bluuebunny/crossref_metadata_2025 huggingface dataset:
Consultation informs strategies to improve functional evidence use in variant classification
Authors: Villani Rehan M. , Terrill Bronwyn , Tudini Emma , McKenzie Maddison E. , Cliffe Corrina C. , Hahn Christopher N. , Lundie Ben , Mattiske Tessa , Matotek Ebony , McEwen Abbye E. , Nickerson Sarah L. , Breen James , Fowler Douglas M. , Christodoulou John , Starita Lea , Rubin Alan F. , Spurdle Amanda B.
Published: December 2024

To determine if a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Experimental assay data can provide strong functional evidence for or against pathogenicity in variant classification, but appears to be underutilised. We surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice. Results indicated that survey respondents are not confident to apply functional evidence, mainly due to uncertainty around practice recommendations. Respondents also identified need for support resources, educational opportunities, and in particular requested expert recommendations and updated practice guidelines to improve translation of experimental data to curation evidence. As an initial step, we have collated a list of functional assays recommended by 19 ClinGen Variant Curation Expert Panels as a source of international expert opinion on functional evidence evaluation. Additional support resources for diagnostic practice are in development.
The striatum is an early, accurate indicator of amyloid burden using [11C]PiB in Down syndrome: comparison of two radiotracers
Authors: McLachlan Max , Bettcher Brecca , McVea Andrew , DiFillipo Alexandra , Zammit Matthew , LeMerise Lisette , Rouanet Jeremy , Price Julie , Tudorascu Dana , Laymon Charles , Keator David , Lao Patrick , Brickman Adam M. , Fryer Tim , Hartley Sigan , Ances Beau M. , Johnson Sterling , Betthauser Tobey , Stone Charles K. , Zaman Shahid , Handen Benjamin , Head Elizabeth , Mapstone Mark , Christian Bradley T.
Published: December 2024

INTRODUCTION

Adults with Down syndrome demonstrate striatum-first amyloid accumulation with [11C]PiB PET imaging, which has not been replicated with [18F]florbetapir (FBP). Early striatal accumulation has not been temporally quantified with respect to global cortical measures.

METHODS

Longitudinal PiB (n=175 participants) and FBP (n=92 participants) data from the Alzheimer Biomarkers Consortium-Down Syndrome were used to measure cortical and striatal binding. Generalized temporal models for cortical and striatal amyloid accumulation were created using the sampled iterative local approximation (SILA) method.

RESULTS

PiB demonstrated greater striatal-to-cortical ratios than FBP. SILA analysis revealed striatal amyloid burden occurs 3.40 (2.39) years earlier than the cortex in PiB. There was no difference between the cortex and striatum in FBP.

DISCUSSION

Among adults with Down syndrome, the striatum consistently accumulates amyloid earlier than the cortex when measured with PiB. This suggests the striatum is more sensitive to the onset of PiB PET-detectable amyloid in Down syndrome.
Trends in Cardiac Arrest Among Heart Failure Patients Aged 25 and Older in the United States: Insights from the CDC WONDER Database
Authors: Muhammad Abdullah Naveed , Neppala Sivaram , Chigurupati Himaja Dutt , Ali Ahila , Rehan Muhammad Omer , Kapaganti Sowjanya , Iqbal Rabia , Naveed Hamza , Ahmed Mushood , Fonarow Gregg C. , Dani Sourbha
Published: December 2024

Background

Cardiac arrest (CA) is a significant cause of mortality in patients with heart failure (HF). Despite improvements in care, disparities in CA-related mortality among HF patients persist. This study seeks to explore demographic patterns and mortality rates.

Methods

CDC WONDER (1999-2023) data was analyzed to assess CA-related mortality in HF patients aged≥25. Using the Joinpoint regression analysis, we calculated age-adjusted mortality rates (AAMR) per 100,000 patients and average annual percentage changes (AAPC) to analyze the mortality trends.

