulfur-oxidizing bacteria (SOB) have developed distinct ecological strategies to obtain reduced sulfur compounds for growth. These range from specialists that can only use a limited range of reduced sulfur compounds to generalists that can use many different forms as electron donors. Forming intimate symbioses with animal hosts is another highly successful ecological strategy for SOB, as animals, through their behavior and physiology, can enable access to sulfur compounds. Symbioses have evolved multiple times in a range of animal hosts and from several lineages of SOB. They have successfully colonized a wide range of habitats, from seagrass beds to hydrothermal vents, with varying availability of symbiont energy sources. Our extensive analyses of sulfur transformation pathways in 234 genomes of symbiotic and free-living SOB revealed widespread conservation in metabolic pathways for sulfur oxidation in symbionts from different host species and environments, raising the question of how they have adapted to such a wide range of distinct habitats. We discovered a gene family expansion of soxY in these genomes, with up to five distinct copies per genome. Symbionts harboring only the “canonical” soxY were typically ecological “specialists” that are associated with specific host subfamilies or environments (e.g., hydrothermal vents, mangroves). Conversely, symbionts with multiple divergent soxY genes formed versatile associations across diverse hosts in various marine environments. We hypothesize that expansion and diversification of the soxY gene family could be one genomic mechanism supporting the metabolic flexibility of symbiotic SOB enabling them and their hosts to thrive in a range of different and dynamic environments.IMPORTANCESulfur metabolism is thought to be one of the most ancient mechanisms for energy generation in microorganisms. A diverse range of microorganisms today rely on sulfur oxidation for their metabolism. They can be free-living, or they can live in symbiosis with animal hosts, where they power entire ecosystems in the absence of light, such as in the deep sea. In the millions of years since they evolved, sulfur-oxidizing bacteria have adopted several highly successful strategies; some are ecological “specialists,” and some are “generalists,” but which genetic features underpin these ecological strategies are not well understood. We discovered a gene family that has become expanded in those species that also seem to be “generalists,” revealing that duplication, repurposing, and reshuffling existing genes can be a powerful mechanism driving ecological lifestyle shifts.

High temporal soil moisture at field scale resolution (10 m–100 m) is important for smart farming decisions. Although, medium and coarse resolution (1 km–50 km) soil moisture information is operationally available on a large scale, high resolution (field scale) datasets are not. This study propose a data assimilation approach to downscale medium resolution (1 km × 1 km) soil moisture information–of intense agriculturally cultivated areas–to field scale. For achieving high transferability of the proposed method, the used input data (Sentinel-1 VV backscatter, Sentinel-2 derived vegetation water content, literature values) can be provided systematically from global operational satellites. Microwave and optical data are used together as input data of a radiative transfer model to derive soil moisture information with high temporal and spatial resolution. The retrieval approach shows a mean ubRMSE for soil moisture estimates of all test fields (Munich-North-Isar test site, Bavaria, Germany) with 0.045 m3/m3 and 0.037 m3/m3 for 2017 and 2018. Furthermore, the retrieved soil moisture estimates cover a broad range of values from 0.05 m3/m3 to 0.4 m3/m3. In addition, the temporal evolution of the soil moisture patterns are in line with precipitation events. Moreover, the drying behavior is matched as well. The proposed method showed that for the test area, high resolution soil moisture time series can be provided by only using remote sensing derived input data. In this way, this study is another step towards providing high spatio-temporal soil moisture information for precision farming purposes.

Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.

