bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacteriophage Kil peptide folds into a predicted helix-turn-helix structure to disruptEscherichia colicell division
Authors: Naha Arindam , Cameron Todd A. , Margolin William 
Published: December 2024

AbstractFtsZ, a eukaryotic tubulin homolog and an essential component of the bacterial divisome, is the target of numerous antimicrobial compounds as well as proteins and peptides, most of which inhibit FtsZ polymerization dynamics. We previously showed that the Kil peptide from bacteriophage λ inhibitsEscherichia colicell division by disrupting FtsZ ring assembly, and this inhibition requires the presence of the essential FtsZ membrane anchor protein ZipA. To investigate Kil’s molecular mechanism further, we employed truncation mutants and molecular modeling to identify the minimal residues necessary for its activity. Modeling suggests that Kil’s core segment folds into a helix-turn-helix (HTH) structure. Deleting either the C-terminal 11 residues or the N-terminal 5 residues of Kil still allowed inhibition ofE. colicell division, but removing both termini nearly abolished this activity, indicating that a minimal region within the Kil HTH core is essential for its function. Another Kil-like peptide from a closely related enterobacterial phage also disrupts FtsZ ring assembly and requires ZipA for this activity. Consistent with its broader activity against FtsZ, λ Kil was able to efficiently inhibit cell division of a uropathogenicE. coli(UPEC) strain. Understanding the function of Kil and similar peptides can potentially reveal additional ways to target FtsZ for antimicrobial therapies as well as elucidate how FtsZ functions in bacterial cell division.
Causal considerations can determine the utility of machine learning assisted GWAS
Authors: Mukherjee Sumit , McCaw Zachary , Amar David , Dey Rounak , Soare Thomas , Xu Kaiwen , Somineni Hari ,   insitro Research Team, Eriksson Nicholas , O’Dushlaine Colm 
Published: December 2024

AbstractMachine Learning (ML) is increasingly employed to generate phenotypes for genetic discovery, either by imputing existing phenotypes into larger cohorts or by creating novel phenotypes. While these ML-derived phenotypes can significantly increase sample size, and thereby empower genetic discovery, they can also inflate the false discovery rate (FDR). Recent research has focused on developing estimators that leverage both true and machine-learned phenotypes to properly control the type-I error. Our work complements these efforts by exploring how the true positive rate (TPR) and FDR depend on the causal relationships among the inputs to the ML model, the true phenotypes, and the environment.Using a simulation-based framework, we study architectures in which the machine-learned proxy phenotype is derived from biomarkers (i.e. inputs) either causally up-stream or downstream of the target phenotype. We show that no inflation of the false discovery rate occurs when the proxy phenotype is generated from upstream biomarkers, but that false discoveries can occur when the proxy phenotype is generated from downstream biomarkers. Next, we show that power to detect variants truly associated with the target phenotype depends on its heritability and correlation with the proxy phenotype. However, the source of the correlation is key to evaluating a proxy phenotype’s utility for genetic discovery. We demonstrate that evaluating machine-learned proxy phenotypes using out-of-sample predictive performance (e.g. phenotypic correlation) provides a poor lens on utility. This is because overall predictive performance does not differentiate between genetic and environmental correlation. In addition to parsing these properties of machine-learned phenotypes via simulations, we further illustrate them using real-world data from the UK Biobank.
The methane-cycling microbiome in intact and degraded permafrost soils of the pan-Arctic
Authors: Wang Haitao , Lindemann Erik , Liebmann Patrick , Varsadiya Milan , Svenning Mette Marianne , Waqas Muhammad , Petters Sebastian , Richter Andreas , Guggenberger Georg , Barta Jiri , Urich Tim 
Published: December 2024

