bluuebunny/crossref_metadata_2025 huggingface dataset:
Treading lightly: Quantitative estimates of seafloor contact for longline trap and hook fishing gear
Authors: Doherty Beau , Lacko Lisa , Kronlund Allen R , Alexander Kenyon , Cox Sean P.
Published: November 2024

Despite increasing calls for sustainability and ecosystem objectives to manage fishing gear interactions with bottom habitats there are few quantitative approaches for assessing risks from bottom contact fishing. Risk assessments for bottom longline fisheries are particularly challenging due to a lack of information for estimating bottom contact areas from longline gear. In this paper, we demonstrate how data sensors and video cameras deployed on fishing gear can be used to quantify the bottom contact area for longline trap and hook fishing gear from the British Columbia Sablefish fishery. Our bottom contact estimates indicate that Sablefish fishing risks to bottom habitat are low in the majority of fishing areas, since 91.8% of the area fished is expected to have had zero bottom contact over the last 17 years. For the other 8.2% of Sablefish fishing areas that experience some contact from fishing gear, the majority are only contacted once. This indicates that most habitats contacted by Sablefish gear can be expected to have a minimum of 17 years to recover between subsequent bottom contact events. We demonstrate an approach for estimating fisheries bottom contact that can be widely implemented across longline fisheries. Our findings address key data gaps in bottom impacts research for longline gear fisheries, allowing fishing risks to be quantified over fine spatial scales. Such quantitative approaches for habitat risk assessment can provide essential information for management decisions aimed at determining acceptable trade-offs between habitat preservation and fishery benefits.
A fish frontier? Itatiaia expedition and biodiversity repositories reveal gaps in fish occurrences in Brazil’s high-altitude aquatic ecosystems
Authors: Soares Guedes Gustavo Henrique , Pacheco da Luz Carlos Henrique , de Jesus Souza Victória , Araújo Francisco Gerson
Published: November 2024

Brazil harbors one of the greatest diversities of freshwater fish in the world; however, the presence or absence of fish in high-altitude aquatic ecosystems remains largely unknown. This study aims to investigate fish occurrence on the Itatiaia Plateau (Itatiaia National Park) at altitudes ranging from 2,140 to 2,543 meters, marking one of the highest-altitude fish surveys conducted in Brazil. Additionally, it analyzes gaps in fish distribution above 2,000 meters in Brazil by compiling approximately 1 million occurrence records from digital biodiversity repositories (SpeciesLink, Salve, SIBBr). Results from the Itatiaia expedition and biodiversity repositories converge to indicate a lack of fish records in high-altitude aquatic ecosystems (> 2,000 m) in Brazil.Psalidodon scabripinnis(Jenyns 1842) is the species with the highest recorded altitude (∼1,944 m). Challenging climatic conditions, physical barriers to dispersal, isolation, historical absence, sampling gaps, and repository biases may be associated with this lack of fish occurrences. This study highlights gaps in knowledge of fish distribution and the potential for future research to discover previously unknown species or species adapted to high altitudes in Brazil.
RNA gradients can guide condensates toward promoters: implications for enhancer-promoter contacts and condensate-promoter kissing
Authors: Goh David , Kannan Deepti , Natarajan Pradeep , Goychuk Andriy , Chakraborty Arup K.
Published: November 2024

We study how protein condensates respond to a site of active RNA transcription (i.e., a gene promoter) due to electrostatic protein-RNA interactions. Our results indicate that condensates can show directed motion towards the promoter, driven by gradients in the RNA concentration. Analytical theory, consistent with simulations, predicts that the droplet velocity has a non-monotonic dependence on the distance to the promoter. We explore the consequences of this gradient-sensing mechanism for enhancer-promoter (E-P) communication using polymer simulations of the intervening chromatin chain. Directed motion of enhancer-bound condensates can, together with loop extrusion by cohesin, collaboratively increase the enhancer-promoter contact probability. Finally, we investigate under which conditions condensates can exhibit oscillations in their morphology and in the distance to the promoter. Oscillatory dynamics are caused by a delayed response of transcription to condensate-promoter contact and negative feedback from the accumulation of RNA at the promoter, which results in charge repulsion.
Bidirectional Peptide Conformation Prediction for MHC Class II using PANDORA
Authors: Rademaker Daniel T. , Parizi Farzaneh M. , van Vreeswijk Marieke , Eerden Sanna , Marzella Dario F. , Xue Li C.
Published: November 2024

Recent discoveries have transformed our understanding of peptide binding in Major Histocompatibility Complex (MHC) molecules, showing that peptides, for some MHC class II alleles, can bind in a reverse orientation (C-terminus to N-terminus) and can still effectively activate CD4+ T cells. These finding challenges established concepts of immune recognition and suggests new pathways for therapeutic intervention, such as vaccine design.

We present an updated version of PANDORA, which, to the best of our knowledge, is the first tool capable of modeling reversed-bound peptides. Modeling these peptides presents a unique challenge due to the limited structural data available for these orientations in existing databases. PANDORA has overcome this challenge through integrative modeling using algorithmically reversed peptides as templates.

