bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Longitudinal ctDNA Monitoring in Metastatic Cancer Patients Treated with an Individualized Neoantigen-directed Vaccine
Authors: Schenk Desiree , Davis Matthew J. , Zhou Rita , Mantilla Alexis , Galbraith Madeline , Spiro Oliver , Petrillo Olivia , Faria do Valle Italo , Ferguson Andrew R. , Jooss Karin , Dhanik Ankur 
Published: December 2024

AbstractPurposeCirculating-tumor DNA (ctDNA) is an emerging, minimally invasive diagnostic and prognostic biomarker for patients receiving a variety of cancer therapies. Comprehensive and robust longitudinal monitoring of ctDNA can provide an understanding of tumor burden, heterogeneity, and response or resistance to treatment.Experimental DesignctDNA of 28 metastatic cancer patients receiving an individualized neoantigen-directed immunotherapy was monitored longitudinally, up to two years, using a unique hybrid next generation sequencing assay targeting tumor-informed and tumor-naïve variants. Patient-specific panels were designed targeting an average of 144 variants per patient. A tumor-naïve universal panel was also designed for inclusion with patient-specific panels to monitor recurrently mutated tumor hotspots (e.g.,KRASandTP53) and genes implicated in immunotherapy resistance (B2M, TAP1/2).ResultsAnalytical characterization of the assay established linearity with a mean variant allele frequency (VAF) ≥0.049%, and a variant-level limit of detection (LOD95) of 0.12%. Tumor-informed variants were detected in 26/28 patients, andde novovariants were observed in 25/28 patients. HLA LOH was also observed. Longitudinal ctDNA data provided key insights into patients’ responses to vaccine treatment.ConclusionsThe hybrid design of the ctDNA monitoring assay provides the sensitivity and specificity required for evaluating patient samples undergoing individualized therapy. It provides an improved capability to understand patient response to experimental therapies and further supports the utility of ctDNA as a cancer biomarker.
Adult visual deprivation engages associative, presynaptic plasticity of thalamic input to cortex
Authors: Murase Sachiko , Severin Daniel , Dye Louis , Mesik Lukas , Moreno Cristian , Kirkwood Alfredo , Quinlan Elizabeth M. 
Published: December 2024

AbstractAssociative plasticity at thalamocortical synapses is thought to be constrained by age in the mammalian cortex. However, here we show for the first time that prolonged visual deprivation induces robust and reversible plasticity at synapses between first order visual thalamus and cortical layer 4 pyramidal neurons. The plasticity is associative and expressed by changes in presynaptic function, thereby amplifying and relaying the change in efferent drive to the visual cortex.
Use of a predictor cue during a speech sound discrimination task in aCntnap2knockout rat model of autism
Authors: Centanni Tracy M. , Gunderson Logun P. K. , Parra Monica 
Published: December 2024

AbstractAutism is a common neurodevelopmental disorder that despite its complex etiology, is marked by deficits in prediction that manifest in a variety of domains including social interactions, communication, and movement. The tendency of individuals with autism to focus on predictable schedules and interests that contain patterns and rules highlights the likely involvement of the cerebellum in this disorder. One candidate-autism gene is contact in associated protein 2 (CNTNAP2), and variants in this gene are associated with sensory deficits and anatomical differences. It is unknown, however, whether this gene directly impacts the brain’s ability to make and evaluate predictions about future events. The current study was designed to answer this question by training a genetic knockout rat on a rapid speech sound discrimination task. Rats withCntnap2knockout (KO) and their littermate wildtype controls (WT) were trained on a validated rapid speech sound discrimination task that contained unpredictable and predictable targets. We found that although both genotype groups learned the task in both unpredictable and predictable conditions, the KO rats responded more often to distractors during training as well as to the target sound during the predictable testing conditions compared to the WT group. There were only minor effects of sex on performance and only in the unpredictable condition. The current results provide preliminary evidence that removal of this candidate-autism gene may interfere with the learning of unpredictable scenarios and enhance reliance on predictability. Future research is needed to probe the neural anatomy and function that drives this effect.
Ozboneviz: An Australian Precedent in FAIR 3D Imagery and Extended Biodiversity Collections
Authors: Weisbecker Vera , Fusco Diana , Ingleby Sandy , Lambrides Ariana B J , Manne Tiina , Maguire Keith , O’Connor Sue , Peachey Thomas J , Samper Carro Sofia C , Stemmer David , Ristevski Jorgo , van Zoelen Jacob D , Viacava Pietro , Yates Adam M , Mein Erin 
Published: December 2024

