bluuebunny/crossref_metadata_2025 huggingface dataset:
Stressors and Subjective Cognition in Daily Life: Tests of Physical Activity and Age as Moderators
Authors: Stuart Nicole S. , Wen Jin H. , Klaiber Patrick , Puterman Eli , DeLongis Anita , Sin Nancy L.
Published: August 2024

Objective

Growing research indicates that daily stress is associated with poorer same-day cognitive performance, for example, memory and attention. However, it is unclear whether this relationship holds across diverse ages and engagement in physical activity (PA), or whether these factors might buffer the relationship between daily stress and subjective cognitive function.

Methods

Ecological momentary assessment data were collected from adults aged 25 to 88 years across British Columbia, Canada. For 14 days, participants (N = 204) wore a triaxial physical activity monitor, reported stressor occurrence in mobile surveys four times per day, and rated their subjective attention and memory at the end of each day.

Results

Multilevel models evaluated daily stressor occurrence as a predictor of subjective attention and memory, with same-day PA engagement and age as moderators. Subjective attention and memory were lower on days when a stressor had occurred, compared to stressor-free days. Neither PA nor age moderated the within-person associations of daily stressors with subjective cognition.

Conclusion

The lack of stress-buffering effects for same-day PA and age raises questions about the contexts in which PA promotes cognitive functioning and about age-related processes underlying stress and cognition. Future work could examine the mechanisms that might explain the link between daily stress and cognition function, as well as the associations of different intensity and forms of physical activity on stress across age groups.
Technologically Comprehensive Reconstruction of Fronto-Orbito-Sphenoidal Craniofacial Fibrous Dysplasia
Authors: Gharibi Loron Ali , Tunaboylu Mehmet Furkan , Bite Uldis
Published: August 2024

Craniofacial fibrous dysplasia (CFD) is a benign bone condition that presents unique challenges due to its proximity to vital organs, esthetic significance, and variability in each case. Consequently, a meticulous and personalized surgical approach becomes imperative. Diverse techniques and technologies have been employed sporadically to tackle various aspects of CFD. Our approach includes a comprehensive integration of emerging methods and technologies, encompassing presurgical strategizing, three-dimensional computer-aided manufacturing (3D-CAM), intraoperative navigation systems, and a prefabricated drilling guide in a fronto-orbito-sphenoidal CFD case. This combined strategy is aimed at effectively addressing the complexities of this demanding ailment. Moreover, a collaborative team consisting of plastic surgeons, neurosurgeons, and oculoplastic surgeons cooperates to orchestrate the procedure. Embracing a multidisciplinary team and a holistic technological strategy appears to be the key to addressing the multifaceted challenges posed by intricate conditions like CFD.
Applications of Extracellular Matrix Biomaterial in Tongue Reconstruction
Authors: Mosquera Camilo , Kang Sara , Ramirez Carlos A.
Published: August 2024

Tongue neoplasms are common in the head and neck region and are primarily treated through surgical interventions. Various reconstruction techniques, such as primary closure, skin grafts, skin substitute biomaterials, and free tissue transfer, are used to address the resulting defects. This study provides an overview of our experience utilizing extracellular matrix-based biomaterials (ECM) for the reconstruction of tongue defects and evaluates the mean volumetric size of postsurgical tongue. This retrospective case series evaluated subjects with tongue defects secondary to benign or malignant resections who underwent reconstruction with ECM-based biomaterials at Ascension Hospital from July 2022 to May 2023. Descriptive variables were collected, and descriptive statistical analyses were conducted. The primary outcome was the volume of postsurgical defect reconstructed. Twenty-five subjects were included: 10 had benign pathology and 15 had malignancy. The mean reconstructed defect volume was 12.65 cm3, ranging between 2 and 35 cm3. Postoperative bleeding, mainly linked to anticoagulation medication, occurred in 20% (n=5) of the cases, and the rate of need for additional procedures was 8%. In conclusion, ECM-based biomaterials are suitable for reconstructing varying sizes of postsurgical tongue defects with no donor-site morbidity. Carefully considering patient factors, including anticoagulation medication use and defect volume, is essential in optimizing outcomes.
Water-tank metabarrier for seismic Rayleigh wave attenuation
Authors: Russillo Andrea Francesco , Arena Felice , Failla Giuseppe
Published: August 2024

An innovative concept of metabarrier is presented for seismic Rayleigh wave attenuation, which consists of a periodic array of cylindrical water tanks acting as resonant units above the soil surface. A pertinent theoretical framework is developed and implemented in COMSOL Multiphysics. The framework treats the dynamics of the water tank by a well-established three-dimensional linear, pressure-based model for fluid-structure interaction under earthquake excitation, accounting for the flexibility of the tank wall; furthermore, the soil is idealized as a homogeneous and isotropic medium. Floquet-Bloch dispersion analysis of the unit cell demonstrates the presence of relevant band gaps in the low-frequency range below 20 Hz and in the higher frequency range as well. The dispersion analysis is validated by comparison with the frequency-domain analysis of a soil domain with a finite array of water tanks. The band gaps are of interest to attenuate seismic Rayleigh waves and, more generally, Rayleigh waves caused by other ground vibration sources such as road or railway traffic. The water-tank resonant units are readily tunable by varying the water level, which allows changing opening frequencies/widths of the wave attenuation zones. This is a remarkable advantage over alternative seismic metamaterials that, in general, are not designed to be tunable.