We have validated the new PANDORA feature through a series of experiments, achieving an average backbone binding-core L-RMSD value of 0.63 Å. Notably, it maintained low RMSD values even when using templates from different alleles and peptide sequences. Our results suggest that PANDORA will be an invaluable resource for the immunology community, aiding in the development of targeted immunotherapies and vaccine design.

Availability

Source code and data is freely available athttps://github.com/X-lab-3D/PANDORA; Contact:Li.Xue@radboudumc.nl
Asymmetric gene flow maintains an abundant range center
Authors: Hancock Zachary B. , Adams Nicole E. , Wood Perry L. , Bradburd Gideon S.
Published: November 2024

The abundant center hypothesis postulates that population density is the highest in the center of the range and declines towards the periphery. While many evolutionary hypotheses have been offered to explain what generates this pattern, ecologically it’s assumed the pattern emerges due to increasing distance from a species ideal niche with edge populations occupying a “marginal” niche of low suitability. However, the ubiquity of the abundant center pattern has recently been questioned. Furthermore, it has proven difficult to assess both the pattern of the abundant center and the potential generative scenarios (e.g., gene swamping, migration limitation) due to the inherent complexity of species ranges. In this study, we evaluate the suitability of the abundant center hypothesis to explain patterns of genetic diversity and inbreeding in shovel bugs – small, sand-burrowing coastal crustaceans. In addition, we evaluate potential biases in migration direction due to the dominant current regimes in the North Atlantic using a common method for querying the site frequency spectrum, the directionality index (𝜓). While patterns of genetic diversity are consistent with an abundant center, we find a strong signature of recent central colonization from the range periphery. Using simulations, we evaluate the performance of 𝜓 under different migration regimes, finding that, in the presence of asymmetric migration, it strongly infers an edge-to-center colonization dynamic. We conclude that asymmetric migration towards the center can lead to signatures of an abundant center without necessarily implying a reduction in niche quality towards the range periphery.
Assessing Structures and Conformational Ensembles of Apo and Holo Protein States Using Randomized Alanine Sequence Scanning Combined with Shallow Subsampling in AlphaFold2 : Insights and Lessons from Predictions of Functional Allosteric Conformations
Authors: Raisinghani Nishank , Parikh Vedant , Foley Brandon , Verkhivker Gennady
Published: November 2024

Proteins often exist in multiple conformational states, influenced by the binding of ligands or substrates. The study of these states, particularly the apo (unbound) and holo (ligand-bound) forms, is crucial for understanding protein function, dynamics, and interactions. In the current study, we use AlphaFold2 that combines randomized alanine sequence masking with shallow multiple sequence alignment subsampling to expand the conformational diversity of the predicted structural ensembles and capture conformational changes between apo and holo protein forms. Using several well-established datasets of structurally diverse apo-holo protein pairs, the proposed approach enables robust predictions of apo and holo structures and conformational ensembles, while also displaying notably similar dynamics distributions. These observations are consistent with the view that the intrinsic dynamics of allosteric proteins is defined by the structural topology of the fold and favors conserved conformational motions driven by soft modes. Our findings support the notion that AlphaFold2 approaches can yield reasonable accuracy in predicting minor conformational adjustments between apo and holo states, especially for proteins with moderate localized changes upon ligand binding. However, for large, hinge-like domain movements, AlphaFold2 tends to predict the most stable domain orientation which is typically the apo form rather than the full range of functional conformations characteristic of the holo ensemble. These results indicate that robust modeling of functional protein states may require more accurate characterization of flexible regions in functional conformations and detection of high energy conformations. By incorporating a wider variety of protein structures in training datasets including both apo and holo forms, the model can learn to recognize and predict the structural changes that occur upon ligand binding.
Investigating the causal network of dementia by employing a causal discovery approach combined with natural language processing models
Authors: Yu Xinzhu , Lophatananon Artitaya , Holmes Vivien , Muir Kenneth R. , Guo Hui
Published: November 2024

INTRODUCTION

Comprehensively studying modifiable risk factors altogether to explore how they contribute to dementia mechanism is imperative for effective interventions.

METHODS

This study utilized natural language processing (NLP) models to pre-select candidate risk factors of dementia from 5,505 variables in the UK Biobank. We then took a holistic machine learning approach, fast causal inference in combination with mixed graphical models, to explore the complex causal mechanisms underlying dementia from 120 imputed variables.

RESULTS

The identified causal network highlighted eight risk factors which may directly or indirectly contribute to dementia. In particular, mental disorders due to brain damage and dysfunction and to physical disease were identified as direct causes as well as mediators on the causal pathways to dementia. Evidence for a direct causal impact of phenotypic age on dementia was less pronounced.

DISCUSSION

Our study offered valuable insights into the mechanisms of dementia. Beyond direct connections to nerve or brain disorders, the potential direct link with biological age highlights its possible value in dementia management. Moreover, the use of NLP models for variable pre-selection introduced an innovative application to medical research. Our study added weight to the accruing evidence that machine learning has a promising future for exploring complex disease mechanisms from high-dimensional data.
TREATMENT OUTCOMES AND ASSOCIATED FACTORS AMONG SEVERELY MALNOURISHED UNDER-FIVE CHILDREN ADMITTED TO JINKA GENERAL HOSPITAL, SOUTH ARI ZONE, SOUTH E THIOPIA REGION
Authors: Tukura Turufat
Published: November 2024

Introduction

Recurrent drought has contributed to household level food insecurity that resulted in malnutrition in the zone. This contributed to high prevalence of children malnutrition.

