bluuebunny/crossref_metadata_2025 huggingface dataset:
YeZzzs Does it: Studying Sleep and Emotion using the Digital Rest-Activity Rhythms of Kanye West’s Tweets
Authors: Reid Matthew J. , Rojo-Wissar Darlynn M. , Mei Michelle , Differding Moira , Smith Michael T , Smith Michael G
Published: February 2025

One of the greatest challenges faced by the field of precision medicine is the identification of biomarkers capable of detecting clinically meaningful change at the individual level, not just amongst large-scale population studies. To this end, the evermore present social mediaverse provides unparalleled access to ecologically-valid databases of digital-biomarkers, that could be leveraged with single-user precision to support mental health care by monitoring use-patterns and emotional state. Despite this potential, investigation into how social-media use can be used to study sleep-wake behaviors has been remarkably scant, in part due to a lack of established methods to detect and estimate sleep using social-media activity. We present here a new approach to using social media-based data to track both sleep and mood, with potential applications to mental health monitoring and prevention. Amongst demonstrating proof of concept, we also provide an ethical and theoretical framework of how to proceed amongst this sensitive but potentially highly fruitful field.
Why we should be sharing our operations: a game theoretic analysis of surgical learning
Authors: Soares AS , Chand M
Published: February 2025

Introduction

Surgical training has traditionally relied on the master-apprentice model, emphasizing supervised repetition and immediate feedback within the operating room. With the advent of minimally invasive surgical techniques, the capability to record and digitally store surgical procedures has introduced new opportunities for detailed analysis and enhanced feedback mechanisms. Despite this potential, there is a lack of comprehensive systems to analyse recorded surgical procedures at scale.

Methods

In this study, we propose a cooperative game-theoretic model to examine the dynamics of surgical training, specifically focusing on the interactions between a master surgeon and an apprentice. The model incorporates both internal knowledge growth—stemming from direct collaboration—and external knowledge growth from supplementary educational resources. A characteristic function is proposed to quantify the utility (knowledge) generated by different coalitions of participants.

Results

Our findings demonstrate that collaboration between the master and apprentice leads to a synergistic increase in total knowledge value, surpassing the sum of their individual contributions. The integration of external resources significantly amplifies this effect, showing an exponential impact on knowledge acquisition over time. Proficiency analysis indicates that combining practical experience with structured external learning resources not only accelerates the apprentice’s progression to proficiency but also enhances the overall knowledge within the surgical community.

Conclusion

The study underscores the potential of applying game-theoretic principles to optimize surgical education. By quantifying the influence of mentor-ship quality and external learning resources, we highlight actionable strategies to enhance surgical training outcomes. Embracing a combination of hands-on practice and external resources accelerates individual skill development and enriches the collective knowledge base. We anticipate that this conceptual framework will inform future educational models and encourage the adoption of collaborative and technology-enhanced learning practices in surgery.
Phasic and tonic pain serve distinct functions during adaptive behaviour
Authors: Tong Shuangyi , Denison Timothy , Hewitt Danielle , Lee Sang Wan , Seymour Ben
Published: February 2025

Pain drives self-protective behaviour, and evolutionary theories suggest it acts over different timescales to serve distinct functions. Whilst phasic pain provides a teaching signal to drive avoidance of new injury, tonic pain is argued to support recuperative behaviour, for instance by reducing motivational vigour. We test this hypothesis in an immersive virtual reality EEG foraging task where subjects harvested fruit in a forest: some fruit elicited brief phasic pain to the grasping hand, and this reduced choice probability. Simultaneously, tonic pressure pain to the contralateral upper arm was associated with reduced action velocities. This could be explained by a free-operant computational framework that formalises and quantifies the function of tonic and phasic pain in terms of motivational vigour and decision value, and model parameters correlated with EEG responses. Overall, the results show how tonic and phasic pain subserve distinct objective motivational functions that support harm minimisation during ongoing adaptive behaviour.
Rēs ipSAE loquunt: What’s wrong with AlphaFold’sipTMscore and how to fix it
Authors: Dunbrack Roland L.
Published: February 2025

AlphaFold’sipTMmetric is used to predict the accuracy of structural predictions of protein-protein interactions (PPIs) and the probability that two proteins interact. Many AF2/AF3 users have experienced the phenomenon that if they trim full-length sequence constructs (e.g. from UniProt) to the interacting domains (or domain+peptide), theiripTMscores go up, even though the structure prediction of the interaction is unchanged. The reason this happens is due to the mathematical formulation ofipTMin AF2/AF3, which scores the interactions of whole chains. If both chains in a PPI complex contain large amounts of disorder or accessory domains that do not form the primary domain-domain or domain/peptide interaction, theipTMscore can be lowered significantly. The score then does not accurately represent the accuracy of the structure prediction nor whether the two proteins actually interact. We have solved this problem by: 1) including only residue pairs in theipTMmetric that have good predicted aligned error (PAE) scores; 2) by adjusting thed0parameter (a function of the length of the query sequences) in the TM score equation to include only the number of residues with good interchainPAEs to the aligned residue; and 3) using thePAEvalue itself and not the probability distributions over the aligned error to calculate the pairwise residue-residuepTMvalues that go into theipTMcalculation. The first two are crucial in calculating highipTMs for domain-domain and domain-peptide interactions even in the presence of many hundreds of residues in disordered regions and/or accessory domains. The third allows us to require only the common output json files of AF2 and AF3 (including the server output) without having to change the AlphaFold code and without affecting the accuracy. We show in a benchmark that the new score, calledipSAE(interaction prediction Score from Aligned Errors), is able to separate true from false complexes more efficiently than AlphaFold2’sipTMscore. The resulting program is freely available athttps://github.com/dunbracklab/IPSAE.
Confirmatory insights intoELMOD3-associated autosomal dominant non-syndromic hearing loss
Authors: Yun Yejin , Park Minjae , Jeong Sohyang , Jung Sung Ho , Lee Sang-Yeon
Published: February 2025