This article is part of the theme issue ‘Current developments in elastic and acoustic metamaterials science (Part 2)’.
Performance of low-threshold, population replacement gene drives in cage populations of the yellow fever mosquito, Aedes aegypti
Authors: Speth Zachary , Rehard David , Norton Patricia , Franz Alexander W.E.
Published: August 2024

Aedes aegypti is the predominant vector for arboviruses including dengue, Zika, and chikungunya viruses, which infect over 100 million people annually. Mosquito population replacement strategies in which pathogen-susceptible mosquitoes in the field are replaced by laboratory-engineered pathogen-resistant strains are novel genetic control measures to inhibit the spread of malaria or arboviral diseases in endemic regions. To suppress arbovirus transmission following this approach, a mosquito strain needs to be transgenically modified to express an antiviral effector molecule which is linked to a gene drive (GD) system to both inhibit viral replication in the mosquito and drive the engineered resistance trait throughout a wild-type population. As a proof-of-concept, we tested the performance of two single locus CRISPR-Cas9 based GD for Ae. aegypti population replacement in small cage populations over 12 generations. Starting from a low release threshold of 1:9 GD bearing males, we observed two GD constructs in which Cas9 was expressed from different promoters increase in frequency in all discrete, non-overlapping cage populations. By generation 12, 56-79% of mosquitoes in six cage populations had at least one GD copy. The allele frequencies of the GD increased from <5% at release to >50% by G7 post-release for the nanos-driven Cas9 GD and by G10 in populations harboring the zpg-driven Cas9 GD. Insertion and deletion mutation (indel) frequency was measured for each discrete generation in pooled samples from the six populations harboring GD. We found that populations with Cas9 expression under control of the nanos-promoter accumulated gene drive blocking indels (GDBI) at more than twice the rate of populations harboring the zpg-promoter driven GD. Both GD produced de novo mutations at similar rates, with a difference in selection being the primary cause of greater indel accrual in the nanos-driven GD populations. Our results demonstrate that two single-locus, CRISPR-Cas9-based homing GD located at an intergenic locus exhibit continuous super-Mendelian inheritance in populations of Ae. aegypti. We further analyze the effects of fitness cost on the stability of low-threshold CRISPR/Cas9 based GD in populations of Ae. aegypti. This study demonstrates the feasibility of low-threshold, single-locus Cas9 gene drives for Ae. aegypti population replacement.
A deep generative model for capturing cell to phenotype relationships
Authors: Weinberger Ethan , Yu Patrick , Lee Su-In
Published: August 2024

Single-cell omics has proven to be a powerful instrument for exploring cellular diversity. With advances in sequencing protocols, single-cell studies are now routinely collected from large-scale donor cohorts consisting of samples from hundreds of donors with the goal of uncovering the molecular bases of higher-level donor phenotypes of interest. For example, to better understand the mechanisms behind Alzheimer's disease, recent studies with up to hundreds of samples have investigated the relationships between single-cell omics measurements and donors' neuropathological phenotypes (e.g. Braak staging). In order to ensure the robustness of such findings, it may be desirable to aggregate data from multiple distinct donor cohorts. Unfortunately, doing so is not always straightforward, as different cohorts may be equipped with different sets of phenotype labels. Continuing the previous Alzheimer's example, recent AD study cohorts have provided various subsets of neuropathological phenotypes, cognitive testing results, and APOE genotype. Thus, it is desirable to be able to infer any missing phenotype labels such that all available cell-level data in the study of a given phenotype of interest could be used. Moreover, beyond simply imputing missing phenotype information, it is often of interest to understand which groups of cells and/or molecular features may be most predictive of a given phenotype of interest. As such, there is a pressing need for computational methods that can connect cell-level measurements with donor-level labels. However, accomplishing this task is not straightforward. While a rich literature exists on learning meaningful low-dimensional representations of cells and for inferring corresponding cell-level labels (e.g. cell type), the donor level prediction task introduces substantial additional complexity. For example, different numbers of cells may be recovered from each donor, and thus our prediction model must be able to handle arbitrary numbers of samples as input. Moreover, ideally our model would not a priori require any additional prior knowledge beyond our cell-level measurements, such as the importance of different cell types for a given prediction task. To resolve these issues, here we propose milVI (multiple instance learning variational inference), a deep generative modeling framework that explicitly accounts for donor-level phenotypes and enables inference of missing phenotype labels post-training. In order to handle varying numbers of cells per donor when inferring phenotype labels, milVI leverages recent advances in multiple instance learning. We validated milVI by applying to impute held-out Braak staging information from an Alzheimer's disease study cohort from Mathys et al, and we found that our method achieved lower error on this task compared to naive imputation methods.
Variable rRNA 2’-O-methylation fine-tunes ribosome function inSaccharomyces cerevisiae
Authors: Gillot Sandra , Marchand Virginie , Motorin Yuri , Baudin-Baillieu Agnès , Namy Olivier
Published: August 2024