At the Jinka General Hospital the treatment outcomes and associated factors were not identified by research where there are high admissions of children with severe acute malnutrition with significant mortality. Therefore, this study was aimed to conduct a retrospective review of records of children admitted with severe acute malnutrition to Jinka General Hospital to assess treatment outcomes and associated factors at stabilization centre

Objective

This study was to assess treatment outcomes and associated factors in children with severe acute malnutrition admitted to Jinka General Hospital.

Method

A hospital record-based data analysis study was conducted to assess the treatment outcomes and associated factors of severe acute malnutrition among a total of 453 children aged 0 to 6 months and 6–59 months old. Severe acute malnutrition registration book and patient charts was used as a source of data. Data was entered into STATA version 16 for analysis. Ordered logistic regression was used to analyse treatment outcome with successful (cured), death (poor) and unknown (unsatisfactory). Variables at P-value <0.05 were considered as predictors of treatment outcome among children admitted with Severe Acute Malnutrition (SAM).

Results

Rehydration Solution for Malnutrition (ResoMal), educational status of mother, exclusive breast feeding, returned defaulter, severe wasting with bilateral Pitting oedema (Marasmus-Kwashiorkor), Infants 0-6 Months of age, and Unconscious were the substantial predictors of death among children admitted with SAM. Whereas therapeutic milk F-100, Gentamycin, sex of the child (male), rural residence, new admission, bilateral Pitting Oedema +++(Kwashiorkor), and some dehydrations were the predictors of recovery among the SAM cases.

Conclusion

exclusive breast feeding, and educational status of mother are the prevention of malnutrition. Targeted intervention of cases based on the enter category to stabilization centres is imperative for better outcome. The study also highlighted that the cure rate was below the SPHERE treatment outcome standard and death rate was at alarming rate according to SPHERE standard and national treatment outcome indicator. Thus, the study recommends management of SAM children through adherence with National Guideline for the Management of Acute Malnutrition in Ethiopia and empowering of women and girls to improve their literacy. This will contribute to improve household level food preparation practice and services to prevent malnutrition among children.
Comprehensive genetic analysis ofSTRCvariants in hereditary hearing impairment using long-read sequencing
Authors: Tsai Cheng-Yu , Lu Yue-Sheng , Chiang Yu-Ting , Lo Ming-Yu , Lin Pei-Hsuan , Tsai Shih-Feng , Hsu Chuan-Jen , Chen Pei-Lung , Hsu Jacob Shu-Jui , Wu Chen-Chi
Published: November 2024

Background: Sensorineural hearing impairment (SNHI) is a common disorder with a significant genetic component. Genetic testing for SNHI often involves next-generation sequencing (NGS), but SNHI-related pathogenicSTRCvariants cannot be directly addressed by conventional NGS due to the complex genomic scenario derived from large genomic rearrangements and a highly homologous pseudogene. Long-read sequencing (LRS) offers an unprecedented resolution to these challenges. Methods: We developed a comprehensive workflow that integrates the PacBio-based LRS approach with marker-mediated refinements to effectively address pseudogene contamination. This methodology was applied to analyze theSTRCgene in a cohort of 100 unrelated Taiwanese patients diagnosed with SNHI of unknown genetic cause after first-tier NGS testing. Results: We identified bi-allelicSTRCvariants in 11 patients (11% diagnostic yield), including homozygous deletions, compound heterozygous deletions and conversions, and compound heterozygous SNVs and CNVs. In total, we detected STRC variants in 27 patients, with 81.6% of these variants occurring in patients with mild to moderate SNHI. Conclusions: This study represents the first large-scale clinical investigation utilizing LRS technology for the genetic diagnosis of SNHI. Our study highlights the diagnostic capabilities of LRS in detecting complex variants within theSTRCand advancing our understanding of the genetic etiology of SNHI that remains unresolved by conventional NGS.
RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection
Authors: Li Yuanyuan , Gao Wenqing , Qiu Yuxin , Pan Jiasong , Guo Qingqing , Liu Xuehe , Geng Lu , Shen Yajie , Hu Zhidong , Li Suhua , Liu Shanshan , Yang Hua , Ge Baoxue , Fan Xiaoyong , Chen Xiangjun , Li Jixi
Published: November 2024

RING1 is an E3 ligase component of the polycomb repressive complex 1 (PRC1) with known roles in chromatin regulation and cellular processes such as apoptosis and autophagy. However, its involvement in inflammation and pyroptosis needs to be better characterized. Here, we found that human RING1, but not RING2, promoted K48-linked ubiquitination of Gasdermin D (GSDMD) and acted as a negative regulator of pyroptosis and bacterial infection.Ring1knockout mice increased the bacterial loads and mortality rate by treatment ofS. typhimurium. Upon infection byM. tuberculosis(Mtb) H37Rv strain, RING1 deletion initially reduced bacterial loads but later increased lung inflammation and impaired immune defense responses in mice. Also,Ring1knockout exacerbated acute sepsis induced by lipopolysaccharide (LPS). Mechanistically, RING1 directly interacts with GSDMD and ubiquitinates the K51 and K168 sites of GSDMD for K48-linked proteasomal degradation, thereby inhibiting pyroptosis. Inhibition of RING1 E3 ligase activity by mutation or small molecular compound increased GSDMD level and cell death during pyroptosis. Our findings reveal that RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection, highlighting RING1 as a potential therapeutic target for combating infectious diseases.