Sensorineural hearing loss (SNHL) is one of the most common sensory disorders, predominantly driven by monogenic causes with a higher Mendelian contribution. AlthoughELMOD3variants have been implicated in both autosomal dominant (DFNA81) and autosomal recessive (DFNB88) hereditary deafness, only a single DFNA81 family has been reported, leaving the pathogenic role of the dominant allele largely unexplored. Through targeted panel sequencing, we herein identified a novel heterozygousELMOD3variant (c.640G>A; p.Gly214Ser) that co-segregates with autosomal dominant hearing loss in a Korean family. Molecular modeling and structure analysis indicates that replacing glycine at residue 214 with serine introduces spatial clashes with adjacent Ala160 and Cys162, thereby disrupting intermolecular interactions and compromising protein stability. Consistent with this, stability assays revealed a rapid degradation rate for the mutant protein.

Furthermore, the ability to localize with F-actin in mutant protein was disrupted compared to the wild-type protein. Based on functional assays, the p.Gly214Ser variant demonstrated the functional pathogenicity and was classified as likely pathogenic according to the ACMG guideline for hearing loss. Collectively, these findings provide confirmatory insights intoELMOD3-associated DFNA81, potentially through a dominant-negative mechanism.
Population-specific Risk of Pharmacogenomics-related Inaccurate Drug Dosing of ICU Patients
Authors: Rostami Mahboubeh R. , Rodriguez-Flores Juan , Hssain Ali Ait , Al Shakaki Alya , Khan Huda , Vakayil Muneera , Karic Edin , Elhamid Maha , Al Tawil Lubna Gamal , Mezey Jason G. , Robay Amal , Crystal Ronald G.
Published: February 2025

Rationale

Intensive care units (ICU) patients are highly vulnerable to inaccurate drug dosing. Pharmacogenomics (PGx) characterizes the influence of inherited genetic variation on drug metabolism, playing an important role in the consequences of a given drug dose.

Objectives

To assess the genetic-based risk of inaccurate drug dosing in the ICU.

Methods

We carried out whole genome sequencing (WGS) of 210 Qataris in ICU care at Hamad Medical Corporation (HMC), Doha, Qatar and assessed the WGS for predicted deleterious variants of genes that metabolize 30 drugs commonly prescribed in the ICU.

Measurements and Main Results

Analysis of 210 Qatari ICU WGS identified 329 variants predicted deleterious associated with 85 genes known to affect metabolism of the 30 ICU drugs. Of the ICU patients that received the 5 most commonly prescribed drugs (warfarin, phenytoin, midazolam, vancomycin, levetiracetam), 93% had deleterious metabolism-related variants. Most (91%) patients carried at least one variant in a gene that that had the potential to affect the metabolism or activity of at least 1 drug that the patient received. Most patients had ≥14 deleterious variants of genes that affect the metabolism of administered drugs. Comparison of the deleterious variants related to metabolism of ICU drugs with African/African American and European populations revealed significant population specificity in ICU related PGx variants.

Conclusions

Together, these data suggest that population specific, pharmacogenomics based on the individual’s genome likely plays a significant role in effective, safe dosing in the ICU setting.
Intervention Mapping: A Multi-stage Investigation to Control Gastrointestinal Tract Infections at Primary Level
Authors: Mahmood Shahzad , Chaudary Nauman Ali , Farooq Raja Mohsin , Haider Hafiz Muhammad Ali , Tahir Umer Raza , Syed Komal
Published: February 2025

Infectious diseases of the gastrointestinal (GI) tract are among the most common primary healthcare presentations, affecting 2.86 million people worldwide. These infections can include bacterial, viral, parasitic and fungal causes, and may present with nausea, diarrhea, abdominal pain, fever and dehydration. The objective of the study is to decrease disease burden through community transmission mitigation. Three selected key strategies illustrate how the mix-methods approach elaborated the quantitative analysis within the applied qualitative framing. Step 1: Research Phases Pre-Intervention: This research consists of three steps Pre-Intervention, Intervention, and Post-Intervention. In the first phase, disease prevalence is assessed and categorized by age, gender, and geography. The second phase implements a public health intervention tailored to disease risk factors and community needs. The final phase evaluates outcomes through data analysis.Findings highlight that targeted community health measures, such as health education, risk prevention, and intervention mapping, can significantly reduce GI infections, emphasizing the importance of evidence-based public health strategies.
3D phenotyping in a Colombian population reveals unique population and ontogenic facial patterns in genetic and rare disorders
Authors: Andreu-Montoriol Mireia , Pujol Marina , Echeverry-Quiceno Luis Miguel , Candelo Estephania , Heredia-Lidón Álvaro , Gómez Eidith , Solís Paula , Ramírez Diana , Ortiz Diana , Sevillano Xavier , Tayà Max Rubert , Esteban Maria Esther , Casado Aroa , Pachajoa Harry , Martínez-Abadías Neus
Published: February 2025