AbstractThe methane-cycling microbiomes in Arctic permafrost-affected soils play crucial roles in the production and consumption of this important greenhouse gas. However, little is known about the distributions of Arctic methanogens and methanotrophs across the regional scale and along the vertical soil profile, as well as their responses to the widespread permafrost thaw. Using a unique sample set from nine different locations across the pan-Arctic, we identified methanogen and methanotroph phylotypes in 729 datasets of 16S rRNA gene amplicons.In 621 samples of intact permafrost soils across the pan-Arctic, only 22 methanogen and 26 methanotroph phylotypes were identified. Relative abundances of both functional groups varied significantly between sites and soil horizons. Only four methanogen phylotypes were detected at all locations, with the hydrogenotrophicMethanobacterium lacusdominating. Remarkably, the permafrost soil methane filter was almost exclusively comprised of a few phylotypes closely related to the obligate methanotrophic speciesMethylobacter tundripaludum.In degraded permafrost sites in Alaska,M. tundripaludumalso dominated the methanotroph microbiome in the wet site. However, in dry, water-drained former permafrost site,Methylocapsaphylotypes, closely related with the atmospheric methane oxidizing bacteria, were exclusively found and dominant, indicating a massive restructuring of the methanotroph guild that consequently resulted in functional changes from a soil methane filter to an atmospheric methane sink.This study provides first insights into the identity and intricate spatial distribution of methanotrophs and methanogens in permafrost soils at a pan-Arctic scale and their responses to different water status after permafrost degradation. These findings point towards a few key microbes particularly relevant for future studies on Arctic CH4dynamics in a warming climate and that under future dry conditions more atmospheric CH4uptake in Arctic upland soils might happen.
Embryonic exposures to flame retardant tetrabromobisphenol A (TBBPA) disrupts dorsoventral patterning in zebrafish
Authors: Senarath Pathirajage Kanchaka , Serradimigni Rosemaria , Sharma Sunil , Dasgupta Subham 
Published: December 2024

AbstractTetrabromobisphenol A (TBBPA), a widely used flame retardant in commercial products such as synthetic textiles, plastics, and electronics poses potential toxicity risks through indoor exposure. This study aims to leverage zebrafish as a model to study TBBPA impacts on zebrafish dorsoventral patterning—a process that lays the foundation of an embryo’s axial determination and localization of specific tissues and organs. Zebrafish embryos were exposed to varying concentrations of TBBPA (0-10 µM) at either 0.75- or 6-hours post-fertilization (hpf) and phenotyped at 8 or 24 hpf. Following this, whole-mount immunohistochemistry (IHC) was conducted out to quantify various proteins important in the BMP signaling pathway, epithelial-to-mesenchymal transition (EMT) and ectoderm and mesoderm germ layers. Importantly, these assessments were done at environmentally relevant concentrations ranging down to nM and pM levels. Our data showed a significant concentration-dependent increase in ventralization phenotypes, marked by enlarged blood island area, coupled with a disruption of the ventral-to-dorsal gradient of pSMAD protein levels, indicating BMP signaling disruptions. Perturbations in epithelial-to-mesenchymal transition (EMT), as evidenced by changes in E- and N-cadherin expression and Snail2 transcription factor levels, indicated impaired cell migration on TBBPA exposures. We then interrogated if TBBPA impacts germ layers and structures derived from specific germ layers. We observed significant concentration-dependent changes in levels of Sox2 and Sox10- both indicators of neural crest cell formation and differentiation from the ectoderm. We also observed a significant reduction of Tbx16- a marker of paraxial mesodermal cells. Collectively, both these data show TBBPA-induced impact on germ layers. Finally, we examined specific cell types derived from ectoderm and mesoderm and showed TBBPA-induced inhibition of cartilage development (derived from ectodermal neural crest cells) and blood cell development (derived from mesodermal cells). Our findings collectively demonstrate that TBBPA-induced disruptions in early developmental signaling and dorsoventral patterning may contribute to systemic toxicity in zebrafish embryos. Importantly, we see these disruptions at environmentally relevant concentrations, reinforcing the importance of continued interrogation of TBBPA in targeting early embryogenesis.
Dissociating Contributions of Theta and Alpha Oscillations from Aperiodic Neural Activity in Human Visual Working Memory
Authors: van Engen Quirine , Chau Geeling , Smith Aaron , Adam Kirsten , Donoghue Thomas , Voytek Bradley 
Published: December 2024