Graphic Abstract

Highlights

E3 ubiquitin ligase RING1 targets GSDMD for proteasomal degradation.

Mice lacking RING1 are more vulnerable toS. typhimuriuminfection and LPS- induced sepsis.

In the early stages ofM. tuberculosis(Mtb) infection,Ring1-/-mice exhibit efficient bacterial clearance.

Chronic inflammation inRing1-/-mice impairs the ability to control Mtb in the late stages of infection.
Nucleosome repositioning in cardiac reprogramming
Authors: Harris Sonalí , Baksh Syeda S. , Wang Xinghua , Anwar Iqra , Pratt Richard E. , Dzau Victor J. , Hodgkinson Conrad P.
Published: November 2024

Early events in the reprogramming of fibroblasts to cardiac muscle cells are unclear. While various histone undergo modification and re-positioning, and these correlate with the activity of certain genes, it is unknown if these events are causal or happen in response to reprogramming. Histone modification and re-positioning would be expected to open up chromatin on lineage-specific genes and this can be ascertained by studying nucleosome architecture. We have recently developed a set of tools to identify significant changes in nucleosome architecture which we used to study skeletal muscle differentiation. In this report, we have applied these tools to understand nucleosome architectural changes during fibroblast to cardiac muscle reprogramming. We found that nucleosomes surrounding the transcription start sites of cardiac muscle genes induced during reprogramming were insensitive to reprogramming factors as well as to agents which enhance reprogramming efficacy. In contrast, significant changes in nucleosome architecture were observed distal to the transcription start site. These regions were associated with nucleosome build-up. In summary, investigations into nucleosome structure do not support the notion that fibroblasts to cardiac muscle cell reprogramming involves chromatin opening and suggests instead long-range effects such as breaking closed-loop inhibition.
A model of Hill-Robertson interference caused by purifying selection in a non-recombining genome
Authors: Becher Hannes , Charlesworth Brian
Published: November 2024

A new approach to modeling the effects of Hill-Robertson interference on levels of adaptation and patterns of variability in a non-recombining genome or genomic region is described. The model assumes a set ofLdiallelic sites subject to reversible mutations between beneficial and deleterious alleles, with the same selection coefficient at each site. The assumption of reversibility allows the system to reach a stable statistical equilibrium with respect to the frequencies of deleterious mutations, in contrast to many previous models that assume irreversible mutations to deleterious alleles. The model is therefore appropriate for understanding the long-term properties of non-recombining genomes such as Y chromosomes, and is applicable to haploid genomes or to diploid genomes when there is intermediate dominance with respect to the effects of mutations on fitness. Approximations are derived for the equilibrium frequencies of deleterious mutations, the effective population size that controls the fixation probabilities of mutations at sites under selection, the nucleotide site diversity at neutral sites located within the non-recombining region, and the site frequency spectrum for segregating neutral variants. The approximations take into account the effects of linkage disequilibrium on the genetic variance at sites under selection. Comparisons with published and new computer simulation results show that the approximations are sufficiently accurate to be useful, and can provide insights into a wider range of parameter sets than is accessible by simulation. The relevance of the findings to data on non-recombining genome regions is discussed.
Convergent evolution of viral-like Borg archaeal extrachromosomal elements and giant eukaryotic viruses
Authors: Banfield Jillian F. , Valentin-Alvarado Luis E. , Shi Ling-Dong , Robinson Colin Michael , Bamert Rebecca S. , Coulibaly Fasseli , Barth Zachary K. , Aylward Frank O. , Schoelmerich Marie C , Lei Shufei , Sachdeva Rohan , Knott Gavin J.
Published: November 2024

Borgs are huge extrachromosomal elements of anaerobic methane-oxidizing archaea. They exist in exceedingly complex microbiomes, lack cultivated hosts and have few protein functional annotations, precluding their classification as plasmids, viruses or other. Here, we usedin silicostructure prediction methods to investigate potential roles for ∼10,000 Borg proteins. Prioritizing analysis of multicopy genes that could signal importance for Borg lifestyles, we uncovered highly represented de-ubiquitination-like Zn-metalloproteases that may counter host targeting of Borg proteins for proteolysis. Also prevalent are clusters of multicopy genes for production of diverse glycoconjugates that could contribute to decoration of the host cell surface, or of putative capsid proteins that we predict multimerize into hexagonal arrays. Features including megabase-scale linear genomes with inverted terminal repeats, genomic repertoires for energy metabolism, central carbon compound transformations and translation, and pervasive direct repeat regions are shared with giant viruses of eukaryotes, although analyses suggest that these parallels arose via convergent evolution. If Borgs are giant archaeal viruses they would fill the gap in the tri(um)virate of giant viruses of all three domains of life.

