bluuebunny/crossref_metadata_2025 huggingface dataset:
Reading Between the Tabloids: An Objective Analysis of the Quality and Readability of Patient Encountered Online Material for Face Transplantation
Authors: Boroumand Sam , Littleton Adam , Aregbe Abidemi , Gu Emily , Huelsboemer Lioba , Stögner Viola A. , Lewis Katelyn , Kauke-Navarro Martin , Haykal Siba , Pomahac Bohdan
Published: October 2024

Face transplantation is a highly sensationalized procedure in the media. The purpose of this study is to assess the content and readability of online materials that prospective patients/public encounter regarding face transplantation. A search for face transplantation was performed on Google. Sites were categorized under 3 groups: established face transplant programs, informational third-party sources (eg, Wikipedia), and news article/tabloid sites. Each site was assessed for readability using 6 different readability metrics, while quality was assessed utilizing JAMA benchmark criteria and DISCERN instrument. One-way ANOVA with post hoc Tukey’s multiple comparisons test was used for analysis. News sources were significantly easier to read than face transplant program sites (10.4 grade reading level vs. 12.4). For the JAMA benchmark, face transplant programs demonstrated the lowest average score relative to third-party sites, and news sources (2.05 vs. 2.91 vs. 3.67, respectively; P<0.001), but had significantly greater DISCERN scores than news sources (53.50 vs. 45.83, P=0.019). News sources were significantly more accessible, readable, and offered greater transparency of authorship compared with reputable sources, despite their lack of expertise on face transplantation. Face transplant programs should update their websites to ensure readability and accessibility of the information provided to the public.
Reading Between the Lines
Authors: Prelock Patricia A. , Knox Sophie , Sepede Elaina , Morris-Baldridge Hope
Published: October 2024

Autistic children experience challenges with narrative language and theory of mind (ToM). This pilot study examined the effects of a parent-led narrative intervention on the ToM of eight school-aged autistic children. Parents read three storybooks over a six-week period emphasizing ToM constructs (i.e., visual perspective-taking, emotion recognition, and false belief understanding). Parents used a script with guiding questions and comments to facilitate their child’s ToM during book reading activities. Two standardized measures of ToM were completed before and following the six-week intervention. Parents also completed daily diaries, reflecting on their child’s understanding of ToM targets emphasized in the book readings. Improved scores on the Theory of Mind Inventory-2 occurred for all but one child and improved scores on the Theory of Mind Task Battery occurred for five of the eight children. Parents’ perceptions of their child’s ToM also indicated improvement from pre- to post-intervention, and parents generally perceived the intervention as effective. Parents effectively delivered a book reading intervention focusing on the development of their child’s ToM skills. The findings from this pilot study offer promise for parent-led intervention for their autistic children and improvements in children’s ToM.
The Post-transplant Lymphoproliferative Disorders—Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol
Authors: Dharnidharka Vikas R. , Wylie Kristine M. , Wylie Todd N. , Ruzinova Marianna B. , Goss Charles W. , Storch Gregory A. , Mehta-Shah Neha , Byers Derek , Walther Leslie , Jaza Lujain , Gu Hongjie , Agarwal Mansi , Green Michael , Moore Erika , Swerdlow Steven H. , Silveira Fernanda , Marks Lianna J. , Gratzinger Dita , Bagg Adam , Law Soi Cheng , Gandhi Maher
Published: October 2024

Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%–80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome. However, the precision medicine tools for determining if a viral genome variant is pathogenic are very limited compared with human genome variants. Further, targeted studies have not implicated a specific viral etiological agent in EBV-negative PTLD. Using novel cutting-edge technologies, we are extracting viral nucleic acids from formalin-fixed, paraffin-embedded archived, or frozen PTLD tissues or plasma, to test for all vertebrate viruses simultaneously in an unbiased fashion, using metagenomic shotgun sequencing (MSS). We are collecting such samples from multiple transplant centers to address the following specific aims and close the following knowledge gaps: (1) Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by PCR) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; (2) determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral groupings, confirmed by other techniques; and (3) develop the necessary computational, algorithmic and software analytic tools required to determine association of EBV genome variants with worse presentations or outcomes in PTLD. Study completion will contribute to better patient care and may provide avenues for novel therapies.
Loss of IVNS1ABP, a gigaxonin paralogue, leads to a progeroid neuropathy due to impaired proteostasis
Authors: Bonnard Carine , Ali Ain Nur , Yuan Fang , Tan Kiat Y. , Lim Yan T. , Chan Puck W. , Ramanathan Nanthini , Kamsani Nur A.B.M. , Chaganty Vindhya , Xiong Ding , Tan Ye S. , Chou Shu-Min , Chourabi Marwa , Narayanan Gunaseelan , Ng Alvin Y.J. , Tohari Sumanty , Yang Meah W. , Karaman Birsen , Turgut Gözde T. , Szenker-Ravi Emmanuelle , Sobota Radoslaw M. , Chen Zhuoyao , Bullock Alex N. , Fathallah Rajaa , Altunoglu Umut , Byrappa Venkatesh , Mathuru Ajay S. , Shboul Mohammad , Zhang Su-Chun , Reversade Bruno
Published: October 2024