AbstractBillions of specimens are in biodiversity collections worldwide, and this infrastructure is crucial for research on Earth’s natural history. Three-dimensional (3D) imagery of specimens is an increasingly important part of the ‘Digital Extended Specimen’ network of metadata. Open access, high fidelity 3D imagery of biodiversity specimens improves researcher efficiency, equity and increases public engagement with collections. We introduce Ozboneviz, an open access collection of FAIR (Findable, Accessible, Interoperable, Reusable) 3D imagery aiming to enhance research capacity in Australasian vertebrate skeletal morphology. Ozboneviz is an Australian test case demonstrating the feasibility of creating multi-institutional, FAIR 3D biodiversity imagery collections. We outline project design, challenges, and use by the international research community. We then discuss the urgent need for investment in infrastructure and curatorial support to progress the digitisation of Australian biodiversity collections in a way that maximises stakeholder benefit and facilitates 3D data discoverability and retrieval.
Integration of serum androgens and Sex Hormone-Binding Globulin for optimized early detection of aggressive prostate cancer
Authors: Lazareva Olga , Riediger Anja , Stegle Oliver , Sültmann Holger , Hohenfellner Markus , Görtz Magdalena 
Published: December 2024

ABSTRACTBackgroundAggressive prostate cancer (PC) represents a significant health concern worldwide. Conventional initial screening methods, primarily based on prostate-specific antigen (PSA) levels, lack specificity, leading to a high rate of unnecessary biopsies and an urgent need for more accurate diagnostic tools. This study addresses the gap by exploring the potential of integrating clinical and routine blood laboratory parameters including a comprehensive hormone assessment to enhance the non-invasive prediction of aggressive PC.MethodsIn a pilot study of 578 patients who were scheduled for a prostate biopsy due to suspicion of PC, we analyzed an extensive panel of 28 laboratory values alongside data on family history, diet, and lifestyle. A logistic regression classifier was developed, and model performance was evaluated using repeated k-fold cross-validation on the complete dataset (n=282). Participants were histologically categorized into three risk groups: healthy, moderate PC (ISUP 1-2 PC), and aggressive PC (ISUP 3-5 PC).ResultsSignificant associations were found between PC aggressiveness and lower levels of androstenedione, Dehydroepiandrosterone-Sulfate (DHEA-S) and free PSA percentage, as well as higher levels of Sex Hormone Binding Globulin (SHBG). The integration of these serum markers with clinical parameters into a new multi-stage risk classifier for PC prediction significantly improved the predictive accuracy. The risk model outperformed PSA-only methods, demonstrating higher sensitivity and specificity in predicting aggressive PC.ConclusionsIncorporating serum markers DHEA-S, androstenedione, and SHBG into a novel risk classifier can improve early detection of aggressive PC. These widely available and cost-effective blood biomarkers could reduce reliance on invasive prostate biopsies and expensive magnetic resonance imaging by providing a more targeted approach to non-invasive prediction of aggressive PC following PSA testing. Our pilot study lays the groundwork for larger-scale research to further explore the integration of androgens and SHBG in future risk stratification models for improved clinical decision making.
From Gut to Brain: Evidence for a Causal Contribution of Gut-Microbiota to Major Depressive Disorder in Humans
Authors: Fehse Leon , Ribeiro Adèle H. , Winter Nils R. , Thanarajah Sharmili Edwin , Fisch Lukas , Welzel Marius , Bang Corinna , Meinert Susanne , Flinkenflügel Kira , Borgers Tiana , Goltermann Janik , Leehr Elisabeth J. , Bloemendaal Mirjam , Natasha Eugenia E. , Mulder Danique , Vasquez Alejandro Arias , Stein Frederike , Thomas-Odenthal Florian , Usemann Paula , Teutenberg Lea , Nenadic Igor , Straube Benjamin , Alexander Nina , Jamalabadi Hamidreza , Jansen Andreas , Nitsch Robert , Lügering Andreas , Reif Andreas , Kittel-Schneider Sarah , Cryan John , Franke Andre , Valderrama Benjamin , Clarke Gerard , Lavelle Aonghus , Dannlowski Udo , Kircher Tilo , Heider Dominik , Hahn Tim 
Published: December 2024