Abstract Background Existing plasmid systems offer a fundamental foundation for gene expression in Cupriavidus necator; however, their applicability is constrained by the limitations of conjugation. Low segregational stabilities and plasmid copy numbers, particularly in the absence of selection pressure, pose challenges. Phytases, recognized for their widespread application as supplements in animal feed to enhance phosphate availability, present an intriguing prospect for heterologous production in C. necator. The establishment of stable, high-copy number plasmid that can be electroporated would support the utilization of C. necator for the production of single-cell protein from CO2. Results In this study, we introduce a novel class of expression plasmids specifically designed for electroporation. These plasmids contain partitioning systems to boost segregation stability, eliminating the need for selection pressure. As a proof of concept, we successfully produced Escherichia coli derived AppA phytase in C. necator H16 PHB− 4 using these improved plasmids. Expression was directed by seven distinct promoters, encompassing the constitutive j5 promoter, hydrogenase promoters, and those governing the Calvin-Benson-Bassham cycle. The phytase activities observed in recombinant C. necator H16 strains ranged from 2 to 50 U/mg of total protein, contingent upon the choice of promoter and the mode of cell cultivation - heterotrophic or autotrophic. Further, an upscaling experiment conducted in a 1 l fed-batch gas fermentation system resulted in the attainment of the theoretical biomass. Phytase activity reached levels of up to 22 U/ml. Conclusion The new expression system presented in this study offers a highly efficient platform for protein production and a wide array of synthetic biology applications. It incorporates robust promoters that exhibit either constitutive activity or can be selectively activated when cells transition from heterotrophic to autotrophic growth. This versatility makes it a powerful tool for tailored gene expression. Moreover, the potential to generate active phytases within C. necator H16 holds promising implications for the valorization of CO2 in the feed industry.

Abstract Study design Single-centre, two-parallel group, methodological randomised controlled trial to assess blinding feasibility. Background Trials of manual therapy interventions of the back face methodological challenges regarding blinding feasibility and success. We assessed the feasibility of blinding an active manual soft tissue mobilisation and control intervention of the back. We also assessed whether blinding is feasible among outcome assessors and explored factors influencing perceptions about intervention assignment. Methods On 7–8 November 2022, 24 participants were randomly allocated (1:1 ratio) to active or control manual interventions of the back. The active group (n = 11) received soft tissue mobilisation of the lumbar spine. The control group (n = 13) received light touch over the thoracic region with deep breathing exercises. The primary outcome was blinding of participants immediately after a one-time intervention session, as measured by the Bang blinding index (Bang BI). Bang BI ranges from –1 (complete opposite perceptions of intervention received) to 1 (complete correct perceptions), with 0 indicating ‘random guessing’—balanced ‘active’ and ‘control’ perceptions within an intervention arm. Secondary outcomes included blinding of outcome assessors and factors influencing perceptions about intervention assignment among both participants and outcome assessors, explored via thematic analysis. Results 24 participants were analysed following an intention-to-treat approach. 55% of participants in the active manual soft tissue mobilisation group correctly perceived their group assignment beyond chance immediately after intervention (Bang BI: 0.55 [95% confidence interval (CI), 0.25 to 0.84]), and 8% did so in the control group (0.08 [95% CI, −0.37 to 0.53]). Bang BIs in outcome assessors were 0.09 (−0.12 to 0.30) and −0.10 (−0.29 to 0.08) for active and control participants, respectively. Participants and outcome assessors reported varying factors related to their perceptions about intervention assignment. Conclusions Blinding of participants allocated to an active soft tissue mobilisation of the back was not feasible in this methodological trial, whereas blinding of participants allocated to the control intervention and outcome assessors was adequate. Findings are limited due to imprecision and suboptimal generalisability to clinical settings. Careful thinking and consideration of blinding in manual therapy trials is warranted and needed. Trial registration ClinicalTrials.gov: NCT05822947 (retrospectively registered)

Abstract Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia–reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer’s acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P

Abstract The mechanisms underlying Parkinson’s disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment, and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population showing signs of oxidative stress-induced damage and premature cellular senescence. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology.