Impaired proteostasis can induce protein aggregation which is toxic to neuronal cells, contributing to neurodegeneration and other signs of aging. In this study, we delineate an early-onset progressive neuropathy evoking Giant Axonal Neuropathy 1. The causative geneIVNS1ABPencodes a E3-ubiquitin ligase adaptor which is a close gigaxonin paralogue. Patient-derived fibroblasts, iPSCs, and neural progenitors exhibited hallmarks of protein accumulation and lysosomal dysfunction. Ubiquitome analysis revealed overlapping targets with gigaxonin, including Vimentin and MAP1B. The biallelic correction to the isogenic wildtype state in disease- relevant motor neurons partly rescued cellular vulnerabilities. A newly generatedivns1abpa/bknockout zebrafish model partially recapitulated the human peripheral neuropathy, exhibiting aberrant primary motor neuron axon pathfinding, leading to impaired locomotion. Our findings indicate that IVNS1ABP functions in the same pathway as gigaxonin, ensuring appropriate cellular turnover of critical protein substrates, whose accumulation leads to accelerated aging in discrete cellular lineages.
Genular: An Integrated Platform for Defining Cellular Identity and Function through Single-Cell Gene Expression and Multi-Domain Biological Data
Authors: Tomic Ivan , Hao Stephanie P , Tomic Adriana
Published: October 2024

Accurately defining cellular identity and function is essential for advancing immunology, understanding disease mechanisms, and developing targeted therapies. However, current bioinformatics tools are limited in their ability to integrate and analyze the vast and diverse single-cell RNA sequencing (scRNA-seq) datasets available, hindering the comprehensive capture of cellular heterogeneity and the identification of subtle genetic changes across immune states, differentiation pathways, and tissue contexts. To overcome these challenges, we introducegenular, an open-source platform that unifies gene expression data analysis across diverse cell types by integrating scRNA-seq data with extensive genomic and proteomic information from 16 databases, including NCBI Gene, Human Protein Atlas, STRING, and UniProt.genularaggregates data from more than 2,893 scRNA-seq experiments, encompassing over 74.5 million unique cells across various tissues and conditions. A key feature ofgenularis calculating a cell marker score for each gene, enabling the quantification of gene expression across cells to derive unique profiles specific to cell types, states, and lineages. Usinggenular, we differentiate T cell memory states, map differentiation profiles by tracking gene expression changes as monocytes mature into macrophages and lymphoid progenitor cells develop into T cells, and capture tissue-specific reprogramming of macrophages, revealing distinct gene expression profiles that enable specialized functions in different tissues. By integrating scRNA-seq data with multi-domain biological information and employing advanced statistical methodologies,genularprovides a scalable platform that accurately defines cellular identities, functional states, and differentiation pathways. This comprehensive approach facilitates breakthroughs in immunology, gene regulation, cellular differentiation, and disease research, enabling a deeper understanding of immune cell functions and their roles in health and disease.
Tricked by Edge Cases: Can Current Approaches Lead to Accurate Prediction of T-Cell Specificity with Machine Learning?
Authors: Culka Martin , Orlova Darya
Published: October 2024

The ability to predict T-cell receptor (TCR) specificity computationally could revolutionize personalized immunotherapies, vaccine development, and the understanding of immunology and autoimmune diseases. While progress depends on obtaining training data that represent the vast range of possible TCR-ligand pairs, systematic assessment of modeling assumptions is equally important and can begin with existing data. We illustrate this by evaluating two ideas currently present in the field1,2: treating TCR specificity and T cell activation as distinct modeling tasks, and using unsupervised models based on sequence similarity for TCR specificity prediction. Although presented as general strategies, we argue these are exceptions rather than universally applicable principles.
Altered AP-1, RUNX and EGR chromatin dynamics drive fibrotic lung disease
Authors: Valenzi Eleanor , Jia Minxue , Gerges Peter , Fan Jingyu , Tabib Tracy , Behara Rithika , Zhou Yuechen , Sembrat John , Das Jishnu , Benos Panayiotis V , Singh Harinder , Lafyatis Robert
Published: October 2024

Pulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1himacrophages as drivers of fibrosis. Single-cell RNA sequencing has delineated fibroblast and macrophages transcriptomes, but limited insight into transcriptional control of profibrotic gene programs. To address this challenge, we analyzed multiomic snATAC/snRNA-seq on explanted SSc-ILD and donor control lungs. The neural network tool ChromBPNet inferred increased TF binding at single base pair resolution to profibrotic genes, including CTHRC1 and ADAM12, in fibroblasts and SPP1 and CCL18 in macrophages. The novel algorithm HALO confirmed AP-1, RUNX, and EGR TF activity controlling profibrotic gene programs and established TF-regulatory element-gene networks. This TF action atlas provides comprehensive insights into the transcriptional regulation of fibroblasts and macrophages in healthy and fibrotic human lungs.
Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer
Authors: Thomas-Jardin Shayna , Suresh Shruthy , Arce Ariana , Novaresi Nicole , Stein Emily , Thomas Lisa , Lewis Cheryl , Ahn Chul , Evers Bret M. , Salvatierra Maria E. , Lui Wei , Khan Khaja , Soto Luisa Maris Solis , Wistuba Ignacio , Minna John D. , O’Donnell Kathryn A.
Published: October 2024

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity. Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. We show that CD155 and PD-L1 are coordinately induced by the ISR, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames (uORFs) in their 5′ UTRs. Analysis of primary human lung tumors identifies a significant correlation between PD-L1 and CD155 expression. ISR activation accelerates tumorigenesis and inhibits T cell function, effects that can be overcome by combining PD-1 blockade with the ISR inhibitor ISRIB. These studies uncover a novel mechanism by which two immune checkpoint proteins are coordinately regulated and suggest a new therapeutic strategy for lung cancer patients.