Results

CA is responsible for a staggering 1,139,963 deaths among HF patients. The AAMRs have decreased from 25.3 in 1999 to 20.6 in 2023 (AAPC: -0.88, p-value < 0.01), the decline was most significant from 1999 to 2011 (APC: -2.95, p < 0.01) before a concerning rise from 2018 to 2021 (APC: 5.10, p-value < 0.01). Disparities are evident, with men facing higher AAMRs than women (24.6 vs. 17.6) and Black individuals at the highest risk (AAMR: 28.8) followed by Hispanics (AAMR: 22.8). Regionally, Mississippi reports the highest AAMR at 52.5, contrasting with Maryland’s lowest rate of 4.3. Moreover, rural areas exhibited higher AAMRs than urban settings (20.9 vs. 20.1).

Conclusion

The rising mortality rates from CA in HF patients—especially among men, Black individuals, and those in rural areas—require our immediate attention. By implementing targeted interventions and enhancing access to healthcare, we can reduce these disparities and improve patient outcomes.
Genetic diversity in the IIS6 domain of Voltage Gated Sodium Channel (VGSC) gene amongAedes aegyptipopulations from different geographical regions in India
Authors: Sumitha MK , Pandiyan G Navaneetha , Kalimuthu M , Paramasivan R , Gupta Bhavna
Published: December 2024

This study provides critical insights into the genetic diversity of the IIS6 domain of theVGSCgene inAedes aegyptipopulations across various regions in India, focusing on two mutations: S989P and V1016G. Samples were collected from seven different cities across the country, including Dibrugarh, Kolkata, Berhampur, Bhopal, Bengaluru, Ghaziabad, and Aurangabad. The IIS6 domain was amplified and sequenced, revealing that the V1016G mutation was found at a higher frequency compared to the S989P mutation. The S989P mutation was most prevalent in Berhampur, followed by Bengaluru, while V1016G mutation showed high frequencies in Dibrugarh, followed by Berhampur. Additionally, the study identified intron polymorphisms within theVGSCgene, with the type A intron being relatively rare. However, the type A intron was observed in samples harbouring both mutant and wild alleles for both mutations. The regional variation in the frequencies of these mutations indicates complex evolutionary dynamics potentially influenced by local environmental factors and insecticide application practices. Interestingly, the high frequency of these alleles also correlated with the genetic structure of the mosquito populations, suggesting that gene flow might be playing a role in spreading these mutations. Regular monitoring of these mutations could serve as important indicators in assessing the status of resistance to pyrethroids and guide nationwide mosquito control efforts. This research underscores the necessity for localized vector control strategies and continuous genetic surveillance to manage insecticide resistance effectively.
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

Purpose

Circulating-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 Design

ctDNA 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).

Results

Analytical 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.

Conclusions

The 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

Associative 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

Autism 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

Billions 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

Background

Aggressive 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.

Methods

In 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).

Results

Significant 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.

Conclusions

Incorporating 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

Major 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

Light 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

Most 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

While 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

Like 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

The 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

Small 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

The 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

Clinical 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.
The association between oscillatory burst features and deviations during human working memory
Authors: Kavanaugh Brian C. , Vigne Megan M. , Thorpe Ryan , Legere Christopher , Acuff W. Luke , Vaughan Noah , Tirrell Eric , Haegens Saskia , Carpenter Linda L. , Jones Stephanie R.
Published: December 2024

Oscillatory power across multiple frequency bands has been associated with distinct working memory (WM) processes. Recent research has shown that previous observations based on averaged power are driven by the presence of transient, oscillatory burst-like events, particularly within the alpha, beta, and gamma bands. However, the interplay between different burst events in human WM is not well understood. The current EEG study aimed to investigate the dynamics between alpha (8-12 Hz)/beta (15-29 Hz) and high frequency activity (HFA; 55-80 Hz) bursts in human WM, particularly burst features and error-related deviations during the encoding and maintenance of WM in healthy adults. Oscillatory burst features within the alpha, beta and HFA bands were examined at frontal and parietal electrodes in healthy young adults during a Sternberg working memory task. Averaged power dynamics were driven by oscillatory burst features, most consistently the burst rate and burst power. Alpha/beta and HFA bursts displayed complementary roles in WM processes, in that alpha and beta bursting decreased during encoding and increased during delay, while HFA bursting had the opposite pattern, i.e., increased during encoding and decreased during the delay. The parietal electrode exhibited faster and stronger variation in burst features across WM stages than the frontal electrode. Critically, weaker variation in burst dynamics across stages was associated with incorrect responses and impaired overall task performance. Together, these results indicate that successful human WM is dependent on the rise and fall interplay between alpha/beta and HFA bursts, with such burst dynamics reflecting a novel target for the development of treatment in clinical populations with WM deficits.
Metagenomic mining reveals novel viral histones in dsDNA viruses
Authors: Liu Yang , Hou Zhuru , Hao Wanshan , Cui Shaoqing , Wang Haibo , Liu Yue
Published: December 2024