Abstract Although patients with rheumatoid arthritis (RA) typically exhibit symmetrical joint involvement, some patients develop alternative disease patterns in response to treatment, suggesting that different molecular mechanism may underlie disease progression depending on joint location. Here, we identify joint-specific changes in RA synovium and synovial fibroblasts (SF) between knee and hand joints. We show that the long non-coding RNA HOTAIR, which is only expressed in knee SF, regulates more than 50% of this site-specific gene expression in SF. HOTAIR is downregulated after stimulation with pro-inflammatory cytokines and is expressed at lower levels in knee samples from patients with RA, compared with osteoarthritis. Knockdown of HOTAIR in knee SF increases PI-Akt signalling and IL-6 production, but reduces Wnt signalling. Silencing HOTAIR inhibits the migratory function of SF, decreases SF-mediated osteoclastogenesis, and increases the recruitment of B cells by SF. We propose that HOTAIR is an important epigenetic factor in joint-specific gene expression in RA.

Buildings with floor heating or thermally activated building structures offer significant potential for shifting the thermal load and thus reduce peak demand for heating or cooling. This potential can be realised with the help of model predictive control (MPC) methods, provided that sufficiently descriptive mathematical models of the thermal characteristics of the individual thermal zones exist. Creating these by hand is infeasible for larger numbers of zones; instead, they must be identified automatically based on measurement data. In this paper an approach is presented that allows automatically identifying thermal models usable in MPC. The results show that the identified zone models are sufficiently accurate for the use in an MPC, with a mean average error below $1.5{\rm \; K}$ for the prediction of the zone temperatures. The identified zone models are then used in a distributed optimisation scheme that coordinates the individual zones and buildings of a city quarter to best support an energy hub by flattening the overall load profile. In a preliminary simulation study carried out for buildings with floor heating, the operating costs for heating in a winter month were reduced by approximately 9%. Therefore, it can be concluded that the proposed approach has a clear economic benefit.

Background The heart can metabolize the microbiota‐derived short‐chain fatty acid butyrate. Butyrate may have beneficial effects in heart failure, but the underlying mechanisms are unknown. We tested the hypothesis that butyrate elevates cardiac output by mechanisms involving direct stimulation of cardiac contractility and vasorelaxation in rats. Methods and Results We examined the effects of butyrate on (1) in vivo hemodynamics using parallel echocardiographic and invasive blood pressure measurements, (2) isolated perfused hearts in Langendorff systems under physiological conditions and after ischemia and reperfusion, and (3) isolated coronary arteries mounted in isometric wire myographs. We tested Na‐butyrate added to injection solutions or physiological buffers and compared its effects with equimolar doses of NaCl. Butyrate at plasma concentrations of 0.56 mM increased cardiac output by 48.8±14.9%, stroke volume by 38.5±12.1%, and left ventricular ejection fraction by 39.6±6.2%, and lowered systemic vascular resistance by 33.5±6.4% without affecting blood pressure or heart rate in vivo. In the range between 0.1 and 5 mM, butyrate increased left ventricular systolic pressure by up to 23.7±3.4% in isolated perfused hearts and by 9.4±2.9% following ischemia and reperfusion, while reducing myocardial infarct size by 81.7±16.9%. Butyrate relaxed isolated coronary septal arteries concentration dependently with an EC50=0.57 mM (95% CI, 0.23–1.44). Conclusions We conclude that butyrate elevates cardiac output through mechanisms involving increased cardiac contractility and vasorelaxation. This effect of butyrate was not associated with adverse myocardial injury in damaged hearts exposed to ischemia and reperfusion.

Summary: Next-generation vaccines may be delivered via the skin and mucosa. The stratified squamous epithelium (SSE) represents the outermost layer of the skin (epidermis) and type II mucosa (epithelium). Langerhans cells (LCs) have been considered the sole antigen-presenting cells (APCs) to inhabit the SSE; however, it is now clear that dendritic cells (DCs) are also present. Importantly, there are functional differences in how LCs and DCs take up and process pathogens as well as their ability to activate and polarize T cells, though whether DCs participate in neuroimmune interactions like LCs is yet to be elucidated. A correct definition and functional characterization of APCs in the skin and anogenital tissues are of utmost importance for the design of better vaccines and blocking pathogen transmission. Here, we provide a historical perspective on the evolution of our understanding of the APCs that inhabit the SSE, including a detailed review of the most recent literature.