Up to 30-40% of genetic and rare disorders present with unique facial patterns. Clinical geneticists have traditionally assessed facial traits to suggest a first diagnosis and direct confirmatory genetic testing. However, to enhance the accuracy of early diagnosis using facial biomarkers, it is crucial to analyze the complexity of facial dysmorphologies using 3D technologies, further understand how facial ontogeny is altered within each condition, and broaden the analysis to include diverse human populations.

In this study, we analyzed the 3D facial phenotypes associated to Down (DS), Morquio (MS), Noonan (NS), and Neurofibromatosis type 1 (NF1) syndromes, in an admixed Latin American population from Colombia, including 47 patients and 49 age matched controls. For each subject, we generated a three-dimensional facial model from 2D images captured by a multi-camera photogrammetric system, and recorded the 3D coordinates of 21 anatomical landmarks. Using geometric morphometrics, we characterized the 3D facial dysmorphologies associated with each syndrome and assessed the range of variation across syndromes as compared to controls. Finally, we tested whether these syndromes alter the ontogenetic trajectory of facial growth.

Our results confirmed statistically significant facial shape differences associated with these genetic conditions, except for NF1. Consistent with our previous 2D analyses, we identified population-specific facial features in the Colombian patients that were not reported in individuals of European descent. Additionally, the pooled 3D analyses revealed a continuous spectrum of facial dysmorphology, with MS exhibiting the most severe dysmorphologies compared to controls. The ontogenic analyses further demonstrated that craniofacial development is altered in DS and MS, but not in RASopathies such as NS and NF1.

Overall, our findings indicate that interpopulation and ontogenic differences in facial phenotypes should be considered to optimize and universalize the use of facial biomarkers. This approach could further help reduce the diagnostic odyssey associated with syndromic and rare conditions.
Projected ecological and disruptive impacts of climate change on malaria in Africa
Authors: Symons Tasmin L. , Moran Alexander , Balzarolo Ann , Vargas Camilo , Robertson Mairi , Lubinda Jailos , Saddler Adam , McPhail Michael , Harris Joseph , Rozier Jennifer , Browne Annie , Amratia Punam , Bertozzi-Villa Amelia , Bhatt Samir , Cameron Ewan , Golding Nick , Smith David L. , Noor Abdisalan M. , Rumisha Susan F. , Palmer Matthew D. , Weiss Daniel J. , Desai Naomi , Potere David , Sukitsch Nicholas , Woods Wendy , Gething Peter W.
Published: February 2025

The implications of climate change for malaria eradication in the 21stcentury remain poorly resolved. Many studies have focussed on parasite and vector ecology in isolation, neglecting the interactions between climate, malaria control, and the socioeconomic environment, including the disruptive impact of extreme weather. Here we integrate 25 years of data on climate, malaria burden, control interventions, socioeconomic factors, and extreme weather events in Africa. Using a geotemporal model linked to an ensemble of climate projections under the Shared Socioeconomic Pathway 2-4.5 (SSP 2-4.5) scenario, we estimate the future impact of climate change on malaria burden in Africa, accounting for both ecological and disruptive effects. Our findings suggest climate change could lead to 123 million (projection range 49.5 million - 203 million) additional malaria cases and 532,000 (195,000 - 912,000) additional deaths in Africa between 2024 and 2050 under current control levels. Contrary to the prevailing focus on ecological mechanisms, extreme weather events emerge as the primary driver of increased risk, accounting for 79% (50-94%) of additional cases and 93% (70%-100%) of additional deaths. Most increases are due to intensification in existing endemic areas rather than range expansion, with significant regional variation in impact. These results highlight the urgent need for climate-resilient malaria control strategies and robust emergency response systems to safeguard progress toward malaria eradication in Africa.
TinA enables kinesin-14/KlpA to exhibit processive minus-end-directed motility
Authors: Visootsat Akasit , Popchock Andrew R. , Gao Yuan , Qiu Weihong
Published: February 2025