Statement of Significance

This study uncovers a novel mechanism for the coordinated translational regulation of the PD- L1/PD1 and CD155/TIGIT immune checkpoint pathways and highlights the ISR as a therapeutic vulnerability for lung cancer. Inhibition of the ISR pathway bolsters PD-1 blockade, potentially unveiling a new therapeutic strategy for lung cancer patients.
Probing Biomass Precursor Synthesis as a Key Factor in Microbial Adaptation to Unadapted Carbon Sources
Authors: Cai Jingyi , Liu Jiayu , Wei Fan , Wu Wenjun , Xu Wenqi , Mao Zhitao , Yuan Qianqian , Ma Hongwu
Published: October 2024

Industrial microorganisms often face challenges in utilizing renewable substrates such as methanol, formate, and xylose. We present findings that the proportion of biomass precursors that must be synthesized from unadapted carbon sources is a critical determinant of the evolutionary driving force and minimal substrate requirements, using a new computational framework, AdaptUC. We predict metabolic engineering strategies for Adaptive Laboratory Evolution (ALE). These strategies enable microorganisms to co-utilize an adapted co-substrate and an unadapted carbon source or, in some cases, rely exclusively on the unadapted source. AdaptUC was validated through experimental records and literature, confirming its effectiveness in identifying gene knockout strategies. Case studies inEscherichia coliandCorynebacterium glutamicumhighlight superior strategies with higher driving forces and reduced substrate requirements. This method has the potential to transform industrial biosynthesis by enabling more efficient use of renewable carbon sources.

Graphic Abstract
Endothelial cell stiffness and type drive the formation of biomechanically-induced transcellular pores
Authors: Siadat Seyed Mohammad , Li Haiyan , Millette Brigid A. , Safa Babak N. , Wong Cydney A. , Fard M. Reza Bahrani , Braakman Sietse T , Tay Ian , Bertrand Jacques A. , Read A. Thomas , Schildmeyer Lisa A. , Perkumas Kristin M. , Stamer W. Daniel , Overby Darryl R. , Ethier C. Ross
Published: October 2024

Formation of transcellular pores facilitates the transport of materials across endothelial barriers. In Schlemm’s canal (SC) endothelium, impaired pore formation is associated with glaucoma. However, our understanding of the cellular processes responsible for pore formation is limited by lack ofin vitroassays. Here, we present a novel platform for studying transcellular pore formation in human endothelial cells. We induced pores in SC cells by seeding them atop micron-sized magnetic beads followed by application of a magnetic field to subject cells to a basal to apical force, mimickingin vivobiomechanical forces. The pore formation process was dynamic, with pores opening and closing. Glaucomatous cells exhibited impaired pore formation that correlated with their increased stiffness. We further discovered that application of forces from the apical to basal direction did not induce pores in SC cells but resulted in formation of pores in other types of endothelial cells. Our studies reveal the central role of cell mechanics in formation of transcellular pores in endothelial cells, and provide a new approach for investigating their associated underlying mechanism/s.
CpGPT: a Foundation Model for DNA Methylation
Authors: de Lima Camillo Lucas Paulo , Sehgal Raghav , Armstrong Jenel , Higgins-Chen Albert T. , Horvath Steve , Wang Bo
Published: October 2024

DNA methylation is a critical epigenetic modification that regulates gene expression and plays a significant role in development and disease processes. Here, we present the Cytosine-phosphate-Guanine Pretrained Transformer (CpGPT), a novel foundation model pretrained on over 1,500 DNA methylation datasets encompassing over 100,000 samples from diverse tissues and conditions. CpGPT leverages an improved transformer architecture to learn comprehensive representations of methylation patterns, allowing it to impute and reconstruct genome-wide methylation profiles from limited input data. By capturing sequence, positional, and epigenetic contexts, CpGPT outperforms specialized models when finetuned for aging-related tasks, including chronological age prediction, mortality risk, and morbidity assessments. The model is highly adaptable across different methylation platforms and tissue types. Furthermore, analysis of sample-specific attention weights enables the identification of the most influential CpG sites for individual predictions. As a foundation model, CpGPT sets a new benchmark for DNA methylation analysis, achieving strong performance in the Biomarkers of Aging Challenge, where it placed second overall in chronological age estimation and first on the public leaderboard in methylation-based mortality prediction.

Highlights

CpGPT is a novel foundation model for DNA methylation analysis, pretrained on over 1,500 datasets encompassing 100,000+ samples.

The model demonstrates strong performance in zero-shot tasks including imputation, array conversion, and reference mapping.

CpGPT achieves state-of-the-art results in mortality prediction and chronological age estimation.