In diesem Artikel werden kleine Unterrichtsprojekte vorgestellt, anhand derer man sich dem Thema Reinforcement Learning – einem Teilbereich des Machine Learning, wie auch überwachtes und überwachtes Lernen – in mehreren Schritten in der Sekundarstufe II nähern kann. Jeder Schritt stößt am Ende auf Grenzen, so dass sich jeweils die nächste Erweiterung anbietet. Am Anfang steht das manuelle Anlegen einer einfachen handschriftlichen Tabelle über entscheidende Züge in einem Spiel. Weil das nur bei einfachen Spielen geht, ist der nächste Schritt das Anlegen und Anpassen einer Q-Tabelle mit kontinuierlicher Evaluation sämtlicher Züge. Im dritten Schritt wird die für manche Fälle nicht mehr ausreichende Q-Tabelle durch ein Neuronales Netz ersetzt.

Collecting data and working with classified information in restricted military settings can present significant research challenges. Academic ideals of transparency and openness clash with the military’s need for secrecy and closedness. This article engages with existing literature on security requirements and research ethics in discussing practical challenges researchers face in military research. Even though military security requirements and principles of research ethics are often perceived as opposites, they also share characteristics: both realms are context-driven, non-objective, and require professional judgment to assess. Through a four-part analysis corresponding to different steps in a research process, the authors develop a practice-oriented guide for researchers accessing and working with classified information in discussing mundane examples of how “insiders” with “privileged access” navigate between ethical research principles and security issues. The article also incites a broader debate on research governance, (self-)imposed restraints and the conditions for critical inquiry in the military domain.

Summary: During aging, blood cell production becomes dominated by a limited number of variant hematopoietic stem cell (HSC) clones. Differentiated progeny of variant HSCs are thought to mediate the detrimental effects of such clonal hematopoiesis on organismal health, but the mechanisms are poorly understood. While somatic mutations in DNA methyltransferase 3A (DNMT3A) frequently drive clonal dominance, the aging milieu also likely contributes. Here, we examined in mice the interaction between high-fat diet (HFD) and reduced DNMT3A in hematopoietic cells; strikingly, this combination led to weight gain. HFD amplified pro-inflammatory pathways and upregulated inflammation-associated genes in mutant cells along a pro-myeloid trajectory. Aberrant DNA methylation during myeloid differentiation and in response to HFD led to pro-inflammatory activation and maintenance of stemness genes. These findings suggest that reduced DNMT3A in hematopoietic cells contributes to weight gain, inflammation, and metabolic dysfunction, highlighting a role for DNMT3A loss in the development of metabolic disorders.

Abstract Understanding the development of humoral immune responses of children and adolescents to SARS-CoV-2 is essential for designing effective public health measures. Here we examine the changes of humoral immune response in school-aged children and adolescents during the COVID-19 pandemic (June 2020 to July 2022), with a specific interest in the Omicron variant (beginning of 2022). In our study “Ciao Corona”, we assess in each of the five testing rounds between 1874 and 2500 children and adolescents from 55 schools in the canton of Zurich with a particular focus on a longitudinal cohort (n=751). By July 2022, 96.9% (95% credible interval 95.3–98.1%) of children and adolescents have SARS-CoV-2 anti-spike IgG (S-IgG) antibodies. Those with hybrid immunity or vaccination have higher S-IgG titres and stronger neutralising responses against Wildtype, Delta and Omicron BA.1 variants compared to those infected but unvaccinated. S-IgG persist over 18 months in 93% of children and adolescents. During the study period one adolescent was hospitalised for less than 24 hours possibly related to an acute SARS-CoV-2 infection. These findings show that the Omicron wave and the rollout of vaccines boosted S-IgG titres and neutralising capacity. Trial registration number: NCT04448717. https://clinicaltrials.gov/ct2/show/NCT04448717 .

