bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanics of cell sheets: plectin as an integrator of cytoskeletal networks
Authors: Outla Zuzana , Prechova Magdalena , Korelova Katerina , Gemperle Jakub , Gregor Martin
Published: January 2025

Epithelia are multicellular sheets that form barriers defining the internal and external environments. The constant stresses acting at this interface require that epithelial sheets are mechanically robust and provide a selective barrier to the hostile exterior. These properties are mediated by cellular junctions which are physically linked with heavily crosslinked cytoskeletal networks. Such hardwiring is facilitated by plakins, a family of giant modular proteins which serve as ‘molecular bridges’ between different cytoskeletal filaments and multiprotein adhesion complexes. Dysfunction of cytoskeletal crosslinking compromises epithelial biomechanics and structural integrity. Subsequent loss of barrier function leads to disturbed tissue homeostasis and pathological consequences such as skin blistering or intestinal inflammation. In this article, we highlight the importance of the cytolinker protein plectin for the functional organization of epithelial cytoskeletal networks. In particular, we focus on the ability of plectin to act as an integrator of the epithelial cytoarchitecture that defines the biomechanics of the whole tissue. Finally, we also discuss the role of cytoskeletal crosslinking in emerging aspects of epithelial mechanobiology that are critical for the maintenance of epithelial homeostasis.
Trace elements increase replicability of microbial growth
Authors: Shimoga Nadig Amit , Gross Rotem , Bollenbach Tobias , Ansmann Gerrit
Published: January 2025

Trace elements are often omitted from chemically defined growth media. From established properties of trace elements, we deduce that this omission makes experiments unnecessarily sensitive to unavoidable contamination with trace elements. We confirm this experimentally by growing 11 bacterial strains in high replicate with and without supplementing trace elements, keeping all other conditions as fixed as possible to isolate the effect of trace elements. We find that supplementing trace elements considerably reduces variability of growth even in this benign scenario, and we argue that typical experimental set-ups exacerbate this. We discuss implications for the design and use of trace-element supplements and in particular argue that their use should be standard practice, as they can reduce variability of almost all experiments using chemically defined media, taking a step towards greater precision and replicability in microbiology.
Synthesis, antimicrobial evaluation, ADMET prediction, molecular docking and dynamics studies of pyridine and thiophene moiety-containing chalcones
Authors: Akhter Fahmida , Marufa Sumita Saznin , Shohag S. M. Anyet Ullah , Nishino Hiroshi , Alam Mohammad Sayed , Haque Md. Aminul , Rahman Mohammad Mostafizur
Published: January 2025

In this study, three pyridine- and four thiophene-containing chalcone derivatives were synthesized via Claisen–Schmidt condensation reaction, where five derivatives were new. Different spectral analyses (IR,
1
H NMR, HRMS) clarified the structures and these proposed compounds were screened for antimicrobial activity by the agar disc diffusion technique. Compound
1c
was conspicuously active against most of the bacterial and fungal strains. It displayed higher activity against
Bacillus cereus
(22.3 ± 0.6 mm),
Shigella sonnei
(43.3 ± 0.6 mm) and
Shigella boydii
(34.0 ± 1.0 mm) compared to the standard ceftriaxone (20.3 ± 0.6 mm, 40.3 ± 0.6 mm and 25.7 ± 0.6 mm, respectively). In addition, the exhibited inhibition zone of compound
1c
against all fungal strains was higher than that of the standard amphotericin B. All the newly synthesized derivatives satisfied the ADME properties, and no toxicological risks were found. All compounds were docked against three protein receptors with the range of binding affinity of −6.3 to −9.6 kcal mol
−1
. Molecular dynamics simulation was scrutinized further for compound
1c
in three protein–ligand complexes where root mean square deviation and root mean square fluctuation data were below 2 Å, proposing its stability inside and minimal structural changes.
A novel imatinib analogue inhibitor of chronic myeloid leukaemia: design, synthesis and characterization—explanation of its folded conformation
Authors: Moreno-Fuquen Rodolfo , Avellaneda-Tamayo Juan F. , Arango-Daraviña Kevin , Ellena Javier , Kennedy Alan R.
Published: January 2025

Chronic myeloid leukaemia (CML) is primarily treated using imatinib mesylate, a tyrosine kinase inhibitor (TKI) targeting the BCR::ABL1 oncoprotein. However, the development of drug resistance and adverse side effects necessitate the exploration of alternative therapeutic agents. This study presents the synthesis and characterization of a novel imatinib analogue, 3-chloro-
N
-(2-methyl-5-((4-(pyridin-2-yl)pyrimidin-2-yl)amino)phenyl)benzamide (PAPP1). The compound’s structure was elucidated using X-ray crystallography and spectroscopic techniques, including NMR, infrared and UV–visible. Crystallographic analysis reveals that PAPP1 consists of a phenyl–amino–pyridine–pyrimidine (PAPP) scaffold with substituted aromatic rings forming a nearly coplanar geometry. Additionally, supramolecular interactions in the crystal are mediated by hydrogen bonds and dispersion forces, forming dimers and layered structures. Molecular docking studies demonstrate strong binding affinity to the ABL1 enzyme, with PAPP1 showing comparable binding energy to imatinib, indicating its potential as a lead compound for further development. Computational studies, including molecular electrostatic potential and vibrational analysis, provide further support for the structural stability and bioactivity of PAPP1. These findings suggest that PAPP could be a promising scaffold for future CML drug design, offering a potential alternative to existing TKIs, and PAPP1 is a promising lead susceptible to optimization.
Forecasting sea otter recolonization: insights from isotopic analysis of modern and zooarchaeological populations
Authors: Elliott Smith Emma A. , Moss Madonna L. , Wellman Hannah P. , Gill Verena A. , Monson Daniel H. , Newsome Seth D.
Published: January 2025