Cellular processes are governed by the regulation of gene expression, often at the level of translation control. The mechanisms of control have been shown to operate at various levels, but there is growing evidence to suggest that rRNA modification patterns play a key role in driving translational modulation of the ribosome. We investigated the intricate relationship between modification status and the decoding activity of the ribosome. We found that the level of 2’-O-methylation at specific nucleotides in the rRNA affects the properties of the ribosome, with consequences for bothSaccharomyces. cerevisiaecell growth and antibiotic sensitivity. More precisely, we demonstrate that methylations within the peptide exit tunnel play an important role in nascent peptide folding. We also demonstrate the modulation of IRES-driven translation by variable methylation at the intersubunit surface of the 60S ribosomal subunit. These findings deepen our understanding of the mechanisms by which 2’-O-methylation confers functional specificity on the ribosome.
TFE3 fusions direct an oncogenic transcriptional program that drives OXPHOS and unveils vulnerabilities in translocation renal cell carcinoma
Authors: Li Jiao , Huang Kaimeng , McBride Fiona , Sadagopan Ananthan , Gallant Daniel S , Thakur Meha , Khanna Prateek , Li Bingchen , Ge Maolin , Weiss Cary N. , Achom Mingkee , Xu Qingru , Huang Kun , Ryback Birgitta A. , Gui Miao , Bar-Peled Liron , Viswanathan Srinivas R.
Published: August 2024

Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven byTFE3gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other renal cancers. This TFE3 fusion-driven OXPHOS program, together with heightened glutathione levels found in renal cancers, renders tRCCs sensitive to reductive stress – a metabolic stress state induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, includingEGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1a and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability to OXPHOS-dependent tRCC cells. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring.
Multimodal magnetic resonance imaging characterizes clinical outcome in chronic traumatic brain injury
Authors: Pélégrini-Issac Mélanie , Hezghia Adrienne , Caron Elsa , Delphine Sébastien , Battisti Valentine , Cassereau Didier , Debarle Clara , Lefort Muriel , Lesimple Blandine , Torkomian Grégory , Degos Vincent , Bernard Rémy , Galanaud Damien , Pradat-Diehl Pascale , Perlbarg Vincent , Bayen Eléonore , Puybasset Louis
Published: August 2024

Moderate to severe traumatic brain injury (TBI) should be considered as a chronic health condition. The corpus callosum is the brain region that suffers most from diffuse axonal injury, leading to long-term functional deficits. Few studies have considered the relationships between inter- and intrahemispheric functional connectivity and structural damages to the corpus callosum in chronic TBI patients. We examined how callosal functional connectivity and white matter alterations relate to clinical outcome using multimodal magnetic resonance imaging (MRI): structural MRI estimates callosal volume, diffusion-weighted MRI enables white matter integrity quantification, resting-state functional MRI assesses neural dysfunction. Seventy-four patients underwent a multimodal MRI session on average 5 years after a moderate-to-severe TBI. Multiple factorial analysis analyzed the relationships between clinical outcome (from severe disability to good recovery, assessed by the Glasgow Outcome Scale extended GOSE), callosal volume, diffusion metrics (fractional anisotropy and mean, axial, and radial diffusivity), and inter- and intrahemispheric functional connectivity. Multiple factorial analysis confirmed that patients with severe disability (GOSE 3-4) had more structural alterations in the corpus callosum than patients with a good recovery (GOSE 7-8). Most importantly, patients able to live independently but unable to work/study in a standard environment (GOSE 5-6) could not be described solely by structural features. They exhibited a lower interhemispheric connectivity between cortical regions mediated by the corpus callosum than patients with a good recovery, and a tendency towards a decrease in intrahemispheric connectivity compared with severely disabled patients. These findings suggest a complex long-term functional impact of moderate-to-severe TBI.
Efficacy, public health impact and optimal use of the Takeda dengue vaccine
Authors: Daniels Bethan Cracknell , Ferguson Neil , Dorigatti Ilaria
Published: August 2024

Dengue is the most common arboviral infection, causing substantial morbidity and mortality globally. The licensing of Qdenga, a second-generation vaccine developed by Takeda Pharmaceuticals, is therefore timely, but the potential public health impact of vaccination across transmission settings needs to be evaluated. To address this, we characterised Qdenga’s efficacy profile using mathematical models calibrated to published clinical trial data and estimated the public health impact of routine vaccine use. We find that efficacy depends on the infecting serotype, serological status, and age. We estimate that vaccination of children aged over six years in moderate to high dengue transmission settings (seroprevalence at 9 years of age > 60%) could reduce the burden of hospitalised dengue by 10-22% on average over ten years. We find some evidence of a risk of vaccine-induced disease enhancement in seronegative vaccine recipients for dengue serotypes 3 and 4, especially for children under six years of age. Because of this, the benefits of vaccination in lower transmission settings are more uncertain, and more data on the long-term efficacy of Qdenga against serotypes 3 and 4 are needed.
Systematic Review of Brain Mechanisms of Oral Multisensory Processing related to Oral Health
Authors: Lin Chia-Shu
Published: August 2024