Sample-specific interpretability is enabled through analysis of attention weights.
Hypermut 3: Identifying specific mutational patterns in a defined nucleotide context that allows multistate characters
Authors: Lapp Zena , Yoon Hyejin , Foley Brian , Leitner Thomas
Published: October 2024

The detection of APOBEC3F- and APOBEC3G-induced mutations in virus sequences is useful for identifying hypermutated sequences. These sequences are not representative of viral evolution and can therefore alter the results of downstream sequence analyses if included. We previously published the software Hypermut, which detects hypermutation events in sequences relative to a reference. Two versions of this method are available as a webtool. Neither of these methods consider multistate characters or gaps in the sequence alignment. Here, we present an updated, user-friendly web and command-line version of Hypermut with functionality to handle multistate characters and gaps in the sequence alignment. This tool allows for straightforward integration of hypermutation detection into sequence analysis pipelines. As with the previous tool, while the main purpose is to identify G to A hypermutation events, any mutational pattern and context can be specified.

Availability and implementation

Hypermut 3 is written in Python 3. It is available as a command-line tool athttps://github.com/MolEvolEpid/hypermut3and as a webtool athttps://www.hiv.lanl.gov/content/sequence/HYPERMUT/hypermutv3.html.

Contact

tkl@lanl.govorseq-info@lanl.gov
Structural and functional insights into nuclear role of Parkinson’s Disease-associated α-Synuclein
Authors: Jos Sneha , Kambaru Archanalakshmi , Prasad Thazhe Kootteri , Parthasarathi Shylaja , Kamariah Neelagandan , Nath Sangeeta , Padmanabhan Balasundaram , Padavattan Sivaraman
Published: October 2024

α-Synuclein (αSyn) plays a critical role in the pathogenesis of ‘Synucleinopathies’. Although increased nuclear αSyn localization induces neurotoxicity, its definitive physiological role remains elusive. Previous studies on nuclear αSyn are limited to its interactions with individual histones and dsDNA, leaving a significant gap in understanding its interactions with assembled histone H2a-H2b dimer and (H3-H4)2tetramer, as well as its role in chromatin regulation. Here, we demonstrated that αSyn binds specifically to both H2a-H2b and (H3-H4)2with high affinity. Truncation studies revealed that αSyn(1-103) region interacts with (H3-H4)2, while the acidic (121-140) C-terminal end is crucial for H2a-H2b binding. Sequence analysis suggests αSyn-dimer binding region contains a conserved DEF/YxP motif present in other dimer-binding histone chaperones. High-resolution structure of αSyn- dimer binding region with H2a-H2b complex reveals that αSyn adopts two binding modes (BM1 and BM2). In BM-1, αSyn utilizes nucleosomal DNA-binding surface, while in BM-2, it engages with both DNA- and the H3-interaction interface. Additionally, dimer recognition by αSyn overlaps with other dimer-binding histone chaperones, suggesting αSyn’s potential role in the nucleosome assembly/disassembly process.
Tumor-specific antibodies elicited by engineered bacteria promote bladder cancer immunotherapy
Authors: Rouanne Mathieu , Chen Noah , Mariuzza Dylan L. , Li Fangda , de los Santos-Alexis Kenia , Savage Thomas M. , Vincent Rosa L. , Mendelsohn Cathy L. , Danino Tal , Arpaia Nicholas
Published: October 2024

The intratumoral microbiome has recently emerged as a new hallmark of cancer, with implications for response or resistance to therapy. While bacteria can either promote or inhibit cancer growth, intratumoral bacteria can also be engineered using synthetic biology to remodel the tumor microenvironment. Here, we engineered the probiotic bacteriumE. coliNissle 1917 (EcN) to express the human chemokine CXCL13, a critical component of germinal center (GC) formation. The GC reaction is a fundamental aspect of adaptive immunity by which antibody affinity develops in secondary lymphoid organs for defense against pathogens. Using orthotopic models of bladder cancer, engineered CXCL13-expressing EcN colonized bladder tumors and elicited GC responses in bladder tumor–draining lymph nodes after intravesical delivery. Furthermore, when combined with PD-1 blockade, engineered EcN amplified the antitumor antibody response and promoted long-term survival and protective immunity upon tumor rechallenge. Thus, we demonstrate that synthetically engineered CXCL13-expressing EcN can enhance the efficacy of PD-1 checkpoint blockade immunotherapy by amplifying tumor-specific humoral immunity.
Scalable Fabrication of a Tough and Recyclable Spore-Bearing Biocomposite Thermoplastic Polyurethane
Authors: Kim Han Sol , White Evan M. , Crane Grant , Patel Kush , Noh Myung Hyun , Rahman Md Arifur , Feist Adam M. , Locklin Jason J. , Pokorski Jonathan K.
Published: October 2024