Melioidosis, caused by the environmental gram-negative bacterium Burkholderia pseudomallei, usually develops in adults with predisposing conditions and in Australia more commonly occurs during the monsoonal wet season. We report an outbreak of 7 cases of melioidosis in immunocompetent children in Australia. All the children had participated in a single-day sporting event during the dry season in a tropical region of Australia, and all had limited cutaneous disease. All case-patients had an adverse reaction to oral trimethoprim/sulfamethoxazole treatment, necessitating its discontinuation. We describe the clinical features, environmental sampling, genomic epidemiologic investigation, and public health response to the outbreak. Management of this outbreak shows the potential benefits of making melioidosis a notifiable disease. The approach used could also be used as a framework for similar outbreaks in the future.

Computational models of homologous protein groups are essential in sequence bioinformatics. Due to the diversity and rapid evolution of viruses, the grouping of protein sequences from virus genomes is particularly challenging. The low sequence similarities of homologous genes in viruses require specific approaches for sequence- and structure-based clustering. Furthermore, the annotation of virus genomes in public databases is not as consistent and up to date as for many cellular genomes. To tackle these problems, we have developed VOGDB, which is a database of virus orthologous groups. VOGDB is a multi-layer database that progressively groups viral genes into groups connected by increasingly remote similarity. The first layer is based on pair-wise sequence similarities, the second layer is based on the sequence profile alignments, and the third layer uses predicted protein structures to find the most remote similarity. VOGDB groups allow for more sensitive homology searches of novel genes and increase the chance of predicting annotations or inferring phylogeny. VOGD B uses all virus genomes from RefSeq and partially reannotates them. VOGDB is updated with every RefSeq release. The unique feature of VOGDB is the inclusion of both prokaryotic and eukaryotic viruses in the same clustering process, which makes it possible to explore old evolutionary relationships of the two groups. VOGDB is freely available at vogdb.org under the CC BY 4.0 license.

Auxetics are materials displaying a negative Poisson’s ratio, i.e., getting thicker in one or both transverse axes when subject to strain. In 2018, liquid crystal elastomers (LCEs) displaying auxetic behaviour, achieved via a biaxial reorientation, were first reported. Studies have since focused on determining the physics underpinning the auxetic response, with investigations into structure–property relationships within these systems so far overlooked. Herein, we report the first structure–property relationships in auxetic LCEs, examining the effect of changes to the length of the spacer chain. We demonstrate that for LCEs with between six and four carbons in the spacer, an auxetic response is observed, with the threshold strain required to achieve this response varying from 56% (six carbon spacers) to 81% (four carbon spacers). We also demonstrate that Poisson’s ratios as low as −1.3 can be achieved. Further, we report that the LCEs display smectic phases with spacers of seven or more carbons; the resulting internal constraints cause low strains at failure, preventing an auxetic response. We also investigate the dependence of the auxetic threshold on the dynamics of the samples, finding that when accounting for the glass transition temperature of the LCEs, the auxetic thresholds converge around 56%, regardless of spacer length.