One Sentence Summary

Protein analyses, informed byin silicoprotein structure prediction, revealed that Borgs share numerous features with giant eukaryotic viruses, suggesting that Borgs have a viral-like lifestyle and evolutionary convergence of large extrachromosomal elements across the Domains of Life.
Evolution and evolvability of rifampicin resistance across the bacterial tree of life
Authors: Bolourchi Negin , Brown Christopher R. P. , Letten Andrew D. , Engelstädter Jan
Published: November 2024

Predicting the ability of bacteria to develop antibiotic resistance is challenging, especially for the vast majority of species for which no experimental data are available. Here, we investi-gated the evolvability and intrinsic presence of rifampicin resistance across the bacterial tree of life. We compiled a panel of known rifampicin resistance mutations, comprising 60 amino acid substitutions within the generpoB. We then screened>18 000 genomes from all major bac-terial groups for the presence of those mutations and determined which mutations can evolve through point mutations. Our results demonstrate that although the evolvability of individual mutations varies considerably across species, overall predicted evolvability is high and relatively homogeneous across bacterial taxa. Rifampicin resistance mutations are present intrinsically in 8% of species. Our analysis provides a global picture of the mutational landscape of rifampicin resistance, including both insight into existing observations as well as predictions informing future work.
GenomicSign: A computational method to discover unique, specific, and amplifiable signatures of target genomic sequences
Authors: Kumar S. Prasanna , Palaniappan Ashok
Published: November 2024

Molecular diagnostics for the rapid identification of infectious, virulent, and pathogenic organisms are key to health and global security. Such methods rely on the identification and detection of signatures possessed by the organism. In this work, we outline a computational algorithm, GenomicSign, to determine unique and amplifiable genomic signatures of a set of target sequences against a background set of non-target sequences. The set of target sequences might comprise variants of a pathogen of interest, say SARS-CoV2 virus. Unique k-mers of the consensus target sequence for a range of k-values are determined, and the threshold k-value yielding a sharp transition in the number of unique k-mers is identified as kopt. Corresponding unique k-mers for k ≥ koptare compared against the set of non-target sequences to identifytarget-specificunique k-mers. A pair of proximal such k-mers could enclose a potential amplicon. Primers to such pairs are designed and scored using a custom scheme to rank the potential amplicons. The top-ranked resulting amplicons are candidates for unique and amplifiable genomic signatures. The entire workflow is demonstrated using a case study with the SARS-CoV2 omicron genome. A case study distinguishing the SARS-CoV2 omicron target strain against non-target other SARS-CoV2 variants is performed to illustrate the workflow. GenomicSign has been implemented in Python and is available as an open-source software under MIT licence (https://www.github.com/apalania/GenomicSign).
Evaluating metabolome-wide causal effects on risk for psychiatric and neurodegenerative disorders
Authors: Gilchrist Lachlan , Mutz Julian , Hysi Pirro , Legido-Quigley Cristina , Koks Sulev , Lewis Cathryn M. , Proitsi Petroula
Published: November 2024

Evidence indicates phenotypic and biological overlap between psychiatric and neurodegenerative disorders. Further identification of underlying mutual and unique biological mechanisms may yield novel multi-disorder and disorder-specific therapeutic targets. The metabolome represents an important domain for target identification as metabolites play critical roles in modulating a diverse range of biological processes. Here, we used Mendelian randomisation (MR) to test the causal effects of ∼1000 plasma metabolites and ∼300 metabolite ratios on anxiety, bipolar disorder, depression, schizophrenia, amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. In total, 85 causal effects involving 77 unique metabolites passed FDR correction and robust sensitivity analyses (IVW-MR OR range: 0.73-1.48;pFDR< 0.05). No evidence of reverse causality was identified. Multivariate analyses implicated sphingolipid metabolism in psychiatric disorder risk and carnitine derivatives in risk for amyotrophic lateral sclerosis and multiple sclerosis. However, polygenic risk scores for prioritised metabolites showed limited prediction in the UK Biobank. Downstream colocalisation in regions containing influential variants identified greater than suggestive evidence (PP.H4 ≥ 0.6) for a shared causal variant for 29 metabolite/psychiatric disorder trait-pairs on chromosome 11 at theFADSgene cluster. Most of these metabolites were lipids containing linoleic or arachidonic acid. Additional colocalisation was identified between the ratio of histidine-to-glutamine, glutamine, Alzheimer’s disease andSPRYD4gene expression on chromosome 12. Although no single metabolite had a causal effect on a psychiatric and a neurodegenerative disease, results suggest a broad effect of lipids across brain disorders. Metabolites identified here may help inform future targeted interventions.
A single-cell transcriptomic atlas of the prefrontal cortex across the human lifespan
Authors: Yang Hui , Clarence Tereza , Scott Madeline R. , Prashant N.M. , Wang Xinyi , Pjanic Milos , Venkatesh Sanan , Hong Aram , Casey Clara , Shao Zhiping , Alvia Marcela , Argyriou Stathis ,   PsychAD Consortium, Auluck Pavan K. , Marenco Stefano , Haroutunian Vahram , Voloudakis Georgios , Bendl Jaroslav , McClung Colleen A. , Lee Donghoon , Fullard John F. , Hoffman Gabriel E. , Girdhar Kiran , Roussos Panos
Published: November 2024