AbstractWhile visual working memory (WM) is strongly associated with reductions in occipitoparietal 8-12 Hz alpha power, the role of 4-7 Hz frontal midline theta power is less clear, with both increases and decreases widely reported. Here, we test the hypothesis that this theta paradox can be explained by non-oscillatory, aperiodic neural activity dynamics. Because traditional time-frequency analyses of electroencephalopgraphy (EEG) data conflate oscillations and aperiodic activity, event-related changes in aperiodic activity can manifest as task-related changes in apparent oscillations, even when none are present. Reanalyzing EEG data from two visual WM experiments (n = 74), and leveraging spectral parameterization, we found systematic changes in aperiodic activity with WM load, and we replicated classic alpha, but not theta, oscillatory effects after controlling for aperiodic changes. Aperiodic activity decreased during WM retention, and further flattened over the occipitoparietal cortex with an increase in WM load. After controlling for these dynamics, aperiodic-adjusted alpha power decreased with increasing WM load. In contrast, aperiodic-adjusted theta power increased during WM retention, but because aperiodic activity reduces more, it falsely appears as though theta “oscillatory” power (e.g., bandpower) is reduced. Furthermore, only a minority of participants (31/74) had a detectable degree of theta oscillations. These results offer a potential resolution to the theta paradox where studies show contrasting power changes. We identify novel aperiodic dynamics during human visual WM that mask the potential role that neural oscillations play in cognition and behavior.Significance statementWorking Memory (WM) is our ability to hold information in mind without it being present in our external environment. Years of research focused on oscillatory brain dynamics to discover the mechanisms of WM. Here, we specifically look at oscillatory and non-oscillatory, aperiodic activity as measured with scalp EEG to test their significance in supporting WM. We challenge earlier findings regarding theta oscillations with our analysis approach, while replicating alpha oscillation findings. Furthermore, aperiodic activity is found to be involved in WM, over frontal regions in a task-general manner, and over anterior regions this activity is reduced with an increase the number of items that are remembered. Thus, we have identified novel aperiodic dynamics during human visual WM.
Stool processing methods for Xpert Ultra testing in childhood tuberculosis: A prospective, multi-country accuracy study
Authors: Jaganath Devan , Nabeta Pamela , Nicol Mark P. , Castro Robert , Wambi Peter , Zar Heather J. , Workman Lesley , Lodha Rakesh , Singh Urvashi B. , Bavdekar Ashish , Sanghavi Sonali , Trollip André , Mace Aurélien , Bonnet Maryline , Lounnas Manon , de Haas Petra , Tiemersma Edine , Alland David , Banada Padmapriya , Cattamanchi Adithya , Ruhwald Morten , Wobudeya Eric , Denkinger Claudia M. ,   the Stool H2H Study Team
Published: December 2024

ABSTRACTBackgroundCentrifuge-free processing methods support stool Xpert Ultra testing for childhood tuberculosis (TB), but there are limited data on their accuracy, acceptability and usability.MethodsWe conducted a prospective evaluation of stool Xpert Ultra in India, South Africa, and Uganda with three methods: Stool Processing Kit (SPK), Simple One-Step (SOS), and Optimized Sucrose Flotation (OSF). Children <15 years old with presumptive TB had respiratory specimen testing with Xpert Ultra and culture. Stool was tested using Xpert Ultra after processing with each method. We compared the accuracy of each method to a microbiological reference standard (MRS) and a composite reference standard (CRS). We surveyed the laboratory staff to assess acceptability and usability of the methods.ResultsWe included 607 children, of whom the median age was 3.5 years (IQR 1.3-7), 48% were female, and 15.5% were HIV positive. Against the MRS, the sensitivities of SPK, SOS and OSF were 36.9% (95% CI 28.6-45.8), 38.6% (95% CI 17.2-51), and 31.3% (95% CI 20.2-44.1), respectively. The specificities of SPK, SOS and OSF were 98.2% (95% CI 96.4-99.3), 97.3% (95% CI 93.7-99.1) and 97.1% (95% CI 93.3-99), respectively. Laboratory staff reported that the methods were acceptable and usable, but SOS was most feasible to implement in a peripheral facility. Sensitivity increased among children who were culture-positive (55-77.3%) and was low (13-16.7%) against the CRS.ConclusionsStool processing methods for Xpert Ultra were acceptable, usable, and performed similarly, with highest sensitivity among children with culture-positive TB.KEY POINTSIn a multi-country diagnostic accuracy study for childhood pulmonary tuberculosis, three stool processing methods for Xpert Ultra were acceptable, usable and performed similarly. Sensitivity was lower than that of sputum Xpert Ultra, but improved in children with culture-positive disease.
Earlier timing of seasonal respiratory infections and seasonal mortality during the COVID-19 pandemic
Authors: Sieber Michael , Traulsen Arne 
Published: December 2024