Abstract Introduction One of the most helpful aspects of intracardiac echocardiography (ICE) implementation in electrophysiological studies (EPS) is the real-time visualisation of catheters and cardiac structures. In this prospective study, we investigated ICE-guided zero-fluoroscopy catheter navigation during radiofrequency (RF) ablation of the cavotricuspid isthmus (CTI) in patients with typical atrial flutter (AFL). Methods and results Thirty consecutive patients (mean age 72.9 ± 11.4 years, 23 male) with ongoing (n = 23) or recent CTI-dependent AFL underwent an EPS, solely utilizing ICE for catheter navigation. Zero-fluoroscopy EPS could be successfully accomplished in all patients. Mean EPS duration was 41.4 ± 19.9 min, and mean ablation procedure duration was 20.8 ± 17.1 min. RF ablation was applied for 6.0 ± 3.1 min (50W, irrigated RF ablation). Echocardiographic parameters, such as CTI length, prominence of the Eustachian ridge (ER), and depth of the CTI pouch on the ablation plane, were assessed to analyse their correlation with EPS- or ablation procedure duration. The CTI pouch was shallower in patients with an ablation procedure duration above the median (4.8 ± 1.1 mm vs. 6.4 ± 0.9 mm, p = 0.04), suggesting a more lateral ablation plane in these patients, where the CTI musculature is stronger. CTI length or ER prominence above the respective median did not correlate with longer EPS duration. Conclusions Zero-fluoroscopy CTI ablation guided solely by intracardiac echocardiography in patients with CTI-dependent AFL is feasible and safe. ICE visualisation may help to localise the optimal ablation plane, detect and correct poor tissue contact of the catheter tip, and recognise early potential complications during the ablation procedure. Graphical Abstract

Abstract As the SARS-CoV-2 pandemic progressed, distinct variants emerged and dominated in England. These variants, Wildtype, Alpha, Delta, and Omicron were characterized by variations in transmissibility and severity. We used a robust mathematical model and Bayesian inference framework to analyse epidemiological surveillance data from England. We quantified the impact of non-pharmaceutical interventions (NPIs), therapeutics, and vaccination on virus transmission and severity. Each successive variant had a higher intrinsic transmissibility. Omicron (BA.1) had the highest basic reproduction number at 8.4 (95% credible interval (CrI) 7.8-9.1). Varying levels of NPIs were crucial in controlling virus transmission until population immunity accumulated. Immune escape properties of Omicron decreased effective levels of immunity in the population by a third. Furthermore, in contrast to previous studies, we found Alpha had the highest basic infection fatality ratio (3.0%, 95% CrI 2.8-3.2), followed by Delta (2.1%, 95% CrI 1.9–2.4), Wildtype (1.2%, 95% CrI 1.1–1.2), and Omicron (0.7%, 95% CrI 0.6-0.8). Our findings highlight the importance of continued surveillance. Long-term strategies for monitoring and maintaining effective immunity against SARS-CoV-2 are critical to inform the role of NPIs to effectively manage future variants with potentially higher intrinsic transmissibility and severe outcomes.

Abstract Within the European‐funded Coordination and Support Action MicrobiomeSupport (https://www.microbiomesupport.eu/), the Workshop ‘Education in Food Systems Microbiome Related Sciences: Needs for Universities, Industry and Public Health Systems’ brought together over 70 researchers, public health and industry partners from all over the world to work on elaborating microbiome‐related educational needs in food systems. This publication provides a summary of discussions held during and after the workshop and the resulting recommendations.

Abstract Microbiological weathering of coarse residue deposit (CRD) kimberlite produced by the Venetia Diamond Mine, Limpopo, South Africa enhanced mineral carbonation relative to untreated material. Cultures of photosynthetically enriched biofilm produced maximal carbonation conditions when mixed with kimberlite and incubated under near surface conditions. Interestingly, mineral carbonation also occurred in the dark, under water-saturated conditions. The examination of mineralized biofilms in ca. 150 µm-thick-sections using light microscopy, X-ray fluorescence microscopy (XFM) and backscatter electron—scanning electron microscopy-energy dispersive x-ray spectrometry demonstrated that microbiological weathering aided in producing secondary calcium/magnesium carbonates on silicate grain boundaries. Calcium/magnesium sulphate(s) precipitated under vadose conditions demonstrating that evaporites formed upon drying. In this system, mineral carbonation was only observed in regions possessing bacteria, preserved within carbonate as cemented microcolonies. 16S rDNA molecular diversity of bacteria in kimberlite and in natural biofilms growing on kimberlite were dominated by Proteobacteria that are active in nitrogen, phosphorus and sulphur cycling. Cyanobacteria based enrichment cultures provided with nitrogen & phosphorus (nutrients) to enhance growth, possessed increased diversity of bacteria, with Proteobacteria re-establishing themselves as the dominant bacterial lineage when incubated under dark, vadose conditions consistent with natural kimberlite. Overall, 16S rDNA analyses revealed that weathered kimberlite hosts a diverse microbiome consistent with soils, metal cycling and hydrocarbon degradation. Enhanced weathering and carbonate-cemented microcolonies demonstrate that microorganisms are key to mineral carbonation of kimberlite.