The dorsolateral prefrontal cortex is central to higher cognitive functions and is particularly vulnerable to age-related decline. To advance our understanding of the molecular mechanisms underlying brain development, maturation, and aging, we constructed a detailed single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, encompassing over 1.3 million nuclei from 284 postmortem samples spanning the full human lifespan (0-97 years). This atlas reveals distinct phases of transcriptomic activity: a dynamic developmental period, stabilization during midlife, and subtle yet coordinated changes in late adulthood. Modeling non-linear age trends across the lifespan shows ten distinct trajectories of the entire transcriptome from all cell types, with notable findings in neurons and microglia, linked to neurodevelopmental disorders and Alzheimer’s disease risk, respectively. Moreover, excitatory neurons exhibit a convergence of gene expression patterns across the lifespan, suggesting the emergence of a common molecular signature of aging. Pseudotime analysis tracing the progression of cellular lineages throughout life reveals key gene clusters with dynamic expression changes that reflect development, maturation, and aging, as well as their connection to brain-related diseases. We uncover significant circadian rhythm reprogramming in late adulthood, characterized by disruption of core clock gene rhythmicity and the emergence of new rhythmic patterns, particularly within microglia and oligodendrocytes. This comprehensive single-cell atlas provides a baseline for understanding the molecular transitions from development through successful aging in the human dorsolateral prefrontal cortex.
Perceptions and Misconceptions of PSA Screening in Switzerland: A Preference Epidemiology Study
Authors: Spitale Giovanni , Germani Federico , Biller-Andorno Nikola
Published: November 2024

Introduction

PSA screening for prostate cancer detection is highly debated due to the challenging balance between its potential benefits and risks, regarding overdiagnosis and overtreatment. This study applies a preference epidemiology approach to understand how individuals evaluate these trade-offs, aiming to identify the thresholds at which people find screening acceptable or burdensome. By examining both personal and societal perspectives on PSA screening, this preference epidemiology study provides insights into how values, preferences, and psychosocial factors influence health-related decision-making.

Methods

A survey of Swiss men aged 55+ examined their awareness of PSA screening, their screening history, and their willingness to participate in future screenings. Hypothetical scenarios illustrating different trade-offs between overdiagnosis and lives saved by PSA screening were presented to the participants. Data were analyzed using Chi-square tests, MANOVA, and thematic analysis.

Results

425 participants were included in the study. Most respondents significantly overestimated PSA screening’s life-saving potential, with a median estimate of 50 deaths prevented versus the current figure of 3 deaths prevented per 1000 persons screened reported in the literature. Over half of the participants supported the use of PSA screening even in a hypothetical scenario where no lives were saved. Personal and family cancer history were associated with increased support for PSA screening.

Discussion and conclusion

Providing factual information about the risks and benefits of PSA screening alone may not ensure fully informed, autonomous decision-making. A systematic understanding of how personal evaluations of the risks and benefits are conducted is essential for the assessment of screening programs, which could inform key policy decisions, such as the integration of screenings into mandatory health insurance packages. These findings highlight the importance for both policy decisions and health communication to go beyond fact-sharing and incorporate systematic evidence from nuanced, value-sensitive evaluations to better support informed and autonomous decision-making.
A Resistance Persistence Index (RPI) for antimicrobial resistance in wastewater
Authors: Hajkowski Michael , Rafael-Mingoa Benjamin , Crystal-Franco Gabriela , Dick Katherine , Acholonu Michael , Nand Sanjiev , Soto Luzmaria , Withers Brennan Nuque , Hernandez Morgan , Cheng Ariel , Anand Archana
Published: November 2024

Antimicrobial resistance (AMR) represents a critical global health challenge, exacerbated by the proliferation of resistance genes in wastewater environments. This study introduces a novel Resistance Persistence Index (RPI) that integrates existing risk assessment frameworks with persistence and mobility metrics of antimicrobial resistance genes (ARGs) in wastewater treatment plant (WWTP) influent. We evaluated samples collected across wet and dry seasons, focusing on the dynamics of ARG diversity, abundance, and their associations with human impact. Our findings indicate a significant increase in unique ARGs during the wet season, with “antibiotic inactivation” as the predominant resistance mechanism. Using Zhang et al.’s ranking framework, we assessed the risk levels of various ARGs, revealing that while fewer high-risk ARGs were identified, they demonstrated substantial abundance. The RPI provided insights into how the combined effects of persistence and mobility influence the risk associated with different ARG families. This integrated framework offers a comprehensive tool for understanding and managing AMR in environmental settings, guiding future surveillance and intervention strategies.
Association of DNA methylation age acceleration with digital clock drawing test performance: the Framingham Heart Study
Authors: Li Zexu , Ding Huitong , Wang Mengyao , Li Yi , Ang Ting Fang Alvin , Ashita Gurnani , Katherine Gifford , Karjadi Cody , Levy Daniel , Au Rhoda , Liu Chunyu
Published: November 2024

Background

Cognitive function measured by digital clock drawing test (dCDT) has drawn attention for their precision, automation, and reproductivity. However, the relationship between digital cognitive metrics and biological aging is lacking.

Methods

We conducted association analyses between cognitive function measured by dCDT and biological aging metrics quantified by five DNA methylation (DNAm) age metrics (Horvath, Hannum, GrimAge, PhenoAge, and DunedinPACE) in the Framingham Heart Study (FHS). We conducted linear regression to investigate the association between cognitive functions (global cognitive function and four sub-domain functions) and DNAm age acceleration, adjusting for covariates. We used a false discovery rate (FDR) < 0.05 for significance.