The compaction of genomic DNA into nucleosomes with the help of histones had long been considered as a fundamental feature exclusive to eukaryotic cells. However, it was recently shown that archaea and bacteria also encode histones. A complex picture has emerged with more recent discoveries of eukaryotic-like histones within one phylum of double-stranded DNA (dsDNA) viruses. Nevertheless, the extent to which other dsDNA viruses encode histones remains largely unexplored. Here we conducted a metagenomic survey of viral histones that were further clustered based on sequence and predicted structural similarities. We identified over 1,500 viral histones and histone-fold proteins, including previously undescribed proteins found in the viral classCaudoviricetes. Structural predictions andin vitroassays demonstrated that histone triplets (where three histone folds are fused) and singlets co-occurring in the same viral genome are capable of forming nucleosome-like particles. Beyond nucleosomal histone functions, our analysis revealed six types of structurally and functionally diverse viral histone-fold proteins, some of which do not have known structural or functional homologs. Altogether, our findings reveal a previously unrecognized diversity of viral histones in dsDNA viruses, expanding the known repertoire, structural diversity, and functional versatility of viral histones beyond nucleocytoplasmic large DNA viruses.

Highlights

Histone triplets and singlets co-occurring in the same dsDNA viral genomes assemble into nucleosome-like particles

Six novel types of structurally and functionally distinct viral histone-fold proteins are identified

The presence of viral histones is significantly positively associated with proteins containing SNF2 chromatin remodeling domain found in viral genomes
Heparanase, a host gene that potently restricts retrovirus transcription
Authors: Waxman Brandon , Salka Kyle , Timilsina Uddhav , Umthong Supawadee , Shukla Deepak , Stavrou Spyridon
Published: December 2024

Heparanase (HPSE) is a heterodimeric β-D-glucoronidase that is critical in mammalian cells for the enzymatic cleavage of membrane associated heparan sulfate moieties. Apart from its enzymatic function, HPSE has important non-enzymatic functions, which include transcriptional regulation, chromatin modification and modulation of various signaling pathways. Interestingly, whileHPSEis an interferon stimulated gene, past reports have shown that it has proviral properties for many different viruses, including Herpes Simplex Virus 1, as it assists virus release from infected cells. Yet any antiviral functions associated with HPSE have not been described. Here we show that HPSE utilizes a hitherto unknown mechanism to restrict retroviruses, by targeting the step of proviral transcription. Moreover, we demonstrate that HPSE blocks transcription initiation by targeting the SP1 transcription factor. Finally, we illustrate that the antiretroviral effect of HPSE is independent of its enzymatic activity. This report describes a novel antiviral mechanism utilized by HPSE to inhibit retrovirus infection.

Importance

Heparanase (HPSE) has emerged as an important factor that has proviral functions for a number of viruses including herpes simplex virus and hepatitis C virus, by assisting in virus egress. However, HPSE is an interferon stimulated gene and thus is a part of the host antiviral defense. Nothing is known about the antiviral functions of HPSE. Here, we examine in depth the role of HPSE during retrovirus infection using two retroviruses, human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus (MLV). In this report, we show that mouse, but not human, HPSE blocks retrovirus infection by targeting provirus transcription. HPSE sequesters the SP-1 transcription factor away from the proviral promoter thereby inhibiting transcription inhibition. In conclusion, our findings identify a novel antiviral function of HPSE and its potential role as an inhibitor of zoonotic transmission of retroviruses.
A genomic resource for exploring bacterial-viral dynamics in seagrass ecosystems
Authors: Ettinger Cassandra L. , Stajich Jason E.
Published: December 2024

Background

Seagrasses are globally distributed marine flowering plants that play foundational roles in coastal environments as ecosystem engineers. While research efforts have explored various aspects of seagrass-associated microbial communities, including describing the diversity of bacteria, fungi and microbial eukaryotes, little is known about viral diversity in these communities.