Abstract Maternal provisioning and the developmental environment are fundamental determinants of offspring traits, particularly in oviparous species. However, the extent to which embryonic responses to these factors differ across populations to drive phenotypic variation is not well understood. Here, we examine the contributions of maternal provisioning and incubation temperature to hatchling morphological and metabolic traits across four populations of the American alligator (Alligator mississippiensis), encompassing a large portion of the species' latitudinal range. Our results show that whereas the influence of egg mass is generally consistent across populations, responses to incubation temperature show population‐level variation in several traits, including mass, head length, head width, and residual yolk mass. Additionally, the influence of incubation temperature on developmental rate is greater at northern populations, while the allocation of maternal resources toward fat body mass is greater at southern populations. Overall, our results suggest that responses to incubation temperature, relative to maternal provisioning, are a larger source of interpopulation phenotypic variation and may contribute to the local adaptation of populations.

ABSTRACT Numerous clinical parameters link to severe coronavirus disease 2019, but factors that prevent symptomatic disease remain unknown. We investigated the impact of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and endemic human coronavirus (HCoV) antibody responses on symptoms in a longitudinal children cohort (n = 2,917) and a cross-sectional cohort including children and adults (n = 882), all first exposed to SARS-CoV-2 (March 2020 to March 2021) in Switzerland. Saliva (n = 4,993) and plasma (n = 7,486) antibody reactivity to the four HCoVs (subunit S1 [S1]) and SARS-CoV-2 (S1, receptor binding domain, subunit S2 [S2], nucleocapsid protein) was determined along with neutralizing activity against SARS-CoV-2 Wuhan, Alpha, Delta, and Omicron (BA.2) in a subset of individuals. Inferred recent SARS-CoV-2 infection was associated with a strong correlation between mucosal and systemic SARS-CoV-2 anti-spike responses. Individuals with pre-existing HCoV-S1 reactivity exhibited significantly higher antibody responses to SARS-CoV-2 in both plasma (IgG regression coefficients = 0.20, 95% CI = [0.09, 0.32], P < 0.001) and saliva (IgG regression coefficient = 0.60, 95% CI = [0.088, 1.11], P = 0.025). Saliva neutralization activity was modest but surprisingly broad, retaining activity against Wuhan (median NT50 = 32.0, 1Q–3Q = [16.4, 50.2]), Alpha (median NT50 = 34.9, 1Q–3Q = [26.0, 46.6]), and Delta (median NT50 = 28.0, 1Q–3Q = [19.9, 41.7]). In line with a rapid mucosal defense triggered by cross-reactive HCoV immunity, asymptomatic individuals presented with higher pre-existing HCoV-S1 activity in plasma (IgG HKU1, odds ratio [OR] = 0.53, 95% CI = [0.29,0.97], P = 0.038) and saliva (total HCoV, OR = 0.55, 95% CI = [0.33, 0.91], P = 0.019) and higher SARS-CoV-2 reactivity in saliva (IgG S2 fold change = 1.26, 95% CI = [1.03, 1.54], P = 0.030). By investigating the systemic and mucosal immune responses to SARS-CoV-2 and HCoVs in a population without prior exposure to SARS-CoV-2 or vaccination, we identified specific antibody reactivities associated with lack of symptom development.IMPORTANCEKnowledge of the interplay between human coronavirus (HCoV) immunity and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is critical to understanding the coexistence of current endemic coronaviruses and to building knowledge potential future zoonotic coronavirus transmissions. This study, which retrospectively analyzed a large cohort of individuals first exposed to SARS-CoV-2 in Switzerland in 2020–2021, revealed several key findings. Pre-existing HCoV immunity, particularly mucosal antibody responses, played a significant role in improving SARS-CoV-2 immune response upon infection and reducing symptoms development. Mucosal neutralizing activity against SARS-CoV-2, although low in magnitude, retained activity against SARS-CoV-2 variants underlining the importance of maintaining local mucosal immunity to SARS-CoV-2. While the cross-protective effect of HCoV immunity was not sufficient to block infection by SARS-CoV-2, the present study revealed a remarkable impact on limiting symptomatic disease. These findings support the feasibility of generating pan-protective coronavirus vaccines by inducing potent mucosal immune responses.