Oral functions related to eating, including mastication, swallowing, and taste, are fundamentally a multisensory experience, that relies on the crossmodal interaction of touch, gustation, temperature, pain, and proprioception. While a majority of studies focus on the multisensory processing related to speech, the brain mechanisms of oral multisensory processing related to eating have remained unknown. The current systematic review will summarize the findings from neuroimaging studies (mainly functional magnetic resonance imaging) focusing on the interaction of multiple sensory stimuli in human participants. Neuroimaging studies of human adults on the interaction between multiple sensory stimuli related to oral functions and published in English were identified and extracted via three electronic databases and reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Nine primary studies were eligible to be included in this review. Three studies investigated the interaction of intraoral (i.e., sensorimotor, taste, and noxious) stimuli. Five studies investigated the interaction between intraoral and extraoral (i.e., auditory, olfactory, and visual) stimuli). One study investigated the audio-visual interaction on dental fear. The studies showed great diversity in the experimental design of crossmodal interaction. In terms of the brain features related to the interaction, the somatosensory and motor areas were mostly reported in the studies. The studies imply the potential application between oral neuroscience and oral healthcare, such as prosthodontic treatment and food selection. Still, the findings should be carefully interpreted due to the diversity in crossmodal interaction and inconsistency of experimental design between the studies. The current systematic review revealed that there have not been consistent findings about the underlying brain mechanisms due to the diversity in the experimental design of crossmodal interaction.
The immune response to SARS-CoV-2 as a recall response susceptible to immune imprinting: a prospective cohort study
Authors: Alvarez-Sierra Daniel , Martínez-Gallo Mónica , Sánchez-Montalvá Adrián , Fernández-Sanmartín Marco , Colobran Roger , Espinosa-Pereiro Juan , Poyatos-Canton Elísabet , Zurera-Egea Coral , Sánchez-Pla Alex , Violan Concepción , Parra Rafael , Alzayat Hammad , Vivancos Ana , Morandeira-Rego Francisco , Urban-Vargas Blanca , Martínez-Cáceres Eva , Hernández-González Manuel , Bas-Minguet Jordi , Katsikis Peter D. , Teniente-Serra Aina , Pujol-Borrell Ricardo
Published: August 2024

Background

The antibody response to SARS-CoV-2 does not follow the immunoglobulin isotype pattern expected in a primary response and is inconsistent with the current interpretation of COVID-19 immunopathology as the result of a primary infection. To better understand the immune response to SARS-CoV-2, it is essential to determine whether it is primary or secondary (or recall). The analysis of highly granular immunological variable trajectories of a homogeneous cohort of patients receiving standardised medical care should discern between primary and secondary responses.

Methods

This is a prospective cohort study of 191 SARS-CoV-2 infection cases and 44 healthy controls from the second wave of COVID-19 in the Barcelona area. The study stratified patients by severity and analysed the trajectories of SARS-CoV-2 antibodies and multiple immune variables for features associated with primary and recall immune responses.

Findings

Isotype-specific antibody trajectories to SARS-CoV-2 proteins revealed a pattern of recall response in 94·2% of cases. In these cases, the detailed trajectories of plasmablasts, B cells, cTfh high-resolution subsets, and cytokines were consistent with a secondary response. The transcriptomic data indicated that this cohort is strictly comparable to contemporary cohorts.

Conclusions

In most cases, the immune response to SARS-CoV-2 is a recall response. This opens the possibility that most COVID-19 cases are subjected to immune imprinting by endemic coronavirus, which, in turn, can contribute to severity by interfering with the immune response to SARS-CoV-2 and by antibody-dependent enhancement. Considering the immune responses to SARS-CoV-2 secondary provides a better perspective to interpret COVID-19 pathology.

Funding

Grants COV20/00416, Cov20/00654, and COV20/00388 from Instituto de Salud Carlos III (ISCIII), Madrid, Spain, co-financed by the European Regional Development Fund (ERDF).
Transparency in the secondary use of health data: Assessing the status quo of guidance and best practices
Authors: R. van den Akker Olmo , Thibault Robert T. , Ioannidis John P. A. , Schorr Susanne G. , Strech Daniel
Published: August 2024

We evaluated what guidance exists in the literature to improve the transparency of studies that make secondary use of health data. To find relevant literature, we searched PubMed and Google Scholar and drafted a list of health organizations based on our personal expertise. We quantitatively and qualitatively coded different types of research transparency: registration, methods reporting, results reporting, data sharing, and code sharing. We found 54 documents that provide recommendations to improve the transparency of studies making secondary use of health data, mainly in relation to study registration (n = 27) and methods reporting (n = 39). Only three documents made recommendations on data sharing or code sharing. Recommendations for study registration and methods reporting mainly came in the form of structured documents like registration templates and reporting guidelines. Aside from the recommendations aimed directly at researchers, we found 31 recommendations aimed at the wider research community, typically on how to improve research infrastructure. Limitations or challenges of improving transparency were rarely mentioned, highlighting the need for more nuance in providing transparency guidance for studies that make secondary use of health data.
Benchmarking the Confidence of Large Language Models in Clinical Questions
Authors: Omar Mahmud , Agbareia Reem , Glicksberg Benjamin S , Nadkarni Girish N , Klang Eyal
Published: August 2024

Background and Aim

The capabilities of large language models (LLMs) to self-assess their own confidence in answering questions in the biomedical realm remain underexplored. This study evaluates the confidence levels of 12 LLMs across five medical specialties to assess their ability to accurately judge their responses.