Thermoplastic polyurethanes (TPUs) are a class of versatile thermoplastic elastomers where most of their products lack a proper recycling strategy or have no end-of-life solutions. To pursue a sustainable end-of-life solution for TPU based products, self-disintegrating biocomposite TPUs have recently been developed by embedding spores of TPU-degrading bacteria into TPUs using melt extrusion. Herein, we improve upon spore-bearing biocomposites and demonstrate industrially-relevant manufacturing conditions for the fabrication of biocomposite TPUs. Spore production was modified to reduce the innate brown color of the resulting materials and, effectively minimize the coloration of biocomposite TPUs. Reduction of FeSO4in a sporulation media generated white spores without compromising spore productivity, viability, morphology or heat-shock tolerance. Biocomposite TPUs containing white spores displayed a 45% increase in toughness compared to TPUs without spores, while retaining ∼90% spore viability post processing. Furthermore, biocomposite TPU fabrication was demonstrated using a scalable continuous extruder followed by injection molding. Biocomposite TPUs generated by these industry-relevant processes exhibited comparable toughness improvement and spore viability to biocomposite TPU prepared using a lab scale microcompounder, while enhancing productivity by 30-fold. Finally, spore addition improved biocomposite TPUs recyclability, enabling 80% toughness retention after 5 rounds of iterative melt processing. Additionally, no negative effect on the lifespan of the generated TPUs was observed over a duration of 1 year of storage. Overall, this study confirmed that spore-bearing biocomposite TPUs are promising for practical applications, offering an accessible method to enhance toughness and sustainability of commercial TPUs through the incorporation of spore-based living fillers.
Towards Robust Evaluation of Protein Generative Models: A Systematic Analysis of Metrics
Authors: Strashnov Pavel , Shevtsov Andrey , Meshchaninov Viacheslav , Ivanova Maria , Nikolaev Fedor , Kardymon Olga , Vetrov Dmitry
Published: October 2024

Abstract

The rapid advancement of protein generative models necessitates robust and principled methods for their evaluation and comparison. As new models of increasing complexity continue to emerge, it is crucial to ensure that the metrics used for assessment are well-understood and reliable. In this work, we conduct a systematic investigation of commonly used metrics for evaluating protein generative models, focusing on quality, diversity, and distributional similarity. We examine the behavior of these metrics under various conditions, including synthetic perturbations and real-world generative models. Our analysis explores different design choices, parameters, and underlying representation models, revealing how these factors influence metric performance. We identify several challenges in applying these metrics, such as sample size dependencies, sensitivity to data distribution shifts, and computational efficiency trade-offs. By testing metrics on both synthetic datasets with controlled properties and outputs from state-of-the-art protein generators, we provide insights into each metric’s strengths, limitations, and practical applicability. Based on our findings, we offer a set of practical recommendations for researchers to consider when evaluating protein generative models, aiming to contribute to the development of more robust and meaningful evaluation practices in the field of protein design.
Evaluation of a Functional Portable Hemodialysis Machine, XKIDNEY
Authors: Lee Jake K. , Derya Dilara , Yang Hanui , Lee Patrick C.
Published: October 2024

Chronic kidney failure and end-stage renal disease (ESRD) are increasing globally, but home hemodialysis offers a critical means of improving patient quality of life and reducing national healthcare costs. This study investigates the performance of a portable hemodialysis (HD) device named XKIDNEY. The efficacy and safety of the device were determined with focus on solute clearance, fluid balancing accuracy, and blood cell integrity in an ex-vivo test environment. A comparison of the performance of XKIDNEY and a conventional HD unit showed that XKIDNEY had superior balancing accuracy without any technical malfunction. In addition, low molecular weight solutes, such as urea and creatinine, were effectively removed. These findings demonstrate that XKIDNEY enhances treatment portability without compromising performance and indicate XKIDNEY is a feasible home hemodialysis option.
Mechanisms ofPseudomonas aeruginosaresistance to Type VI Secretion System attacks
Authors: Tejada-Arranz Alejandro , Plack Annika , Antelo-Varela Minia , Kaczmarczyk Andreas , Klotz Alexander , Jenal Urs , Basler Marek
Published: October 2024

The Type VI Secretion System (T6SS) is a molecular nanomachine that injects toxic effector proteins into the environment or neighbouring cells, playing an important role in interbacterial competition and host antagonism during infection. Pseudomonas aeruginosa encodes three T6SSs. The H1-T6SS delivers toxins in response to attacks mediated by the T6SS of aggressive bacteria, suggesting that P. aeruginosa can resist T6SS assaults. The mechanisms of resistance are poorly characterized. Here, we performed a CRISPRi screen to identify pathways involved in resistance to T6SS effectors of Acinetobacter baylyi and Vibrio cholerae. We show that members of the GacA/GacS regulon, such as the mag operon or aas, and GacA-independent factors, such as the outer membrane protein OprF, confer resistance to different types of T6SS toxins. Interestingly, some of these T6SS resistance mechanisms lead to higher antibiotic susceptibility, suggesting complex evolutionary links between T6SS and antibiotic resistance.
Sex difference in incidence of bipolar and anxiety disorders: findings from the Global Burden of Disease Study 2021
Authors: Zhu Xingke , Lv Qing
Published: October 2024

Background

Bipolar disorder and anxiety disorders are two prominent mental disorders that represent a significant global health challenge.

Objective

The Global Burden of Disease Study 2021 (GBD 2021) was employed to evaluate sex differences in the incidence of bipolar disorder (BD) and anxiety disorder (ANX) globally by year, age, and socioeconomic status.