Kinesin-14 motors contribute to spindle assembly by localizing to spindle poles and anchoring the minus ends of spindle microtubules. Unlike other kinesin-14 motors, KlpA uniquely exhibits plus-end-directed motility on single microtubules as individual homodimers. However, the mechanism by which KlpA achieves minus-end-directed motility on single microtubules remains elusive. Here, we report that TinA, a highly conserved microtubule-anchoring protein, serves as an activator of KlpA for minus-end-directed motility. TinA directly interacts with KlpA to form minus-end-directed complexes that exhibit continuous movement on microtubules with two distinct velocity modes. The assembly of KlpA-TinA complexes depends on TinA binding to the central stalk of KlpA. Furthermore, TinA is a microtubule-binding protein, with its C-terminal region playing a critical role in microtubule interaction. Deletion of the C-terminus of TinA markedly reduces its microtubule-binding ability and severely impairs the formation of KlpA-TinA complexes. Nonetheless, KlpA-TinA complexes formed without the C-terminus of TinA still exhibit minus-end-directed motility, albeit with a single velocity mode. Collectively, these findings provide critical mechanistic insights into how TinA modulates KlpA, enabling the kinesin-14 motor to achieve minus-end-directed motility.
Smoke exposure triggers rapid transcriptional changes and reveals glycosyltransferases linked to smoke taint in ripening grape berries
Authors: Paineau Manon , Liang Chen , Cochetel Noe , Shivani  , Figueroa-Balderas Rosa , Thilmony Roger , Rumbaugh Arran , Cantu Dario
Published: February 2025

With the increasing frequency of wildfires, vineyards are more often exposed to smoke, resulting in a higher risk of smoke taint in wine. This taint imparts undesirable “smoky” and “ashy” aromas and causes significant economic losses. Smoke-derived volatile phenols (VPs) in grape berries, metabolized into stable, non-volatile glycoconjugates via glycosyltransferases (GTs), underlie smoke taint formation. Here, we present the dwarf grapevine cultivar Pixie as a model system for smoke taint research. We generated a phased, telomere-to-telomere diploid genome using HiFi long-read sequencing, along with an expression atlas spanning 30 replicated samples across various tissues and developmental stages. We also constructed a second telomere-to-telomere assembly for Pinot Noir to assessGTexpression during berry ripening in the field. Controlled smoke-exposure experiments profiledGTexpression and enabled transcriptome-wide analyses at multiple time points. We measured VPs in both smoke-exposed and control samples, revealing 12GT1genes significantly upregulated by smoke, namedVitis vinifera smoke-inducible UGTs(VviSIUGTs). Their expression peaked one day post-exposure and declined by day three, mirroring glycoside accumulation dynamics. Gene co-expression network analyses highlighted stress-responsive modules enriched in theseVviSIUGTs, while transcription factor binding site analyses pinpointed stress-related regulatory elements in their promoters. These findings provide new insights into the molecular basis of smoke taint and identify potential targets for breeding and biotechnological interventions aimed at developing grapevine cultivars with reduced susceptibility to smoke damage.
Commensal acidification of specific gut regions produces a protective priority effect against enteropathogenic bacterial infection
Authors: Yang Jane L. , Zhu Haolong , Sadh Puru , Aumiller Kevin , Guvener Zehra T. , Ludington William B.
Published: February 2025

The commensal microbiome has been shown to protect against newly introduced enteric pathogens in multiple host species, a phenomenon known as a priority effect. Multiple mechanisms can contribute to this protective priority effect, including antimicrobial compounds, nutrient competition, and pH changes. InDrosophila melanogaster,Lactiplantibacillus plantarumhas been shown to protect against enteric pathogens. However, the strains ofL. plantarumstudied were derived from laboratory flies or non-fly environments and have been found to be unstable colonizers of the fly gut that mainly reside on the food. To study the priority effect using a naturally occurring microbial relationship, we isolated a wild-fly derived strain ofL. plantarumthat stably colonizes the fly gut in conjunction with a common enteric pathogen,Serratia marcescens. Flies stably associated with theL. plantarumstrain were more resilient to oralSerratia marcescensinfection as seen by longer lifespan and lowerS. marcescensload in the gut. Throughin vitroexperiments, we found thatL. plantaruminhibitsS. marcescensgrowth due to acidification. We used gut imaging with pH-indicator dyes to show thatL. plantarumreduces the gut pH to levels that restrictS. marcescensgrowthin vivo. In flies colonized withL. plantarumprior toS. marcescensinfection,L. plantarumandS. marcescensare spatially segregated in the gut andS. marcescensis less abundant whereL. plantarumheavily colonizes, indicating that acidification of specific gut regions is a mechanism of a protective priority effect.
A connection betweenVibrio choleraemotility and inter-animal transmission
Authors: Campbell Ian W. , Dehinwal Ruchika , Morano Alexander A. , Dailey Katherine G. , Zingl Franz G. , Waldor Matthew K.
Published: February 2025

Outbreaks of cholera are caused by the highly transmissive pathogenVibrio cholerae. Here, a transposon screen revealed that inactivation of theV. choleraemotility-linked genemotVincreases infant mouse intestinal colonization. Compared to wild-typeV. cholerae, a ΔmotVmutant, which exhibits heightened motility in the form of constitutive straight swimming, localizes to the crypts earlier in infection and over a larger area of the small intestine. Aberrant localization of the mutant was associated with an increased number ofV. choleraeinitiating infection, and elevated pathogen burden, diarrhea, and lethality. Moreover, the deletion ofmotVcausesV. choleraeto transmit from infected suckling mice to naïve littermates more efficiently. Even in the absence of cholera toxin, the ΔmotVmutant continues to transmit between animals, although less than in the presence of toxin, indicating that phenotypes other than cholera toxin-driven diarrhea contribute to transmission. Collectively, this work provides experimental evidence linking intra-animal bottlenecks, colonization, and disease to inter-animal transmission.
Discovering new amyloid-like peptides using all-atom simulations and artificial intelligence
Authors: Kuang Xiaohan , Jalali Sharareh , Rahman Tasnima , Michalowski Jadhy , Sheng-Wong Caren , Wong-Ekkabut Jirasak , Su Zhaoqian , Dias Cristiano L.
Published: February 2025