Methods

We used 1,965 multiple-choice questions assessing clinical knowledge from internal medicine, obstetrics and gynecology, psychiatry, pediatrics, and general surgery areas. Models were prompted to provide answers and to also provide their confidence for the correct answer (0–100). The confidence rates and the correlation between accuracy and confidence were analyzed.

Results

There was an inverse correlation (r=-0.40, p=0.001) between confidence and accuracy, where worse performing models showed paradoxically higher confidence. For instance, a top performing model, GPT4o had a mean accuracy of 74% with a mean confidence of 63%, compared to a least performant model, Qwen-2-7B, which showed mean accuracy 46% but mean confidence 76%. The mean difference in confidence between correct and incorrect responses was low for all models, ranging from 0.6% to 5.4%, with GPT4o having the highest differentiation of 5.4%.

Conclusion

Better performing LLMs show more aligned overall confidence levels. However, even the most accurate models still show minimal variation in confidence between right and wrong answers. This underscores an important limitation in current LLMs’ self-assessment mechanisms, highlighting the need for further research before integration into clinical settings.
Testing of retail cheese, butter, ice cream and other dairy products for highly pathogenic avian influenza in the US
Authors: Suarez David L. , Goraichuk Iryna V. , Killmaster Lindsay , Spackman Erica , Clausen Nicole J. , Colonius Tristan J. , Leonard Cynthia L. , Metz Monica L.
Published: August 2024

The recent outbreak of highly pathogenic avian influenza (HPAI) in dairy cows has created public health concerns about the potential of consumers being exposed to live virus from commercial dairy products. Previous studies support that pasteurization effectively inactivates avian influenza in milk and an earlier retail milk survey showed viral RNA, but no live virus could be detected in the dairy products tested. Because of the variety of products and processing methods in which milk is used, additional product testing was conducted to determine if HPAI viral RNA could be detected in retail dairy samples, and for positive quantitative real-time RT-PCR (qRT-PCR) samples to be tested for presence of live virus. Revised protocols were developed to extract RNA from solid dairy products including cheese and butter. The solid dairy product was mechanically liquified with garnet and zirconium beads in a bead beater diluted 1 to 4 with BHI media. This pre-processing step was suitable in allowing efficient RNA extraction with standard methods. Trial studies were conducted with different cheese types with spiked in avian influenza virus to show that inoculation of the liquified cheese into embryonating chicken eggs was not toxic to the embryos and allowed virus replication. A total of 167 retail dairy samples, including a variety of cheeses, butter, ice cream, and fluid milk were collected as part of nationwide survey. A total of 17.4% (29/167) of the samples had detectable viral RNA by qRT-PCR targeting the matrix gene, but all samples were negative for live virus after testing with embryonating egg inoculation. The viral RNA was also evaluated by sequencing part of the hemagglutinin gene using a revised protocol optimized to deal with the fragmented viral RNA. The sequence analysis showed all viral RNA positive samples were highly similar to previously reported HPAI dairy cow isolates. Using the revised protocols, it was determined that HPAI viral RNA could be detected in a variety of dairy products, but existing pasteurizations methods effectively inactivate virus assuring consumer safety.
The accuracy of large language models in labelling neurosurgical ‘case-control studies’ and risk of bias assessment: protocol for a study of interrater agreement with human reviewers
Authors: Igoli Joanne , Osunronbi Temidayo , Olukoya Olatomiwa , Daniel Jeremiah Oluwatomi Itodo , Alemenzohu Hillary , Kanu Alieu , Kihunyu Alex Mwangi , Okeleke Ebuka , Oyoyo Henry , Shekoni Oluwatobi , Jesuyajolu Damilola , Alalade Andrew F
Published: August 2024

Introduction

Accurate identification of study designs and risk of bias (RoB) assessment is crucial for evidence synthesis in research. However, mislabelling of case-control studies (CCS) is prevalent, leading to a downgraded quality of evidence. Large Language Models (LLMs), a form of artificial intelligence, have shown impressive performance in various medical tasks. Still, their utility and application in categorising study designs and assessing RoB needs to be further explored. This study will evaluate the performance of four publicly available LLMs (ChatGPT-3.5, ChatGPT-4, Claude 3 Sonnet, Claude 3 Opus) in accurately identifying CCS designs from the neurosurgical literature. Secondly, we will assess the human-LLM interrater agreement for RoB assessment of true CCS.

Methods

We identified thirty-four top-ranking neurosurgical-focused journals and searched them on PubMed/MEDLINE for manuscripts reported as CCS in the title/abstract. Human reviewers will independently assess study designs and RoB using the Newcastle-Ottawa Scale. The methods sections/full-text articles will be provided to LLMs to determine study designs and assess RoB. Cohen’s kappa will be used to evaluate human-human, human-LLM and LLM-LLM interrater agreement. Logistic regression will be used to assess study characteristics affecting performance. Ap-value < 0.05 at a 95% confidence interval will be considered statistically significant.