Method

We estimated sex-specific incidence of BD and ANX from GBD 2021 globally and in 204 countries and territories from 1990 to 2021. The sociodemographic index (SDI) was used to gauge national socioeconomic development and the Health Organization (WHO) region was used as a division of regions. Differences in age-standardized incidence rates (ASRs) by sex (absolute and relative) and risk ratios (95% confidence interval) were calculated annually and by age. Annual percent change (APC) was calculated by joinpoint regression modeling and linear regression analyses were performed to explore the socioeconomic factors associated with sex differences in incidence.

Results

The absolute and relative sex difference in ASRs of BD showed a slight declining trend during 1990 and 2021, with absolute difference decreasing from 2.50 to 1.83, and relative difference decreasing from 1.08 to 1.06; The absolute and relative sex difference in ASRs of ANX showed an increasing trend during 1990 and 2021, with absolute difference increasing from 170.02 to 208.08, and relative difference increasing from 1.35 to 1.36. Worldwide, females had a higher risk of BD and ANX than males in 1990and 2021. The highest Risk ratios of BD and ANX were observed in the European Region in 2021.The greatest relative sex difference of BD was 1.09 in the age group of 30-34. The greatest relative difference of ANX was 1.51 in the age group of 20-24. Relative sex differences of BD and ANX were significantly and positively correlated with SDI (BD, standardized β = 0.27 (95% CI, 0.22 to 0.33),P< 0.001; ANX, standardized β = 0.80 (95% CI, 0.47 to 1.14),P< 0.001).

Conclusions

Sex difference in the incidence of anxiety disorders and bipolar disorder have persisted worldwide over the past several decades, and the rates have consistently been higher among females than males. The sex difference in the global incidence of bipolar disorder has shown a slight improvement, but that in the global incidence of anxiety disorders has not been effectively mitigated. The sex difference is even more pronounced at younger ages and in more developed nations. The findings emphasize the significance of sex-specific health policies to reduce sex differences in the incidence of bipolar and anxiety disorders.
Clinical evolution and medical resource utilization in adult patients with respiratory syncytial virus infection at a community hospital in Argentina
Authors: Bengolea Agustin , Ruiz Juan I , Vega Celina G. , Manzotti Matias , Zuccarino Nadia , Rey Ares Lucila
Published: October 2024

Objective

To describe the hospital medical resources used in adults hospitalized with respiratory syncytial virus infection and to evaluate the association of comorbidities with resource utilization and clinical outcomes.

Design

A retrospective cohort study was conducted using the electronic healthcare database of Hospital Alemán, Buenos Aires, Argentina. It included hospitalized patients aged 18 years or older who had a positive test for respiratory syncytial virus between September 2010 and December 2023. Data were analyzed using standard statistical methods following STROBE guidelines.

Results

Among 72 hospitalized adults with confirmed respiratory syncytial virus infection, the mean length of hospital stay was 12.18 days (SD 12.91), and 27 (37.5%) patients required intensive care unit admission. Healthcare resource utilization was substantial, with 26% needing non-invasive ventilation and 11% requiring mechanical ventilation. Additionally, 75% received antibiotics, and 68.05% were treated with corticosteroids. Cardiovascular comorbidities were significantly associated with severe disease outcomes and intensive care unit admission (OR 3.53, 95% CI: 1.00-12.54). Comparative analysis with 226 influenza patients showed respiratory syncytial virus patients had longer hospital stays and higher intensive care unit admission rates.

Conclusions

Respiratory syncytial virus infection in adults resulted in substantial medical resource utilization and significant intensive care unit admission and ventilation support requirements. Cardiovascular comorbidities are associated with increased severity and intensive care unit admission admissions. Compared to influenza, respiratory syncytial virus leads to longer hospital stays and higher intensive care unit admissions, highlighting the need for tailored management strategies for respiratory syncytial virus in adult populations. Further research should focus on optimizing treatment protocols and preventive measures for respiratory syncytial virus.
Neural field theory as a framework for modeling and understanding consciousness states in the brain
Authors: Polyakov Daniel , Robinson P.A. , Makbili Avigail , Gosseries Olivia , Shriki Oren
Published: October 2024

Understanding the neural correlates of consciousness remains a central challenge in neuroscience. In this study, we explore the potential of neural field theory (NFT) as a computational framework for representing consciousness states. While prior research has validated NFT’s capacity to differentiate between normal and pathological states of consciousness, the relationship of its parameters to the representation of consciousness levels remains unclear.

Here, we fitted a corticothalamic NFT model to EEG data collected from healthy individuals and patients with disorders of consciousness. We then comprehensively explored the correlations between the fitted NFT parameters and features extracted from both experimental and simulated EEG data, across various states of consciousness. The identified correlations not only highlight the model’s ability to differentiate between states of consciousness, but also shed light on the physiological bases of these states, pinpointing potential biomarkers.