Establishing the fundamental relationships between peptide sequences and fibril formation is critical both for understanding protein misfolding processes and for guiding biomaterial design. Here, we combine all-atom molecular dynamics (MD) simulations with artificial intelligence (AI) to investigate how subtle variations in the arrangement of a short peptide sequence affect its propensity to form fibrils. Our results show that small shifts in the distribution of hydrophobic residues and charge clusters can significantly influence both the nucleation rate and the stability of cross-βstructures. To rapidly extend this analysis over a wide sequence space, we developed an active learning–enhanced framework—Machine Learning for Molecular Dynamics (ML4MD)—that iteratively refines its predictions based on MD-derived aggregation data. ML4MD efficiently screens numerous peptide permutations and guides the discovery of previously unrecognized fibril-prone sequences, achieving an area under the receiver operating characteristic (ROC) curve (AUC) of 0.939. Overall, ML4MD streamlines the rational design of amyloid-like peptides by integrating detailed atomistic simulations with rapid and high-accuracy ML predictions.
Lysogen formation governs colonies while lytic infection is more prevalent in single cells of the bloom-forming cyanobacterium,Microcystis
Authors: Huang X. , Chase EE , Zepernick BN , Martin RM , Krausfeldt LE , Pound HL , Wu H. , Zheng Z. , Wilhelm SW
Published: February 2025

While the bloom-forming cyanobacteriumMicrocystiscan exist as free-living single cells or within dense mucilaginous colonies, the drivers and consequences of colony formation remain unclear. Here, we integrated metatranscriptomic datasets from twoMicrocystisbloom events in Lake Taihu, China, to analyze and validate the functional differences between colonial and single-cellMicrocystis. Our results confirmed colony expression profiles were disproportionately enriched inMicrocystistranscripts (and functions) compared to other prokaryotic taxa. Concomitantly, viral infection strategies diverged byMicrocystiscommunity morphology: colony-associated cells expressed lysogeny-associated genes, while single cells exhibited increased signatures of lytic infection. These data are consistent with the hypothesis thatMicrocystiscolonies foster conditions favorable to lysogen formation—likely due to local high cell densities and the resulting advantage of superinfection immunity—whereas solitary cells experience stronger lytic pressure. On a broader scale, our findings refine the understanding of bloom dynamics by identifying how community morphological states coincide with distinct host–virus interactions. Cumulatively, this work underscores the importance of colony formation in shapingMicrocystisecology and highlights the need for mechanistic studies that disentangle the interplay between phage infection modes, colony formation, and microbial community structure.
Reversible lipid mediated pH-gating of connexin-46/50 by cryo-EM
Authors: Jarodsky Joshua M. , Myers Janette B. , Reichow Steve L.
Published: February 2025

Gap junctions, formed by connexin proteins, establish direct electrical and metabolic coupling between cells, enabling coordinated tissue responses. These channels universally respond to intracellular pH changes, closing under acidic conditions to limit the spread of cytotoxic signals during cellular stress, such as ischemia. Using cryo-electron microscopy (cryo-EM), we uncover insights into the structural mechanism of pH-gating in native lens connexin-46/50 (Cx46/50) gap junctions. Mild acidification drives lipid infiltration into the channel pore, displacing the N-terminal (NT) domain and stabilizing pore closure. Lipid involvement is both essential and fully reversible, with structural transitions involving an ensemble of gated-states formed through non-cooperative NT domain movement as well as minor populations of a distinct destabilized open-state. These findings provide molecular insights into pH-gating dynamics, illustrating how structural changes may regulate gap junction function under cellular stress and linking Cx46/50 dysregulation to age-related cataract formation.
Modeling cerebral developmentin vitrowith L-MYC-immortalized human neural stem cell-derived organoids
Authors: Velazquez Ojeda Alejandra , Awabdeh Dina , Brewster Blake , Rockne Russell , O’Meally Denis , Yin Hongwei Holly , Carlesso Nadia , Brown Christine E. , Gutova Margarita , Barish Michael E.
Published: February 2025

A promising advance forex vivostudies of human brain development and formulation of therapeutic strategies has been the adoption of brain organoids that, to a greater extent than monolayer or spheroid cultures, recapitulate to varying extents the patterns of tissue development and cell differentiation of human brain. Previously, such studies been hampered by limited access to relevant human tissue, inadequate humanin vitromodels, and the necessity of using rodent models that imperfectly reproduce human brain physiology. Here we present a novel organoid-based research platform utilizing L-MYC-immortalized human fetal neural stem cells (LMNSC01) grown in a physiological 4% oxygen environment.