Conclusion

If the human-LLM agreement is high, LLMs could become valuable teaching and quality assurance tools for critical appraisal in neurosurgery and other medical fields. This study will contribute to validating LLMs for specialised scientific tasks in evidence synthesis. This could lead to reduced review costs, faster completion, standardisation, and minimal errors in evidence synthesis.
Plasma and CSF neurofilament light chain distinguish neurodegenerative from primary psychiatric conditions in a clinical setting
Authors: Eratne Dhamidhu , Kang Matthew JY , Lewis Courtney , Dang Christa , Malpas Charles B , Keem Michael , Grewal Jasleen , Marinov Vladimir , Coe Amy , Kaylor-Hughes Cath , Borchard Thomas , Keng-Hong Chhoa , Waxmann Alexandra , Saglam Burcu , Kalincik Tomas , Kanaan Richard , Kelso Wendy , Evans Andrew , Farrand Sarah , Loi Samantha , Walterfang Mark , Stehmann Christiane , Li Qiao-Xin , Collins Steven , Masters Colin L , Santillo Alexander F , Zetterberg Henrik , Blennow Kaj , Berkovic Samuel F , Velakoulis Dennis ,   The MiND Study Group
Published: August 2024

INTRODUCTION

Many patients with neurodegenerative disorders (ND) face diagnostic delay and misdiagnosis. We investigated blood and cerebrospinal fluid (CSF) neurofilament light chain (NfL) to distinguish ND from primary psychiatric disorders (ND), a common challenge in clinical settings.

METHODS

Plasma and CSF NfL levels were measured and compared between groups, adjusting for age, sex, weight.

RESULTS

337 participants included: 136 ND, 77 PPD, 124 Controls. Plasma NfL was 2.5 fold elevated in ND compared to PPD and had strong diagnostic performance (area under the curve, AUC 0.86, 81%/85% specificity/sensitivity) that was comparable to CSF NfL (2 fold elevated, AUC 0.89, 95%/71% specificity/sensitivity). Diagnostic performance was especially strong in younger people (40-<60years). Additional findings were cut-offs optimised for sensitivity and specificity, and issues important for future clinical translation

CONCLUSIONS

This study adds important evidence for a simple blood-based biomarker to assist as a screening test for neurodegeneration and distinction from PPD, in clinical settings.
Genotyping sequence-resolved copy-number variations using pangenomes reveals paralog-specific global diversity and expression divergence of gene duplication
Authors: Ma Walfred , Chaisson Mark JP
Published: August 2024

Copy-number variable (CNV) genes are important in evolution and disease, yet sequence variation in CNV genes remains a blindspot in large-scale studies. We present ctyper, a method that leverages pangenomes to produce allele-specific copy numbers with locally phased variants from NGS reads. Benchmarking on 3,351 CNV genes includingHLA,SMN, andCYP2D6, and 212 challenging medically-relevant (CMR) genes poorly mapped by NGS, ctyper captures 96.5% of phased variants with ≥99.1% correctness of copy number on CNV genes and 94.8% of phased variants on CMR genes. Applying alignment-free algorithms, ctyper takes only 1.5 hours to genotype a genome on a single CPU. Its results improve predictions of gene expression compared to known eQTL variants. Allele-specific expression quantified divergent expression on 7.94% of paralogs and tissue-specific biases on 4.68% of paralogs. We found reduced expression ofSMN-2 due toSMN1-conversions, potentially affecting spinal muscular atrophy, and increased expression of translocated duplications ofAMY2B. Overall, ctyper enables biobank-scale genotyping of CNV and CMR genes.
Predicting the translation efficiency of messenger RNA in mammalian cells
Authors: Zheng Dinghai , Persyn Logan , Wang Jun , Liu Yue , Montoya Fernando Ulloa , Cenik Can , Agarwal Vikram
Published: August 2024

The degree to which translational control is specified by mRNA sequence is poorly understood in mammalian cells. Here, we constructed and leveraged a compendium of 3,819 ribosomal profiling datasets, distilling them into a transcriptome-wide atlas of translation efficiency (TE) measurements encompassing >140 human and mouse cell types. We subsequently developed RiboNN, a multitask deep convolutional neural network, and classic machine learning models to predict TEs in hundreds of cell types from sequence-encoded mRNA features, achieving state-of-the-art performance (r=0.79 in human and r=0.78 in mouse for mean TE across cell types). While the majority of earlier models solely considered 5′ UTR sequence, RiboNN integrates contributions from the full-length mRNA sequence, learning that the 5′ UTR, CDS, and 3′ UTR respectively possess ~67%, 31%, and 2% per-nucleotide information density in the specification of mammalian TEs. Interpretation of RiboNN revealed that the spatial positioning of low-level di- and tri-nucleotide features (i.e., including codons) largely explain model performance, capturing mechanistic principles such as how ribosomal processivity and tRNA abundance control translational output. RiboNN is predictive of the translational behavior of base-modified therapeutic RNA, and can explain evolutionary selection pressures in human 5′ UTRs. Finally, it detects a common language governing mRNA regulatory control and highlights the interconnectedness of mRNA translation, stability, and localization in mammalian organisms.
Relative phase of distributed oscillatory dynamics implements a working memory in a simple brain
Authors: Dunn Raymond L. , Costello Caitriona , Borchardt Jackson M. , Sprague Daniel Y. , Chiu Grace C. , Miller Julia M. , L’Etoile Noelle , Kato Saul
Published: August 2024