Our results provide valuable insights into how consciousness levels are represented within the NFT framework and into the dynamics of brain activity across various consciousness states. This underscores the potential of NFT as a useful tool for consciousness research, facilitatingin-silicoexperimentation.
Restoring the Multiple Sclerosis Associated Imbalance of Gut Indole Metabolites Promotes Remyelination and Suppresses Neuroinflammation
Authors: Jank Larissa , Singh Saumitra S. , Lee Judy , Dhukhwa Asmita , Siavoshi Fatemeh , Joshi Deepika , Minney Veronica , Gupta Kanak , Ghimire Sudeep , Deme Pragney , Schoeps Vinicius A. , Soman Karthik , Ladakis Dimitrios , Smith Matthew , Borkowski Kamil , Newman John , Baranzini Sergio E. , Waubant Emmanuelle L. , Fitzgerald Kathryn C. , Mangalam Ashutosh , Haughey Norman , Kornberg Michael , Chamling Xitiz , Calabresi Peter A. , Bhargava Pavan
Published: October 2024

In multiple sclerosis (MS) the circulating metabolome is dysregulated, with indole lactate (ILA) being one of the most significantly reduced metabolites. We demonstrate that oral supplementation of ILA impacts key MS disease processes in two preclinical models. ILA reduces neuroinflammation by dampening immune cell activation as well as infiltration; and promotes remyelination andin vitrooligodendrocyte differentiation through the aryl hydrocarbon receptor (AhR). Supplementation of ILA, a reductive indole metabolite, restores the gut microbiome’s oxidative/reductive metabolic balance by lowering circulating indole acetate (IAA), an oxidative indole metabolite, that blocks remyelination and oligodendrocyte maturation. The ILA-induced reduction in circulating IAA is linked to changes in IAA-producing gut microbiota taxa and pathways that are also dysregulated in MS. Notably, a lower ILA:IAA ratio correlates with worse MS outcomes. Overall, these findings identify ILA as a potential anti-inflammatory remyelinating agent and provide insights into the role of gut dysbiosis-related metabolic alterations in MS progression.

One Sentence Summary

Indole lactate, a postbiotic metabolite reduced in MS, corrects gut microbiome metabolic imbalances associated with remyelination and neuroinflammation.
Minimally invasive electrocorticography (ECoG) recording in common marmosets
Authors: Spadacenta Silvia , Dicke Peter W. , Thier Peter
Published: October 2024

Electrocorticography (ECoG) enables high spatio-temporal resolution recordings of brain activity with excellent signal quality, making it essential for pre-surgical mapping in epilepsy patients and increasingly useful in neuroscience research, including the development of brain-machine interfaces. The relatively minimal cortical convolution in non-human primate (NHP) brains facilitates ECoG recordings, in particular in the common marmoset (Callithrix jacchus), whose lissencephalic (unfolded) brain surface provides broad cortical access. One of the key advantages of ECoG recordings is the ability to study interactions between distant brain regions. The standard approach is the usage of large electrode arrays, which, however, require extended trepanations and a trade-off between size and electrode spacing. This study introduces an alternative ECoG approach for examining interactions between multiple distant cortical areas in marmosets, combining the advantages of circumscribed trepanations with high-density electrode arrays at specific sites of interest. Two adult marmosets underwent ECoG implantation across frontal, temporal, and parietal regions of interest, assessed by circumscribed trepanations to position individual high density electrode arrays. Postoperative monitoring showed rapid recovery and no long-term complications. The animals remained healthy, and stable neural recordings were successfully obtained during behavioral tasks, highlighting the method’s effectiveness for long-term cortical monitoring.
The influence of temporal context on vision over multiple time scales
Authors: Lee Kacie , Rideaux Reuben
Published: October 2024

Past sensory experiences influence perception of the present. Multiple research subfields have emerged to study this phenomenon at different temporal scales. These fall into three categories: the influence of immediately preceding sensory events (micro), short sequences of events (meso), and regularities over long sequences of events (macro). In a single paradigm, we examined the influence of temporal context on perception at each scale. We identify two distinct mechanisms that operate across all scales. The first is moderated by attention and supports rapid motor responses to expected events. The second is independent of task-demands and dampens the feedforward neural responses to expected events, leading to unexpected events eliciting earlier and more precise neural representations. We further show that perceptual recall exclusively reflects neural representations during this initial feedforward stage and that serial dependence (recall biases towards previous events) is explained by expectation of sensory stability over time.
Prediction of dynamic balance state and recovery following stroke using fMRI graph analysis
Authors: Symonitz Or , Joubran Katherin , Puzis Rami , Shmuelof Lior
Published: October 2024

Stroke is associated with damage to neural tissue and is the leading cause of long-term sensory-motor disability in adults. Dynamic balance impairments are one of the most debilitating outcomes of stroke, leading to increased falls and loss of mobility. While the recovery of motor functions following stroke was shown to be affected by the initial brain damage, the ability to predict recovery based on neural markers is limited due to the involvement of multiple brain areas in dynamic balance, and the limited size of available datasets. We apply graph-theory-based neural markers to predict the extent of recovery in the presence of rehabilitative treatment and the passage of time on a dataset of 21 subjects after stroke. We report that global features are more informative than local features, describing individual regions. We also report that recovery level is predicted more accurately (85%) than dynamic balance state (76%). Our results demonstrate the feasibility of graph-based analyses on limited datasets and may contribute to clinical goal setting and to mapping the neural substrates of dynamic balance.
Investigating the Causal Link Between Serum Iron Status and Pernicious Anaemia Risk: A Mendelian Randomisation Study
Authors: Cimadevila Guillermo Comesaña , Thain Alfie , Dib Marie-Joe , Ahmadi Kourosh R
Published: October 2024

Introduction

Pernicious anaemia (PA) is characterised by vitamin B12deficiency due to autoimmune-mediated destruction of gastric parietal cells and the consequent loss of intrinsic factor. A considerable proportion of PA patients also exhibit iron deficiency (ID), both before or at (20.7-52%) and after (46.4%) PA diagnosis. However, findings from observational studies do not clarify whether ID contributes to PA risk or is a consequence of the PA disease process. Given the high prevalence of ID at PA diagnosis, we hypothesised that reduced iron status may play a causal role in PA risk.