AbstractSeasonal respiratory infections typically surge within a limited time window, but the exact timing within a given year is hard to predict. The disruptions caused by the COVID-19 pandemic led to dramatic changes in the transmission dynamics of many pathogens, providing a unique opportunity to study the determinants and robustness of the seasonal timing of epidemics. Combining detailed data on acute respiratory infections from Germany with an epidemiological model, we analyzed changes in the timing of seasonal epidemics. The seasonal surge in infections occurred substantially earlier during the COVID-19 pandemic, and was reflected in a corresponding shift in the seasonality of all-cause mortality. We show that this is a consistent, but transient outcome of disrupted epidemic seasonality, predictable from basic epidemiological principles.
Self-reported Stress Perception in Breast Cancer Patients Treated with Integrative Metal Color Light Therapy: The LUCIA Study Protocol
Authors: Oei Shiao Li , Groß Jessica , Ganz Michaela , Streffer Charlotte , Grieb Gerrit , Freytag Lysander , Johnson Sophia , Schad Friedemann , Thronicke Anja 
Published: December 2024

AbstractIntroductionMany breast cancer patients benefit from appropriate oncological therapies, but also experience side effects or ongoing restrictions that have a significant impact on health-related quality of life. Non-Pharmaceutical Interventions (NPIs) such as sport, movement, art therapy, yoga or mindfulness-based stress reduction, can help to reduce distress and pain and support resilience strategies. Metal Colored Light (MCL) therapy, an integrative art therapy using metal colored glasses, has been used in the past to relieve symptoms, improve quality of life and support coping strategies. The LUCIA study aims for the first time to systematically investigate whether self-reported perception of stress can be influenced in breast cancer patients through a series of MCL.Methods and analysisThe LUCIA-study will enroll 60 breast cancer patients treated with MCL therapy, which consists of nine individual MCL sessions per patient over a six-week period. The primary outcome is the analysis of self-reported stress perception of breast cancer patients using the National Comprehensive Cancer Network (NCCN) Distress Thermometer. Secondary endpoints include the Internal Coherence Scale (ICS) and quality of life using the European Organization for Research and Treatment of Cancer Questionnaire C30 (EORTC-QLQ-C30). Longitudinal changes in symptom burden will be assessed and multivariate analyses performed.Ethics and disseminationsThe present study is approved by the ethics committee of the Medical Association Berlin within the Network Oncology with the reference number Eth-27/10. The results will be presented at scientific conferences and published.Trial registration numberThe study was registered at the German Register for Clinical Trials under DRKS00013335 on 27/11/2017.Strengths and limitations of this studySelf-reported stress perception of each participant in this LUCIA study will be evaluated before (T0) and after the Metal Colored Light (MCL) therapy (T1).Changes in self-reported distress burden, internal coherence and health-related quality of life will be followed and asked three months (T2) and six months (T3) after T0.Prospective evaluation of all participants.Sources of bias and potential confounding can be limited through the use of multivariate analyses.There is no direct control or placebo group and no blinding.
Neuropeptide-mediated temporal sensory filtering in a primordial nervous system
Authors: Wyss Livia S. , Bray Samuel R. , Wang Bo 
Published: December 2024