Results

To begin to address this, we leveraged metagenomic sequencing data to generate a catalog of bacterial metagenome-assembled genomes (MAGs) and phage genomes from the leaves of the seagrass,Zostera marina. We expanded the robustness of this viral catalog by incorporating publicly available metagenomic data from seagrass ecosystems. The final MAG set represents 85 high-quality draft and 62 medium-quality draft bacterial genomes. While the viral catalog represents 354 medium-quality, high-quality, and complete viral genomes. Predicted auxiliary metabolic genes in the final viral catalog had putative annotations largely related to carbon utilization, suggesting a possible role for phage in carbon cycling in seagrass ecosystems.

Conclusions

These genomic resources provide initial insight into bacterial-viral interactions in seagrass meadows and are a foundation on which to further explore these critical interkingdom interactions. These catalogs highlight a possible role for viruses in carbon cycling in seagrass beds which may have important implications for blue carbon management and climate change mitigation.
Unveiling the power of employer branding: enhancing talent retention through organizational advocacy
Authors: Choudhary Shiwani , Joshi Richa
Published: December 2024

Purpose

This study aims to explore the relationship between employer branding and talent retention, also examining the mediating role of organizational advocacy. Additionally, it investigates the moderating effect of supervisor support and coworker support in the connection between organizational advocacy and talent retention.

Design/methodology/approach

To achieve the objectives, a cross-sectional survey with convenience sampling was used to collect data from employees in the IT sector. PLS-SEM modeling was then employed to conduct the analysis.

Findings

The study revealed that dimensions of employer branding positively influenced organizational advocacy, supporting talent retention. Moreover, the study observed a significant moderating effect of supervisor support and coworker support concerning organizational advocacy and talent retention.

Practical implications

This study offers valuable insights for a wide range of IT professionals. The results emphasize the significance of employer branding in shaping organizational advocacy and talent retention. Additionally, the supportive attitude of supervisors and coworkers plays a crucial role in retaining talented employees within an organization. The study validates the connections between employer branding dimensions and key variables, aiding in the refinement of existing theories and the creation of new conceptual frameworks in organizational behavior and human resource management. These findings can help managers and practitioners improve employer branding to engage their workforce effectively.

Originality/value

The authors have advanced social exchange theory by studying the link between employer branding and talent retention. The paper highlights the uniqueness of their investigation, which explores how employer branding influences talent retention with a focus on organizational advocacy, influenced by the level of support from supervisors and coworkers. This study will be a valuable resource for future academia, revealing the significant impact of employer branding on organizational advocacy and talent retention.
How can a global icon become a local icon? A qualitative case study of the Taipei Performing Arts Centre
Authors: Goudsmit Inge
Published: December 2024

Purpose

This study aims to redirect attention from the symbolic significance of global iconic architecture towards exploring its impact and significance within their situated urban context; seeking to unpack whether and how a “situated multiplicity” of residents collectively shape these structures into local icons through their embodied performance and active engagement, creating an “urban meaning” rather than symbolic meaning.

Design/methodology/approach

We conducted an inductive empirical analysis of the Taipei Performing Arts Centre (TPAC), using a mixed-method iterative approach including 160 surveys, observational mapping, and 53 interviews with citizens and experts in the TPAC neighbourhood.

Findings

The spectacular image of a global icon can sometimes alienate citizens because of its design, and thus affect their embodied performance. However, we found divergent interpretations of iconicity, including residents who see economic, cultural and social benefits, and contributions to the internationalisation of local urban landscapes. Future aspirations for engagement with the TPAC are centred on the public plaza, highlighting the importance of prioritising public spaces in the design and operation of iconic buildings to foster community engagement and social interactions.

Practical implications

The study’s findings have implications for policy makers, planners and architects seeking to embed global iconic buildings into neighbourhood planning initiatives.

Originality/value

Minimal scholarly attention has been paid to citizens’ perspectives of iconic buildings. By addressing this gap, we contribute to a holistic perspective of how active and embodied practices shape the urban context and give it meaning. Furthermore, this study suggests practical ways in which such buildings can serve various populations.
Insights into food security: affordability perspectives from Bayesian belief network models
Authors: Qazi Abroon
Published: December 2024

Purpose

This study investigates the dependencies between the Global Food Security Index (GFSI) and its affordability-related indicators using Bayesian belief network (BBN) models. The research also aims to prioritise these indicators within a probabilistic network setting.