Placental trophoblastic site tumor (PSTT) is a rare type of gestational trophoblastic neoplasia (GTN). PSTT has a higher mortality than other types of gestational trophoblastic disease (GTD), with a rate of 16.1%, due to its relatively unpredictable behavior and reduced response to chemotherapy. Its diagnostic and management are very challenging in Low resources settings particularity in Haiti where MRI, PET Scan and IHC are not available. Further, the follow-up is very difficult because of social, political, and economic issues limiting the capacity of our patients to be present at all scheduled visits. No case of PSTT has been publicly described yet the Haitian experience in the literature in the management of such case compared to the developed world. We present a case of PSTT successfully diagnosed and managed at Mirebalais University Hospital (MUH) in Haiti with the support of telepathology and intentional partners while highlighting the difference that we observed compare to the developed world.

Background: Oxymel is a functional beverage with a rich historical background of use in multiple societies. Various simple and compound oxymels are prescribed in certain complementary and traditional medical systems, including traditional Persian Medicine. In recent years, numerous clinical and preclinical studies have been conducted in the pharmacy and food industry to investigate the efficacy of various oxymel formulations. This article aims to systematically review and summarize interventional studies on oxymel in both clinical research and animal models. Methods: Relevant articles were searched in Embase, MEDLINE, Web of Science Core Collection, Scopus, and Google Scholar from inception to July 2023 using the keyword “Oxymel” and its equivalents in other languages. Animal and human interventional studies were selected from the search results for review. Results: This review includes twenty studies, comprising twelve clinical trials, two case studies, and six animal studies. The most commonly reported actions of oxymel include positive effects on the cardiovascular system, as well as antioxidant and anti-inflammatory properties. Furthermore, compound oxymel formulations have demonstrated additional benefits depending on the inclusion of specific medicinal herbs. Conclusion: Based on our findings, oxymel appears to be a valuable functional food for healthy individuals and a potentially effective and safe treatment option for managing certain diseases such as asthma, obesity, and type 2 diabetes. However, further clinical trials with larger sample sizes and longer durations are needed to fully elucidate the potential side effects and benefits of both simple and compound oxymels in various disease states.

Background: The objective of healthy aging strategies is to support interventions targeting autonomy loss prevention, with the assumption that these interventions are likely to be efficient by simultaneously improving clinical outcomes and saving costs. Methods: We compare the economic impact of two interventions targeting frailty prevention in older European populations: a multicomponent intervention including physical activity monitoring, nutrition management, information and communications technology use and a relatively simple healthy aging lifestyle education program based on a series of workshops. Our sample includes 1,519 male and female participants from 11 European countries aged 70 years or older. Our econometric model explores trends in several outcomes depending on intervention receipt and frailty status at baseline. Results: Implementing a multicomponent intervention among frail older people does not lead to a lower use of care and do not prevent quality of life losses associated with aging. However, it impacts older people's sense of priorities and interest in the future. We find no statistically significant differences between the two interventions, suggesting that the implementation of a multicomponent intervention may not be the most efficient strategy. The impact of the interventions does not differ by frailty status at baseline. Conclusions: Our results show the need to implement healthy aging strategies that are more focused on people's interests.