AbstractMajor Depressive Disorder (MDD) is a highly prevalent, severe mental health condition that constitutes one of the leading causes of disability worldwide. While recent animal studies suggest a causal role of the gut microbiome in the pathophysiology of MDD models, evidence in humans is still unclear due to small sample sizes, inconsistent clinical assessment of MDD diagnosis, and methodological limitations regarding causal inference in cross-sectional data. Here, we explicitly address these shortcomings to investigate the potential causal link between the gut microbiome and MDD: First, we replicate previous findings using one of the largest multicenter MDD cohorts for which microbiome data and in-depth diagnostic assessment are available (N=1,269 MDD patients and controls). We find a significant difference between healthy controls and MDD patients for the relative abundance of the four taxaEggerthella,Hungatella,Coprobacillus, andLachnospiraceaeFCS020. Second, we employ state-of-the-art, fully data-driven causal inference tools within Judea Pearl’s framework, allowing us to derive model constraints from the data rather than relying on potentially strong, unrealistic assumptions. Using this approach, we found data-driven evidence forEggerthella and Hungatellaas causal contributors to MDD. Furthermore, we show thatEggerthellaandHungatellaabundances are associated with MDD beyond the influence of body mass index, identifying two distinct pathways linking MDD to the gut microbiome. Finally, the difference in relative abundance of these taxa between healthy and MDD patients was independent of antidepressant medication. Our study provides the first evidence for a potential causal role of gut-microbiota in the pathophysiology of depression in humans.
PISA: versatile microscope for 3D single molecule light sheet imaging
Authors: Taniguchi Yuichi , Nishimura Kazuya , Yoshida Yamato , Kim Sooyeon , Kamarulzaman Latiefa , Priest David G. , Ohno Masae 
Published: December 2024

AbstractLight sheet microscopy combines high sensitivity and imaging speeds with low photodamage, however a remaining hurdle to its widespread adoption is its requirement for special sample preparation. Our new microscope - planar illumination microscope for single molecule imaging for all purpose (PISA) - significantly relieves these restrictions to enable light sheet imaging of coverslip-mounted samples as commonly analyzed in biological microscopes. We show how this technology now permits high-throughput imaging using multi-well plates. Further, the ability of 3D single molecule imaging in microlitre or mm3scale volumes over the coverslip improves the sensitivity of biochemical gel-based fluorometric assays to atto/zepto molar levels. PISA will facilitate widespread adoption of light sheet imaging for a variety of biological, biochemical and medical investigations.
Easy come, easier go: mapping the loss of flagellar motility across the tree of life
Authors: Philip Jamiema Sara , Grewal Sehhaj , Scadden Jacob , Puente-Lelievre Caroline , Matzke Nicholas J. , McNally Luke , Baker Matthew AB 
Published: December 2024

AbstractMost bacterial swimming is powered by the bacterial flagellar motor, a nanomachine that self-assembles from up to 45 proteins into a membrane-spanning complex. The number and types of proteins involved in the flagellar motor vary widely. Predicting flagellar motility from genomic data can facilitate large-scale genomic studies where experimental validation may not be feasible. Using sequence and structural homology, we conducted a homology searches for 54 flagellar pathway genes across 11,365 bacterial genomes. We developed and validated a classifier to predict whether a specific genome was motile and mapped the evolution of flagellar motility across the microbial tree of life. We determined that the ancestral state was motile, and the rate of loss of motility was 4 times the rate of gain.
Protozoal populations drive system-wide variation in the rumen microbiome
Authors: Kobel Carl M. , Leu Andy , Vera-Ponce de León Arturo , Øyås Ove , Lai Wanxin , Altshuler Ianina , Hagen Live H. , Wollenberg Rasmus D. , Søndergaard Mads T. , Bakshani Cassie R. , Willats William G. T. , Nicoll Laura , McIlroy Simon J. , Hvidsten Torgeir R. , Schmidt Oliver , Greening Chris , Tyson Gene W. , Roehe Rainer , Aho Velma T. E. , Pope Phillip B. 
Published: December 2024