We report the existence of a working memory system in the nematodeC. elegansthat is employed for deferred action in a sensory-guided decision-making process. We find that the turn direction of discrete reorientations during navigation is under sensory-guided control and relies on a working memory that can persist over an intervening behavioral sequence. This memory system is implemented by the phasic interaction of two distributed oscillatory dynamical components. The interaction of oscillatory neural ensembles may be a conserved primitive of cognition across the animal kingdom.
EMMPRIN confers metabolic advantage for monocytes and macrophages to promote disease in a model of multiple sclerosis
Authors: Kaushik DK , Das A , Silva C , D’Mello C , de Almeida LGN , Ghasemi N , Neri P , Dufour A , Bahlis NJ , Xue M , Yong VW
Published: August 2024

Monocytes and monocyte-derived macrophages have important roles in the initiation and progression of multiple sclerosis (MS). These cells undergo metabolic reprogramming to generate immunophenotypes that promote leukocyte infiltration, axonal degeneration and demyelination, worsening MS pathology. The mechanisms that dictate metabolic programs in monocytes and macrophages in MS remain unclear. We previously reported that extracellular matrix metalloproteinase inducer (EMMPRIN, CD147), a glycoprotein that acts as a chaperone of monocarboxylate transporter 4 (MCT4), assisted with glycolysis-driven pro-inflammatory phenotype in macrophages in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Using newly-generated CCR2CreERT2:EMMPRINfl/fl(CCR2:EMMP) mice, we report that presymptomatic deletion of EMMPRIN in CCR2+ monocytes prevented or reduced clinical disability of EAE. This was correspondent with decreased infiltration of leukocytes into the CNS. Single cell RNA-seq of blood monocytes from EAE and proteomics analysis of macrophages from CCR2:EMMP−/−mice revealed significant alterations in metabolic programs, particularly reduced glycolysis and elevated mitochondrial electron transport and fatty acid oxidation, which were linked to their reduced pro-inflammatory traits. Our findings implicate EMMPRIN as a key regulator of metabolic pathways that exacerbate pro-inflammatory functions of monocytes in MS.
Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukaemia
Authors: Lewis Alexander C. , Gruber Emily , Franich Rheana , Armstrong Jessica , Kelly Madison J. , Opazo Carlos M. , Mawal Celeste H. , Birrell Alexandra , So Joan , Ting Keziah , Brown Fiona , Wei Andrew H. , Powell Jason A. , Brown Kristin K. , Johnstone Ricky W. , Kats Lev M.
Published: August 2024

The ubiquitous metabolite heme has diverse enzymatic and signalling functions in most mammalian cells. Cells can salvage heme from the extracellular environment or synthesise hemede novofrom succinyl-CoA and glycine through a series of 8 enzymatic reactions catalysed by heme biosynthesis enzymes (HBEs) localised in the mitochondria and the cytosol1,2. Through integrated analyses of mouse models, human cell lines and primary patient samples, we identifyde novoheme biosynthesis as a selective dependency in acute myeloid leukaemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukaemic stem cells (LSCs) to downregulate HBEs. The resultant low heme state upregulates self-renewal genes via the heme sensing transcription factor BACH1, but also places leukaemia cells on the threshold of heme starvation. Genetic or pharmacological inhibition of HBEs induces cuproptosis, a form of programmed cell death caused by copper accumulation and oligomerisation of lipoylated proteins3. Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that controls gene expression and drug sensitivity in AML and implicates HBE inhibition as a novel cuproptosis trigger.
Examining NF-κB genomic interactions by ChIP-seq and CUT&Tag
Authors: Daly Allison E. , Schiffman Allison , Hoffmann Alexander , Smale Stephen T.
Published: August 2024

An understanding of the mechanisms and logic by which transcription factors coordinate gene regulation requires delineation of their genomic interactions at a genome-wide scale. Chromatin immunoprecipitation-sequencing (ChIP-seq) and more recent techniques, including CUT&Tag, typically reveal thousands of genomic interactions by transcription factors, but without insight into their functional roles. Due to cost and time considerations, optimization of ChIP experimental conditions is typically carried out only with representative interaction sites rather than through genome-wide analyses. Here, we describe insights gained from the titration of two chemical crosslinking reagents in genome-wide ChIP-seq experiments examining two members of the NF-κB family of transcription factors: RelA and c-Rel. We also describe a comparison of ChIP-seq and CUT&Tag. Our results highlight the large impact of ChIP-seq experimental conditions on the number of interactions detected, on the enrichment of consensus and non-consensus DNA motifs for the factor, and on the frequency with which the genomic interactions detected are located near potential target genes. We also found considerable consistency between ChIP-seq and CUT&Tag results, but with a substantial fraction of genomic interactions detected with only one of the two techniques. Together, the results demonstrate the dramatic impact of experimental conditions on the results obtained in a genome-wide analysis of transcription factor binding, highlighting the need for further scrutiny of the functional significance of these condition-dependent differences.
Epidemiological inferences from serological responses to cross-reacting pathogens
Authors: O’Driscoll Megan , Hozé Nathanaël , Lefrancq Noémie , Ribeiro Dos Santos Gabriel , Hoinard Damien , Rahman Mohammed Ziaur , Paul Kishor Kumar , Naser Titu Abu Mohd , Alam Mohammad Shafiul , Hossain Mohammad Enayet , Vanhomwegen Jessica , Cauchemez Simon , Gurley Emily S , Salje Henrik
Published: August 2024