We visualized developmental processes in LMNSC01 brain organoids for over 120 daysin vitroby immunofluorescence and NanoString gene expression profiling. Gene expression patterns revealed by NanoString profiling were quantitatively compared to those occurring during normal brain development (BrainSpan database) using theSingscoremethod. We observe similar developmental patterns in LMNSC01 organoids and developing cortex for genes characterizing neurons, astrocytes, and oligodendrocytes, and multiple pathways including those involved in apoptosis, neuronal cytoskeleton, neurotransmission, and metabolism. Notable properties of this LMNSC01 platform are its initiation with immortalized authentic human neural stem cells, growth in a physiological oxygen environment, the consistency of the organoids produced, and favorable comparison of their gene expression patterns with those reported for normal cortical development.

Ex vivostudies of human brain development has been advanced by adoption of organoids recapitulating to varying extentsin uteropatterns of tissue development and cell differentiation. We here present an organoid-based human cortical development platform employing immortalized fetal neural stem cells (LMNSC01) grown in a physiological (4% oxygen) environment. Characterizing LMNSC01 organoids for over 120 daysin vitroby immunofluorescence and expression profiling (using NanoString), and then comparing these profiles to those of normal cortical development (BrainSpan database), revealed similar developmental patterns for neurons, astrocytes and oligodendrocytes. Notable properties of this platform are its initiation with immortalized authentic human NSCs, growth at physiological oxygen concentration, and subsequent favorable comparison of their gene expression patterns with those observed during cortical development.
Synthetic community Hi-C benchmarking provides a baseline for virus-host inferences
Authors: Shatadru Rokaiya Nurani , Solonenko Natalie E. , Sun Christine L. , Sullivan Matthew B.
Published: February 2025

Microbiomes are now recognized as key influencers of diverse ecosystems, but it is increasingly evident that viruses impose significant constraints on these microbial communities. While viromics has expanded virus genomic catalogs, identifying hosts for these viruses remains a major challenge due to the limitations in scaling for cultivation and to the uncertain reliability ofin silicopredictions for understudied virosphere regions. A promising recent advance, Hi-C, a proximity ligation-based method, aims to infer virus-host linkages by analyzing sequences from cross-linked virus and host genomic fragments. This approach has been applied in at least seven studies, yet its accuracy has not been systematically assessed. Here we evaluate Hi-C performance in predicting virus-host interactions using a synthetic community consisting of four bacterial strains and nine phages with known, experimentally determined, quantitative interactions. Our analysis revealed that Hi-C linkage scores used in the literature perform poorly (13% specificity, 100% sensitivity). By converting linkage scores to Z-scores and applying filtering (Z-score ≥ 0.5), we dramatically increased prediction accuracy, though at reduced sensitivity (96% specificity, 57% sensitivity). These findings provide empirical data and establish guidelines for interpreting Hi-C inferred virus-host linkages, with the aim of improving its reliability across diverse ecosystems.
Neural dynamics of proactive and reactive cognitive control in medial and lateral prefrontal cortex
Authors: Khan Anas U. , Hoy Colin , Anderson Kristopher L. , Piai Vitoria , Stephens David King- , Laxer Kenneth D. , Weber Peter , Lin Jack J. , Knight Robert T. , Bentley J. Nicole
Published: February 2025

Goal-directed behavior requires adjusting cognitive control to both react to and prepare for conflict. Previous work indicates theta oscillations and population activity in dorsomedial prefrontal cortex (dmPFC) and dorsolateral prefrontal cortex (dlPFC) are critical for reactive control. However, the neural mechanisms supporting proactive control are less clear. Here, we investigated the neural basis of behavioral adaptations when control is prepared in anticipation of conflict using intracranial EEG (iEEG) in dmPFC and dlPFC during a Stroop task where conflict frequency was manipulated across blocks. We observed canonical conflict-driven increases in dmPFC theta and in dmPFC and dlPFC local population activity, as indexed by high frequency activity (HFA). Conflict also suppressed theta power in both regions after the response, accentuated a pre-response beta desynchronization selectively in dlPFC, and increased a post-response beta rebound in both regions. Importantly, we identified a pre-trial marker of proactive control where dmPFC theta power increased before trials when conflict was expected, and theta, beta, and HFA conflict signals in both regions were enhanced when conflict was rare and diminished when conflict was common. These findings reveal shared HFA but dissociable oscillatory dynamics in dmPFC and dlPFC during reactive conflict processing, highlight pre-trial dmPFC theta as a potential substrate for proactive control, and refine the roles of dmPFC and dlPFC in control adaptations.
StackGlyEmbed: Prediction of N-linked Glycosylation sites using protein language models
Authors: Nafi Md Muhaiminul Islam , Rahman M Saifur
Published: February 2025

N-linked glycosylation is one of the most basic post-translational modifications (PTMs) where oligosaccharides covalently bond with Asparagine (N). These are found in the conserved regions like N-X-S or N-X-T where X can be any residue except Proline (P). Prediction of N-linked glycosylation sites has great importance as these PTMs play a vital role in many biological processes and functionalities. Experimental methods, such as mass spectrometry, for detecting N-linked glycosylation sites are very expensive. Therefore, prediction of N-linked glycosylation sites has become an important research field. In this work, we propose StackGlyEmbed, a stacking ensemble machine learning model, to computationally predict N-linked glycosylation sites. We have explored embeddings from several protein language models and built the stacking ensemble using SVM, XGB and KNN learners in the base layer, with a second SVM model in the meta layer. StackGlyEmbed achieves 98.2% sensitivity, 92.5% balanced accuracy, 89.1% F1-score and 82.6% MCC in independent testing, outperforming the existing SOTA methods. StackGlyEmbed is freely available athttps://github.com/nafcoder/StackGlyEmbed.
Multi-omics-based analysis of the effect of longevity genes on the immune relevance of colorectal cancer
Authors: Huang Yichu , Min Guangtao , Wang Hongpeng , Jiang Lei
Published: February 2025