Design/methodology/approach

The research utilises BBN models to analyse data from 113 countries in 2022. Nine indicators related to food affordability, including income inequality, safety net programmes and trade freedom, are examined to understand their impact on food security. The methodology involves statistical modelling and analysis to identify critical factors influencing food security and to provide a comprehensive understanding of the global food affordability landscape.

Findings

The study reveals that income inequality, the presence and efficacy of safety net programmes and the degree of trade freedom are significant determinants of food affordability and overall food security outcomes. The analysis reveals marked disparities in performance across different countries, highlighting the need for context-specific interventions. The findings suggest that improving safety net programmes, implementing trade policy reforms and addressing income inequality are crucial for enhancing food affordability and security.

Originality/value

This research contributes to the literature by using BBN models to comprehensively analyse the relationship between the GFSI and affordability-related indicators. The study provides novel insights into how different socioeconomic factors influence food security across a diverse range of countries. The study offers actionable recommendations for policymakers to address food security challenges effectively, thereby supporting the development of more equitable and resilient food systems globally.
Analysis of the impact of human resources employees’ perceptions on the process of digital transformation
Authors: Stef Anda , Crișan Emil Lucian
Published: December 2024

Purpose

Employees’ perceptions of digital transformation (DT) affect digital technology adoption and utilization. These attitudes, such as digital preparation or acceptance of digitization, are linked to personal and organisational resources. The goal is to assess employees’ impressions of (1) DT in general and (2) the organization’s DT efforts, focusing on how these efforts affect their field of activity and (3) their DT expectations.

Design/methodology/approach

Using the Unified Theory of Acceptance and Use Technology (UTAUT), a model was built and examined from three perspectives: demographic characteristics, employee views of DT and organisational activities in DT. We used semi-structured interviews with ten international HR employees to validate the model.

Findings

Because the IT company we studied has several digital technologies, global HR departments, and varied organisational contexts, we started with “purposive sampling”. The principal findings offer the model an extensive understanding of how demographic characteristics, employees’ views of digital transformation (DT), and organisational DT activities affect digital technology uptake and use expectations.

Originality/value

This research may help companies plan for HR department digital technology installation and use. The approach can enable further research on digital technology uptake in businesses and practical ways to meet employee expectations.
Experimental investigation of the post-fire response of single-shear bolted lap joints
Authors: Chakar Sara , El Ghor Ahmad , Hantouche Elie
Published: December 2024

Purpose

This study aims at investigating experimentally the behavior of single-shear bolted lap joints with N-bolts and X-bolts (XB) after exposure to fire temperatures.

Design/methodology/approach

Sixteen single-bolted lap joints with M20 Grade 8.8 bolt are heated to various targeted temperatures ranging from 400 °C to 900 °C and subsequently cooled back to ambient temperature. Following the heating and cooling stages, the specimens are subjected to direct tension tests to determine the reduction in shear capacity and slip resistance of the lap joints. Post-fire reduction factors are estimated from the axial load–displacement curves to determine the residual strength of N-bolted and X-bolted lap joints after exposure to fire temperatures. These reduction factors are incorporated into Equation J3-1 of ANSI/AISC 360 (2022) for the design of simple bolted connections acting in shear after fire exposure.

Findings

The results show that X-bolted lap joints exhibit a larger reduction in bolt shear capacities compared to those with N-bolts. The shear strength of lap joints with N-bolts begins to degrade after exposure to 500 °C, reaching a maximum reduction in shear strength of 40% at 900 °C. Conversely, the strength of lap joints with XB starts to degrade after exposure to temperatures beyond 400 °C, reaching a maximum reduction in shear strength of 42% at 750 °C. The post-fire reduction factors computed in this study showed that XB reduction factors are more conservative than the N-bolts and those available in the literature.

Practical implications

This study provides preliminary data for the development of design guidelines of bolted connections with N-bolts and XB after fire exposure.

Originality/value

This study provides preliminary data for the development of design guidelines of bolted connections with N-bolts and XB after fire exposure.