AbstractSensory filtering – prioritizing relevant stimuli while ignoring irrelevant ones – is crucial for animals to adapt and survive in complex environments. While this phenomenon has been primarily studied in organisms with complex nervous systems, it remains unclear whether simpler organisms also possess such capabilities. Here, we studied temporal information processing inSchmidtea mediterranea, a freshwater planarian flatworm with a primitive nervous system. Using long-term behavioral imaging and oscillatory ultraviolet (UV) light stimulations with rhythms matching the timescale of the animal’s short-term memory (∼minutes), we observed that planarians initially ignored rhythmic oscillations in UV intensity but eventually began tracking them after several cycles, demonstrating sensory filtering. We identified two neuropeptides, knockdown of which eliminated the initial ignoring phase and led to immediate stimulus-tracking, suggesting that these neuropeptides mediate an active sensory gating mechanism preventing response to transient fluctuations in stimuli. Notably, when UV stimulation was coupled with synchronous visible light oscillations, the planarians tracked the combined signals immediately, indicating that coherence across sensory modalities can override the initial gating. Our findings demonstrate that even simple nervous systems can filter temporal information and that this mechanism is mediated by neuropeptides. Unlike classical fast-acting small-molecule neurotransmitters, neuropeptides provide a slower, sustained, and global form of modulation that allows for more sophisticated control of sensory processing.Significance statementWe show that simple nervous systems can use specific neuropeptides to achieve sensory filtering, a behavior previously thought to require complex brain architecture. This neuropeptide-mediated sensory gating mechanism reveals a fundamental role for neuropeptides in temporal information processing, offering insights into the mechanistic and evolutionary origins of attention-like behaviors.
Hyperactive PLCG1 drives non-canonical signaling to promote cell survival
Authors: Zeng Longhui , Zhang Xinyan , Xiong Yiwei , Sato Kazuki , Hajicek Nicole , Sondek John , Su Xiaolei 
Published: December 2024

AbstractOne of the long-standing questions in cell signaling field to identify and characterize key signaling nodes out of a complex network. Phospholipase Cγ1 (PLCG1) was identified as the most frequently mutated gene in adult T-cell leukemia/lymphoma, suggesting a critical function of PLCG1 in driving T cell activation. However, it remains unclear how these mutations regulate T cell physiology and pathology. Here we investigated three common leukemia/lymphoma associated mutations (R48W, S345F, and D1165H). We discovered that these mutations induced hyperactive T cell signaling and caused pro-survival phenotypes. PLCG1 mutants enhanced LAT condensation, calcium influx, and ERK activation. They promoted T cell proliferation, induced cell aggregation, and rendered resistance to vorinostat, an FDA-approved drug for cutaneous T-cell lymphoma. The resistance to vorinostat depended on ERK signaling and can be reversed with an ERK inhibitor. Mechanistically, alpha smooth muscle actin, which was specifically induced by PLCG1 mutants, directly bound PLCG1 to promote its activation. Together, these results demonstrated that hyperactive PLCG1 promoted T cell survival and drug resistance through inducing non-canonical signaling.
Establishment of bovine extraembryonic endoderm cells
Authors: Ming Hao , Scatolin Giovanna N. , Ojeda Alejandro , Jiang Zongliang 
Published: December 2024

AbstractUnderstanding the mechanisms of hypoblast development and its role in the implantation is critical for improving farm animal reproduction, but it is hampered by the lack of research models. Here we report that a chemical cocktail (FGF4, BMP4, IL-6, XAV939, and A83-01) enables de novo derivation and long-term culture of bovine extraembryonic endoderm cells (bXENs). Transcriptomic and epigenomic analyses confirmed the identity of bXENs and revealed that they are resemble hypoblast lineages of early bovine peri-implantation embryos. We showed that bXENs help maintain the stemness of bovine ESCs and prevent them from differentiation. In the presence of a signaling cocktail sustaining bXENs, the growth and progression of epiblasts are also facilitated in the developing pre-implantation embryo. Furthermore, through 3D assembly of bXENs with bovine ESCs and TSCs, we developed an improved bovine blastocyst like structure (bovine blastoid) that resembles blastocyst. The bovine XENs and blastoids established in this study represent accessiblein vitromodels for understanding hypoblast development and improving reproductive efficiency in livestock species.