Multiplex immunoassays are facilitating the parallel measurement of antibody responses against multiple antigenically-related pathogens, generating a wealth of high-dimensional data which depict complex antibody-antigen relationships. In this study we develop a generalizable analytical framework to maximise inferences from multi-pathogen serological studies. We fit the model to measurements of IgG antibody binding to 10 arboviral pathogens from a cross-sectional study in northwest Bangladesh with 1,453 participants. We used our framework to jointly infer the prevalence of each pathogen by location and age, as well as the levels of between-pathogen antibody cross-reactivity. We find evidence of endemic transmission of Japanese encephalitis virus as well as recent outbreaks of dengue and chikungunya viruses in this district. Our estimates of antibody cross-reactivity were highly consistent with phylogenetic distances inferred from genetic data. Further, we demonstrated how our framework can be used to identify the presence of circulating cross-reactive pathogens that were not directly tested for, representing a potential opportunity for the detection of novel emerging pathogens. The presented analytical framework will be applicable to the growing number of multi-pathogen studies and will help support the integration of serological testing into disease surveillance platforms.
Loss of PI5P4Kα slows the progression of aPtenmutant basal cell model of prostate cancer
Authors: Triscott Joanna , Lehner Marika , Benjak Andrej , Reist Matthias , Emerling Brooke M. , Ng Charlotte K.Y. , de Brot Simone , Rubin Mark A.
Published: August 2024

While early prostate cancer (PCa) depends on the androgen receptor (AR) signaling pathway, which is predominant in luminal cells, there is much to be understood about the contribution of epithelial basal cells in cancer progression. Herein, we observe cell-type specific differences in the importance of the metabolic enzyme phosphatidylinositol 5-phosphate 4-kinase alpha (PI5P4Kα; gene namePIP4K2A) in the prostate epithelium. We report the development of a basal-cell-specific genetically engineered mouse model (GEMM) targetingPip4k2aalone or in combination with the tumor suppressor phosphatase and tensin homolog (Pten). PI5P4Kα is enriched in basal cells, and no major histopathological changes were detectable following gene deletion. Notably, the combined loss ofPip4k2aslowed the development ofPtenmutant mouse prostatic intraepithelial neoplasia (mPIN). Through the inclusion of a lineage tracing reporter, we utilize single-cell RNA sequencing to evaluate changes resulting fromin vivodownregulation ofPip4k2aand characterize cell populations influenced in the established Probasin-Cre and Cytokeratin 5 (CK5)- Cre driven GEMMs. Transcriptomic pathway analysis points towards the disruption of lipid metabolism as a mechanism for reduced tumor progression. This was functionally supported by shifts of carnitine lipids in LNCaP PCa cells treated withsiPIP4K2A. Overall, these data nominate PI5P4Kα as a target for PTEN mutant PCa.

One Sentence Summary

Loss of PI5P4Kα slows cancer progression in prostate basal cells.
VARIETAL SCREENING OF BLACKGRAM GENOTYPES AGAINST CERCOSPORA LEAF SPOT (Cercospora canescens)
Authors: Shrestha Siddhanta , Bohara Sinchan , Oli Sarita , Nainabasti Anjal , Bohara Khem Raj , Upadhyaya Kriti , Basnet Indira
Published: August 2024

Screening of 12 blackgram genotypes against Cercospora Leaf Spot (Cercospora canescens) was carried out in RCB design with 3 replications in research plot of Mid-West Academy and Research Institute, Tulsipur, Dang during Bhadra to Mangsir, 2078 B.S. The blackgram genotypes were brought from Grain Legumes Research Program, Khajura, Banke. Disease severity was taken 3 times at 40, 47, and 54 days after sowing. Disease scoring was done as a percentage of leaf area infected on the individual plant at 7-day intervals and disease incidence, disease severity, mean AUDPC, and mean yield was calculated. Disease incidence was not significant among the tested genotypes. Disease severity at 40, 47, and 54 DAS was highly significant among the genotypes. Mean disease score and mean area under disease progressive curve (AUDPC) were also highly significant. Among the genotypes, 10 genotypes were categorized as moderately resistant and 2 genotypes (BLG 0066-1-1 and BLG 0035-1) were categorized as moderately susceptible. The highest Mean AUDPC value (324.1) was possessed by BLG 0035-1 followed by BLG 0066-1-1 (317.6). The lowest mean AUDPC value (175) was possessed by BLG 0069-1. A highly significant difference was found in yield among the black gram genotypes. The highest yield (799 kg/ha) by obtained by BLG 0068-2 followed by Rampur mas (769 kg/ha). The lowest yield (495 kg/ha) was obtained by BLG 0066-1.