AbstractWhile rapid progress has been made to characterize the bacterial and archaeal populations of the rumen microbiome, insight into how they interact with keystone protozoal species remains elusive. Here, we reveal two distinct rumen community types (RCT-A and RCT-B) that are not strongly associated with host phenotype nor genotype but instead linked to protozoal community patterns. We leveraged a series of multi-omic datasets to show that the dominantEpidiniumspp. in animals with RCT-B employ a plethora of fiber-degrading enzymes that present enrichedPrevotellaspp. a favorable carbon landscape to forage upon. Conversely, animals with RCT-A, dominated by generaIsotrichaandEntodinium, harbor a more even distribution of fiber, protein, and amino acid metabolizers, reflected by higher detection of metabolites from both protozoal and bacterial activity. We reveal microbiome variation across key protozoal and bacterial populations is interlinked, which should act as an important consideration for future development of microbiome-based technologies.
SARS-CoV-2 predation of Golgi-bound PI4P primes the massive activation of the DNA Damage Response kinase ATM in the cytoplasm
Authors: Rebendenne Antoine , Soulet Caroline , Valadaõ Ana-Luiza Chaves , Bonaventure Boris , McKellar Joe , Moncorgé Olivier , Goujon Caroline , Moriel-Carretero María 
Published: December 2024

AbstractLike all viruses, SARS-CoV-2, the causative agent of COVID-19, relies on host cell resources to replicate. Our study reveals that, among these resources, SARS-CoV-2 hijacks the oxysterol-binding protein 1 (OSBP1) transporter to exploit the Golgi-bound phosphatidylinositol-4-phosphate (PI4P) pool. This leads to a depletion of Golgi-resident PI4P, triggering the activation of the ATM DNA Damage Response (DDR) kinase in the cytoplasm. As such, ATM, typically anchored to PI4P at the Golgi in an inactive state, undergoes auto-phosphorylation and cytoplasmic release upon SARS-CoV-2-induced PI4P depletion. Conversely, pharmacological inhibition of ATM auto-phosphorylation, which stabilizes its interaction with PI4P, significantly impairs SARS-CoV-2 replication. The requirement for PI4P and impact of ATM inhibition might be conserved across coronaviruses, as similar effects were observed with HCoV-229E. Finally, SARS-CoV-2-induced, cytoplasmic ATM pre-activation primes cells for an accelerated response to DNA damage, which might contribute to the severe outcomes of COVID-19 observed in cancer patients undergoing chemo- or radiotherapy. Therefore, this study uncovers a DNA damage-independent mode of ATM activation and highlights the potential of ATM inhibitors as therapeutic agents against COVID-19.
Cultivation and molecular characterization of foley catheterized urine, clean catch urine, and vaginal swabs from pregnant women prior to delivery
Authors: Greenberg Jonathan M. , Romero Roberto , Alhousseini Ali , Winters Andrew D. , Tarca Adi L. , Gilbert Nicole M. , Gomez-Lopez Nardhy , Hassan Sonia S. , Theis Kevin R. 
Published: December 2024

ABSTRACTThe bladder and urine have historically been considered sterile, especially in the context of clinical assessment. Yet, enhanced culture techniques and advances in DNA sequencing surveys have revealed a low microbial biomass microbiota in the bladders of most healthy individuals. Yet very few studies have investigated the urinary microbiota of pregnant women, who are at increased risk of urinary tract infections (UTIs) that can lead to pregnancy complications such as spontaneous preterm birth. To better understand the potential role of a bladder microbiota during pregnancy, we characterized the urinary microbiota of 25 pregnant women (delivering at or beyond 36 weeks gestation) by comparing the bacterial profiles of their paired catheter urine, clean catch urine, and vaginal swabs through both cultivation and molecular microbiological survey methods. For culture, three bacterial taxa were detected in at least 20% of all urine samples (Lactobacillusspecies, coagulase negativeStaphylococcusspecies, andUreaplasma urealyticum). All three taxa were detected less frequently in Foley catheter urine than in clean catch urine.Ureaplasma urealyticumwas the most frequently recovered bacterium in Foley catheter urine (13/25 women). It was also identified as being more relatively abundant in Foley catheter urine than in the vagina through 16S rRNA gene surveys. Other lower abundance Gram-positive anaerobic cocci (i.e.,FinegoldiaandAnaerococcus)were also more relatively abundant in Foley catheter urine than clean catch urine or vaginal swabs. However, all sample types had high relative abundances ofLactobacillusandGardnerellaspecies. Overall, this suggests that, although vaginal microbiota contamination cannot be completely avoided, Foley catheterized urine is effective at characterizing the low abundance bladder microbiota, includingUreaplasma,Finegoldia,andAnaerococcusspecies. This warrants their further consideration as commensal members of the bladder microbiome during pregnancy.
Structural basis for gene silencing by siRNAs in humans
Authors: Sarkar Sucharita , Gebert Luca F. R. , MacRae Ian J. 
Published: December 2024