Background

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, with its incidence and recurrence rates steadily rising. To explore the relationship between CRC and longevity-associated genes, and to offer new therapeutic avenues for CRC treatment, we developed a prognostic model based on these genes to predict the outcomes for CRC patients. Additionally, we conducted an immune correlation analysis.

Methods

We conducted a comprehensive analysis of the effects of 81 longevity-associated genes in CRC by integrating multiple omics datasets. This analysis led to the identification of two distinct molecular subtypes and revealed that alterations in longevity-related genes across various layers were linked to clinicopathological features, prognosis, and cell infiltration characteristics within the tumor microenvironment (TME). The training and validation cohorts for the models were derived from the TCGA-COAD, TCGA-READ, and GSE35279 datasets. Subsequently, we developed a risk score model, and the Kaplan–Meier method was employed to estimate overall survival (OS). Ultimately, we established a prognostic model based on five longevity-associated genes: BEDN3, EXOC3L2, CDKN2A, IL-13, and CAPN9. Furthermore, we assessed the correlations between the risk score and factors such as immune cell infiltration, microsatellite instability, and the stem cell index.

Results

Our comprehensive bioinformatics analysis revealed a strong association between longevity genes and CRC. The risk score derived from the five newly identified longevity-associated genes was determined to be an independent prognostic factor for CRC. Patients categorized by this risk score demonstrated significant differences in immune status and microsatellite instability.

Conclusion

Our comprehensive multi-omic analysis of longevity-associated genes highlighted their potential roles in the tumor immune microenvironment, clinicopathological features, and prognosis, offering new insights for the treatment of CRC.
Identification of the immune-associated enhancer RNA SATB1-AS1 as a novel biomarker for thymic cancer prognosis
Authors: Wang Hongpeng , Huang Yichu , Min Guang-tao , Jiang Lei
Published: February 2025

Abstracts

Objective

To screen key enhancer RNAs (eRNAs) in thymoma (THYM) through The Cancer Genome Atlas (TCGA) database and explore their potential as prognostic molecules and therapeutic targets in THYM.

Methods

Gene expression RNA-seq profiles of 33 cancer types were retrieved and downloaded from the TCGA database, and Kaplan–Meier survival analysis and Spearman correlation analysis were applied to screen eRNAs and target genes associated with survival in THYM patients. The correlation of target eRNAs with clinical features was assessed. Gene set enrichment analysis was performed to investigate the potential biological functions of target eRNAs. Validation of the prognostic potential of target eRNAs across cancers in other cancer types.

Results

In THYM, SATB1-AS1 and the target gene SATB1 were associated with poor patient prognosis, and SATB1-AS1 expression was correlated with patient stage (P<0.05). Gene and pathway enrichment analyses revealed that SATB1-AS1 was associated with leukocyte transendothelial migration, natural killer cell-mediated cytotoxicity, neutrophil extracellular trap formation, PD-L1 expression and the PD-1 checkpoint pathway in cancer.

Conclusion

SATB1-AS1 may be a key eRNA in THYM and has the potential to be a marker and therapeutic target for the early diagnosis and prognosis of THYM.
Chronic early-life obesity linked to childhood impulsivity predicts long-term psychosis trajectory through dose-dependent cerebellar dysmaturation in 22q11.2 Deletion Syndrome
Authors: Sandini Corrado , Reich Natacha , Delavari Farnaz , Pajic Lara , Escelsior Andrea , Forrer Silas , Imparato Andrea , Kojovic Nada , Latreche Caren , Parlatini Valeria , Cortese Samuele , Schneider Maude , Eliez Stephan
Published: February 2025

Background

Recent epidemiological evidence links early-life obesity and metabolic dysregulation to adult psychosis vulnerability, though a causal relationship remains unclear. Establishing causality in highly heritable psychotic disorders requires: 1) demonstrating that early-life metabolic factors mediate between genetic vulnerability and psychosis trajectory, 2) dissecting mechanisms leading to early-life obesity in genetically vulnerable individuals, and 3) clarifying downstream neurodevelopmental pathways linking early-life obesity to psychosis symptoms.

Methods

To address these key issues, we investigated bidirectional pathways linking behavioral, BMI, and neurodevelopment trajectories in a unique longitudinal cohort of 184 individuals at high genetic risk for psychosis, due to 22q11.2 Deletion Syndrome (22q11DS), and 182 neurotypical controls, followed-up since childhood. We combined repeated BMI measurements with clinical/neurocognitive phenotyping and neuroimaging. We investigated the relationship between BMI trajectories with risk of psychosis and tested whether altered cortical or cerebellar development could underlie this association.