Results

Among the 1,798 FHS participants (mean age 65±13, 53% women), we found that a lower dCDT total score is associated with DNAm age acceleration. Larger magnitudes of associations were observed in older participants (≥ 65 years). The dCDT total score showed the strongest association with the DundinPACE in the pooled sample (beta = −2.1, FDR = 0.0004), the younger (beta = −1.9, FDR = 0.02), and older age group (beta = −2.2, FDR = 0.01). The dCDT total score was significantly associated with age acceleration estimated by Horvath (beta=-1.9, FDR =0.01) and PhenoAge (beta=-2.5, FDR=0.01) in older participants while not in the pooled sample or younger participants (<65 years). In sub-domain cognitive functions, we found that simple motor function was significantly associated with DunedinPACE (FDR = 0.005) in both age groups and associated with GrimAge (FDR = 0.05 in older age group), indicating the deterioration in various organ systems may particularly impact this domain.

Discussion

Our findings suggest that cognitive function measured by a digital clock drawing test is associated with DNAm age acceleration in middle-aged and older participants in the FHS, potentially shedding light on the epigenetic mechanisms underlying digitally measured cognitive function.
Diagnosing Appendicitis with Precision: A Comparative Analysis of Modified Alvarado and RIPASA Scoring Systems in a Northern Divisional Hospital of Bangladesh
Authors: Naz Nafisa , Monower Md Mostafa , Shahid Shah Md Ahsan , Hossain Syeda Momena , Ahmad Tanvir , Islam Baharul
Published: November 2024

Objective

This study aimed to evaluate the diagnostic efficacy of the Modified Alvarado Scoring System (MASS) and the Raja Isteri Pengiran Anak Saleha Appendicitis (RIPASA) scoring system, assessing their sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy.

Methods

A cross-sectional analysis was conducted at the Department of General Surgery, Rajshahi Medical College Hospital, Bangladesh, from September to December 2020. The study included 138 purposively selected individuals aged 13 years and above, suspected of acute appendicitis. Data were collected through structured interviews, detailing socio-demographic characteristics, medical history, clinical examinations, and specific laboratory tests (CBC, Urine RE). Histopathology reports from post-operative cases were used as the gold standard for diagnosis. MASS and RIPASA scores, derived from their respective criteria, were analyzed using STATA.

Results

Participants had a mean age of 26.2 years, with males constituting 55.0% of the sample. The MASS scoring system reported a sensitivity of 79.8%, specificity of 57.9%, PPV of 92.2%, NPV of 31.4%, and an overall diagnostic accuracy of 76.8%. In contrast, the RIPASA scoring system demonstrated a sensitivity of 96.6%, specificity of 73.7%, PPV of 95.8%, NPV of 77.8%, and a diagnostic accuracy of 93.5%. ROC AUC analysis yielded values of 0.6886 for MASS and 0.8516 for RIPASA, indicating a statistically significant difference (p<0.05).

Conclusion

The findings highlight the superior clinical utility of the RIPASA scoring system over MASS, particularly in settings with limited access to advanced diagnostic facilities. Adopting the RIPASA scoring system could significantly enhance the diagnosis of acute appendicitis, suggesting its potential for improving clinical outcomes in similar healthcare environments.
Light-dependent flavin redox and adduct states control the conformation and DNA binding activity of the transcription factor EL222
Authors: Chaudhari Aditya S. , Favier Adrien , Tehrani Zahra Aliakbar , Kovaľ Tomáš , Andersson Inger , Schneider Bohdan , Dohnálek Jan , Černý Jiří , Brutscher Bernhard , Fuertes Gustavo
Published: November 2024

The activity of the transcription factor EL222 is regulated through protein-chromophore adduct formation, interdomain dynamics, oligomerization and protein-DNA interactions, all triggered by photo-excitation of its flavin mononucleotide (FMN) cofactor. To gain molecular-level insight into the photocycle of EL222, we applied complementary methods: macromolecular X-ray crystallography (MX), nuclear magnetic resonance (NMR) spectroscopy, optical spectroscopies (infrared and UV/visible), molecular dynamics/metadynamics (MD/metaD) simulations, and protein engineering using non-canonical amino acids. The observation of only subtle atomic displacements between crystal structures of EL222 with and without blue-light back-illumination, was confirmed by NMR data indicating no major changes in secondary structure and fold compactness. Kinetic experiments in solution provided evidence for two distinct EL222 conformations (lit1 and lit2) that become sequentially populated under illumination. These two lit states were assigned to covalently-bound N5protonated, and non-covalently-bound hydroquinone forms of FMN, respectively. Molecular modeling revealed differential dynamics and domain separation times arising from the three FMN states (oxidized, adduct, and reduced). Furthermore, while the dark state is largely monomeric, both lit states undergo slow monomer-dimer exchange. The photoinduced loss of α-helicity, seen by infrared difference spectroscopy, was ascribed to dimeric EL222 species. Unexpectedly, NMR revealed that all three EL222 species (dark, lit1, lit2) can associate with DNA to some extent, but only under illumination a high population of stable complexes is obtained. Overall, we propose a refined model of EL222 photo-activation where photoinduced changes in the oxidation state of FMN and thioadduct formation shift the population equilibrium towards an open conformation that favors self-association and DNA-binding.