Methodology

We conducted two-sample Mendelian Randomisation (MR) analyses to evaluate the causal effect between systemic iron status and PA risk. Genetic association data for iron status were sourced from the deCODE study. Additionally, PA-relevant associative data with the chosen SNPs were obtained from genome-wide-association-study (GWAS) summary statistics, primarily from R10FinnGenrelease and from the GWAS conducted by Laisk et al. (2021) for replication purposes. Participant data consisted of 3,694 cases of PA and 393,684 controls. Inverse-variance weighted analysis was the primary MR method, with sensitivity analyses including Egger, and weighted-median estimates, additionally to testing for horizontal pleiotropy and heterogeneity.

Results

Four SNPs were strongly associated with systemic iron status and were used as genetic instruments. We found that genetically predicted iron status was not significantly associated with PA risk (odds ratio per 1 standard deviation increase in serum iron: 1.13, 95% confidence interval 0.80-1.58,P=0.49). Sensitivity analyses had consistent results, indicating that MR assumptions were not violated and highlighting a null result subjectivity due to the presence of horizontal pleiotropy and heterogeneity.

Conclusion

This is the first MR study investigating the potential causal relationship between iron status and PA risk. Our results show that genetically predicted iron status is not associated with a significantly increased PA risk among individuals of European ancestry. Further research is needed to understand the manifestation of ID in PA.
AI-based deformable hippocampal mesh reflects hippocampal morphological characteristics in relation to cognition in healthy older adults
Authors: Park Wonjung , Valdés Hernández Maria del C. , Kim Jaeil , Muñoz Maniega Susana , Sneden Fraser , Ferguson Karen J. , Bastin Mark E. , Wardlaw Joanna M. , Cox Simon R. , Park Jinah
Published: October 2024

Magnetic resonance imaging (MRI)-derived hippocampus measurements have been associated with different cognitive domains. The knowledge of hippocampal structural deformations as we age has contributed to our understanding of the overall aging process. Different morphological hippocampal shape analysis methods have been developed, but it is unclear how their principles relate and how consistent are the published results in relation to cognition in the normal elderly in the light of the new deep-learning-based (DL) state-of-the-art modeling methods. We compared results from analysing the hippocampal morphology using manually-generated binary masks and a Laplacianbased deformation shape analysis method, with those resulting from analysing SynthSeg-generated hippocampal binary masks using a DL method based on the PointNet architecture, in relation to different cognitive domains. Whilst most previously reported statistically significant associations were also replicated, differences were also observed due to 1) differences in the binary masks and 2) differences in sensitivity between the methods. Differences in the template mesh, number of vertices of the template mesh, and their distribution did not impact the results.

Highlights

Newdeep-learning-based hippocampal 3D-shape modeling method replicates hippocampal shape reported associations with cognition

New deep-learning-based hippocampal 3D-shape modeling method has increased sensitivity than a conventional Lapalcian-based deformation method

Accuracy in hippocampal binary masks is crucial in the AI-based shape modeling method
Structural elements of cyanobacterial co-factor-independent phosphoglycerate mutase that mediate regulation by PirC
Authors: Orthwein Tim , Alford Janette Theresa , Becker Nathalie Sofie , Fink Phillipp , Forchhammer Karl
Published: October 2024

The 2,3-bisphosphoglycerate-independent phosphoglycerate mutase (iP-GAM) has been identified as a crucial regulating key point in the carbon storage metabolism of cyanobacteria. Upon nitrogen starvation, the iPGAM is inhibited by the PII-interacting regulator PirC, released from its interaction partner PII due to elevated 2-oxoglutarate levels. In-silico analysis of 338 different iPGAMs revealed a deep-rooted distinctive evolution of iPGAMs in cyanobacteria. Additionally, cyanobacterial iPGAMs possess a unique loop structure and an extended C-terminus. Our analysis suggests that iPGAM forms a complex with three individual PirC monomers. Complex affinity is affected by the unique loop and the C-terminal structural elements. A C-terminal truncated enzyme showed loss of control by PirC and two-fold increased enzymatic activity compared to the iPGAM-WT. By contrast, deleting the loop structure drastically reduced the activity of this variant. By replacing the WT iPGAM in Synechocystis with different iPGAM variants, in which these structural elements were deleted, it became apparent that deletion of the C-terminal element showed a similar overproduction of polyhydroxybutyrate as deletion of the iPGAM-regulator PirC. However, in contrast to the latter, these strains showed higher overall biomass accumulation, making them a better chassis for a production strain for PHB or other valuable substances than the PirC-deficient mutant. These findings significantly contribute to our understanding of the metabolic pathways in cyanobacteria and open up new avenues for further research in this field, inspiring future investigations and discoveries.