Results

Childhood behavioral impulsivity predicted early and progressive deviations in BMI trajectories. In turn, pubertal BMI-increases were associated with concomitant worsening of depressive symptoms, while chronic BMI-increases emerging during childhood predicted the subsequent emergence of psychosis during late-adolescence/early-adulthood. The duration of increased BMI-status was associated with emergence of motor and cognitive disorganization, a key schizophrenia symptom domain, which was linked to progressive gray matter volume reductions in posterior-inferior cerebellum.

Conclusions

These findings suggest that metabolic dysregulation associated with obesity may link childhood behavioral impulsivity to psychosis vulnerability in 22q11DS, by influencing cerebellar maturation. These findings might support preventive interventions targeting early-life metabolic trajectories in individuals at risk of psychosis.
OMKar: optical map based automated karyotyping of genomes to identify constitutional abnormalities
Authors: Dehkordi Siavash Raeisi , Jia Zhaoyang , Estabrook Joey , Hauenstein Jen , Miller Neil , Güleray-Lafci Naz , Neesen Jürgen , Hastie Alex , Chaubey Alka , Chun Pang Andy Wing , Dremsek Paul , Bafna Vineet
Published: February 2025

The whole genome karyotype refers to the sequence of large chromosomal segments that make up an individual’s genotype. karyotype analysis, which includes descriptions of aneuploidies and other rearrangements is crucial for understanding genetic risk factors, for diagnosis, treatment decisions, and genetic counseling linked to constitutional disorders. The current karyotyping standard is based on microscopic examination of chromosomes, a complex process that requires high expertise and offers Mb scale resolution.

Optical Genome Mapping (OGM) technology can identify large DNA lesions in a cost-effective manner. In this paper, we developed OMKar, a method that uses OGM data to create a virtual karyotype. OMKar processes Structural (SV) and Copy Number (CN) Variants as inputs and encodes them into a compact breakpoint graph. It recomputes copy numbers using Integer Linear Programming to maintain CN balance and then identifies constrained Eulerian paths representing entire donor chromosomes. In tests using 38 whole genome simulations of constitutional disorders, OMKar reconstructed the karyotype with 88% precision and 95% recall on SV concordance and 95% Jaccard score on CN concordance. We applied OMKar to 50 prenatal, 41 postnatal, and 63 parental samples from ten different sites. OMKar reconstructed the correct karyotype in 144 out of 154 samples, covering 25 of 25 aneuploidies, 32 of 32 balanced translocations, and 72 of 82 unbalanced variations. Detected constitutional disorders included Cri-du-chat, Wolf-Hirschhorn, Prader-Willi deletions, Down, and Turner syndromes. Importantly, it identified a plausible genetic mechanism for five cases of constitutional disorder that were not detected by other technologies.

Together, these results demonstrate the robustness of OMKar for OGM-based karyotyping. OMKar is publicly available athttps://github.com/siavashre/OMKar.
Development and psychometric testing of EPAT-16: A short and valid measure for patient-centeredness from the patient’s perspective
Authors: Christalle Eva , Kriston Levente , Zeh Stefan , Führes Hannah , Schellhorn Alica , Hahlweg Pola , Zill Jördis , Härter Martin , Scholl Isabelle
Published: February 2025

Background

We previously developed the EPAT-64, a patient-reported experience measure designed to assess patient-centeredness (PC) across 16 dimensions of the validated integrative model of PC. While its modular structure makes it highly adaptable to examine certain dimensions of PC, generating an overall PC score requires assessing all 64 items. This is often challenging in routine settings with limited resources. Therefore, we developed and psychometrically tested a 16-item short form.

Methods

We conducted a cross-sectional study involving adult inpatients and outpatients receiving treatment for cardiovascular diseases, cancer, musculoskeletal disorders, and mental health conditions in Germany. To ensure comprehensive content coverage, we selected one item per dimension based on content relevance as well as item characteristics such as item difficulty and item-total correlation. We assessed the structural validity of a unidimensional model using confirmatory factor analysis (CFA), measured reliability with McDonald’s Omega, and evaluated construct validity by investigating the intercorrelation of the EPAT-16 sum score with measures of general health status and satisfaction with care.

Results

All items of the final EPAT-16 showed high acceptability and good item-total correlations, with approximately two-thirds demonstrating appropriate item difficulty. CFA showed a slight misfit of the unidimensional model, but high average variance explained. McDonald’s Omega showed high reliability. All hypotheses about construct validity were confirmed.

Conclusions

The EPAT-16 demonstrated good psychometric properties, making it a feasible tool for assessing overall PC when resource constraints preclude using the full EPAT-64. In particular, it can be used in routine care for feedback and quality improvement, as well as in research to assess relationships with other relevant variables. Since its items were designed generically, it can be used for different medical conditions and settings, for example, for public reporting. Future research should evaluate the EPAT-16 in diverse, independent patient samples to confirm that its positive characteristics are consistent across different populations and cultures.

Patient or Public Contribution

Patients did not participate as active members of the research team. However, for the research proposal, several patient organizations provided positive feedback on the study aims and their relevance, signed a collaboration agreement, and later supported recruitment by distributing study information.