Significance Statement

Flavin-binding light-oxygen-voltage (LOV) proteins constitute a prominent example of highly evolved chromophore-containing proteins that convert light into biochemical changes in the cell. However, it is not well understood how blue-light orchestrates changes in LOV structure and function. Here we show that the dynamics, oligomerization and DNA-binding properties of the photocontrolled transcription factor EL222 are dependent on both the flavin redox state and thioadduct formation. In the dark, monomeric EL222 forms transient encounter complexes with DNA. Under illumination, two distinct lit states are sequentially generated, termed lit1 and lit2, that are both able to assemble into EL222:DNA (2:1) complexes. Our results reveal the coupling between flavin photochemistry (protonation and covalent linkage) and fold stability in EL222 and potentially other flavoproteins.
De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes
Authors: Gjoni Ketrin , Ren Xingjie , Everitt Amanda , Shen Yin , Pollard Katherine S
Published: November 2024

Three-dimensional genome organization plays a critical role in gene regulation, and disruptions can lead to developmental disorders by altering the contact between genes and their distal regulatory elements. Structural variants (SVs) can disturb local genome organization, such as the merging of topologically associating domains upon boundary deletion. Testing large numbers of SVs experimentally for their effects on chromatin structure and gene expression is time and cost prohibitive. To address this, we propose a computational approach to predict SV impacts on genome folding, which can help prioritize causal hypotheses for functional testing. We developed a weighted scoring method that measures chromatin contact changes specifically affecting regions of interest, such as regulatory elements or promoters, and implemented it in the SuPreMo-Akita software (Gjoni and Pollard 2024). With this tool, we ranked hundreds of de novo SVs (dnSVs) from autism spectrum disorder (ASD) individuals and their unaffected siblings based on predicted disruptions to nearby neuronal regulatory interactions. This revealed that putative cis-regulatory element interactions (CREints) are more disrupted by dnSVs from ASD probands versus unaffected siblings. We prioritized candidate variants that disrupt ASD CREints and validated our top-ranked locus using isogenic excitatory neurons with and without the dnSV, confirming accurate predictions of disrupted chromatin contacts. This study establishes disrupted genome folding as a potential genetic mechanism in ASD and provides a general strategy for prioritizing variants predicted to disrupt regulatory interactions across tissues.
An Accessible 3D HepG2/C3A Liver Spheroid Model Supporting the Complete Intrahepatocytic Lifecycle ofPlasmodium falciparum
Authors: Alqurashi Salwa Omar , Caygill Claire H , Adolfi Adriana , Carson Jessica , Sturm Angelika , Dechering Koen J , Reimer Lisa , Pennington Shaun H , Sharma Parveen , Ward Stephen A , Biagini Giancarlo A.
Published: November 2024

Current liver-stagePlasmodium falciparummodels are complex, expensive, and largely inaccessible, hindering research progress. Here, we show that a 3D liver spheroid model grown from immortalized HepG2/C3A cells supports the complete intrahepatocytic lifecycle ofP. falciparum. Our results demonstrate sporozoite infection, development of exoerythrocytic forms, and breakthrough infection into erythrocytes. The 3D-grown spheroid hepatocytes are structurally and functionally polarised, displaying enhanced albumin and urea production and increased expression of key metabolic enzymes, mimickingin vivoconditions – relative to 2D cultures. This accessible, reproducible model lowers barriers to malaria research, promoting advancements in fundamental biology and translational research.
Electrical Coordinated Reset Stimulation Induces Network Desynchronization in an in Vivo Model of Status Epilepticus
Authors: Ehrens Daniel , Aeed Fadi , Otor Yara , Charu Vivek , Razavi Babak , Sarma Sridevi V. , Schiller Yitzhak , Tass Peter A.
Published: November 2024

Epilepsy, a neurological disorder characterized by recurrent seizures, profoundly impacts individuals worldwide. Various electrical stimulation protocols have been investigated to mitigate epileptic seizures, among which Coordinated Reset (CR) stimulation may have potential for inducing long-lasting neural desynchronization. This study explores the acute effects of CR stimulation on synchronization dynamics during Status Epilepticus (SE) in an in vivo animal model. An electrographically sustained seizure-state was induced via 4-aminopyridine (4AP) administration to CA3. Custom-designed electrode probes were implanted to facilitate simultaneous recording and electrical stimulation. Analytical univariate and bivariate features were constructed from the LFP time-series recording. Feature metrics focused on spike synchronization metrics and continuous signal analysis of amplitude, spectral power and phase synchronization across electrode pairs and frequency bands. Significance of modulation was assessed through permutation testing of the observed differences between the CR-stimulated group (N=5) compared to the control (no stimulation) group (N=3) during SE. Results showed overall decrease in amplitude and power univariate features, and a significant modulation of bivariate synchronization and connectivity measures across the spectrum between the CR stimulation and control group. Our findings underscore the potential effectiveness of CR stimulation in attenuating excessive neural synchronization, paving the way for further exploration of CR stimulation as a viable intervention for network desynchronization of epileptiform activity and subsequently treatment of seizures.