SummarySmall interfering RNAs (siRNAs) guide mRNA cleavage by human Argonaute2 (hAgo2), leading to targeted gene silencing. Despite their laboratory and clinical impact, structural insights into human siRNA catalytic activity remain elusive. Here, we show that disrupting siRNA 3’-end binding by hAgo2 accelerates target cleavage and stabilizes its catalytic conformation, enabling detailed structural analysis. A 3.16 Å global resolution cryo-EM reconstruction reveals that distortion of the siRNA–target duplex at position 6 allows target RNA entry into the catalytic cleft and shifts Lysine-709, a previously unrecognized catalytic residue, into the active site. A pyrimidine at target nucleotide t10 positions another unrecognized catalytic residue, Arginine-710, for optimal cleavage. Expansion of the guide-target duplex major groove docks the scissile phosphate for hydrolysis and subsequent groove compression after position 16 permits target RNAs to exit the catalytic cleft. These findings reveal how hAgo2 catalyzes siRNA target hydrolysis, providing a high-resolution model for therapeutic design.
Chemical genomics informs antibiotic and essential gene function inAcinetobacter baumannii
Authors: Tran Jennifer S , Ward Ryan D , Iruegas-López Rubén , Ebersberger Ingo , Peters Jason M 
Published: December 2024

AbstractThe Gram-negative pathogen,Acinetobacter baumannii, poses a serious threat to human health due to its role in nosocomial infections that are resistant to treatment with current antibiotics. Despite this, our understanding of fundamentalA. baumanniibiology remains limited, as many essential genes have not been experimentally characterized. These essential genes are critical for bacterial survival and, thus, represent promising targets for drug discovery. Here, we systematically probe the function of essential genes by screening a CRISPR interference knockdown library against a diverse panel of chemical inhibitors, including antibiotics. We find that most essential genes show chemical-gene interactions, allowing insights into both inhibitor and gene function. For instance, knockdown of lipooligosaccharide (LOS) transport genes increased sensitivity to a broad range of chemicals. Cells with defective LOS transport showed cell envelope hyper-permeability that was dependent on continued LOS synthesis. Using phenotypes across our chemical-gene interaction dataset, we constructed an essential gene network linking poorly understood genes to well-characterized genes in cell division and other processes. Finally, our phenotype-structure analysis identified structurally related antibiotics with distinct cellular impacts and suggested potential targets for underexplored inhibitors. This study advances our understanding of essential gene and inhibitor function, providing a valuable resource for mechanistic studies, therapeutic strategies, and future key targets for antibiotic development.
Risk and Uncertainty Communication in Deployed AI-based Clinical Decision Support Systems: A scoping review
Authors: Gray Nicholas , Page Helen , Buchan Iain , Joyce Dan W. 
Published: December 2024

AbstractClinical decision support systems (CDSS) employing data-driven technology such as artificial intelligence, machine– and statistical-learning are increasingly deployed in health-care settings. These systems often provide clinicians with diagnostic, prognostic, or risk scores modelled from curated patient-level data and frequently involve iterative and non-deterministic optimisation of flexible, parameterised models. All of these data and algorithms have uncertainties associated with them that should be taken into account when used to support clinical decisions at the patient level. This scoping review aims to describe the literature on how deployed data-driven CDSSs present information about uncertainty to their intended users. We describe common clinical applications of CDSSs, characterise the decisions that are being supported, and examine how the CDSS provides outputs to end users, including uncertainty at the individual patient level, as well as indirect measures such as CDSS performance against a reference standard. We conclude with a discussion and recommendations on how CDSS development can be improved.