Retrospective datasets offer essential context for conservation by revealing species’ ecological roles before industrial-era human impacts. We analysed isotopic compositions of pre-industrial and modern sea otters (
Enhydra lutris
) to reconstruct pre-extirpation ecology and offer insights for management. Our study focuses on southeast Alaska (SEAK), where sea otters are recolonizing, and northern Oregon, where translocations are being considered. We measured bulk bone collagen
δ
13
C and
δ
15
N values and essential amino acid
δ
13
C values of extirpated sea otters from archaeological contexts, and bulk isotopic values from vibrissae of modern SEAK sea otters. We compare these results with published isotopic data of potential prey and additional archaeological datasets. In SEAK, our data show pre-industrial sea otter populations consumed infaunal bivalves and used soft-sediment (33%) and kelp forest habitats (67%), with sub-regional variation. We anticipate current populations will expand into this historical niche, and conflict with regional traditional/subsistence bivalve fisheries will persist. In northern Oregon, isotopic data from extirpated sea otters indicate past consumption of low trophic level invertebrates and a stronger reliance on kelp forests (88%) rather than soft-sediment habitats, highlighting the importance of kelp forests for future translocations. Our work exemplifies the value of historical ecology in informing conservation strategies for recovering species.
Feature-selective adaptation of numerosity perception
Authors: Caponi Camilla , Castaldi Elisa , Grasso Paolo Antonino , Arrighi Roberto
Published: January 2025

Perceptual adaptation has been widely used to infer the existence of numerosity detectors, enabling animals to quickly estimate the number of objects in a scene. Here, we investigated, in humans, whether numerosity adaptation is influenced by stimulus feature changes as previous research suggested that adaptation is reduced when the colour of adapting and test stimuli did not match. We tested whether such adaptation reduction is due to unspecific novelty effects or changes of stimuli identity. Numerosity adaptation was measured for stimuli matched or unmatched for low-level (colour, luminance, shape and motion) or high-level (letters' identity and face emotions) features. Robust numerosity adaptation occurred in all conditions, but it was reduced when adapting and test stimuli differed for colour, luminance and shape. However, no reduction was observed between moving and still stimuli, a readable change that did not affect the item’s identity. Similarly, changes in letters' spatial rotations or face features did not affect adaptation magnitude. Overall, changes in stimulus identity defined by low-level features, rather than novelty in general, determined the strength of the adaptation effects, provided these changes were readily noticeable. These findings suggest that numerosity mechanisms operate on categorized items in addition to the total quantity of the set.
Scaling of shoot and root respiration of woody and herbaceous plants
Authors: Kurosawa Yoko , Mori Shigeta , Ferrio Juan P. , Nishizono Tomohiro , Masyagina Oxana V. , Yamaji Keiko , Koyama Kohei , Haruma Toshikatsu , Doyama Kohei , Hoshino Tomoki , Murayama Hideki , Yagi Mitsuharu , Yokozawa Masayuki , Tomiyama Shingo
Published: January 2025

Woody and herbaceous plants are the main components of global terrestrial ecosystems, and their growth, adaptation and survival depend largely on the metabolism of shoots and roots. Therefore, understanding size-scaling of metabolic rates in woody and herbaceous plants, and in shoots and roots, is a fundamental issue in ecology. However, few empirical studies have examined metabolic scaling exponents across a wide range of plant sizes. Using whole-plant chamber systems, we measured respiration rates of entire root systems and shoots of 96 woody species (
n
= 1243) and 33 herbaceous species (
n
= 463) from various terrestrial biomes, with plant masses spanning nine orders of magnitude. Scaling exponents for relationships between respiration rates and fresh mass were greater in shoots than in roots, and both were greater in herbaceous plants than in woody plants. Furthermore, scaling of whole-plant respiration, including various species, converged separately for woody and herbaceous plants. These findings suggest some general physico-chemical constraints on energy use by shoots and roots of individual plants in various terrestrial biomes, including forests and grasslands. These data will advance our understanding of terrestrial ecosystem structure and function.
Maternal deposition of hormones and contaminants shape the gonadal transcriptome in American alligators
Authors: Smaga Christopher R. , Bock Samantha L. , Johnson Josiah M. , Paitz Ryan T. , Letter Andrew , Deem Vincent , Brunell Arnold , Parrott Benjamin B.
Published: January 2025

Environmental conditions influence the maternal deposition of hormones into eggs, which is hypothesized to adaptively modify developmental outcomes in offspring. However, most ecosystems harbour environmental contaminants capable of disrupting endocrine signaling, and maternal exposure to these compounds has the potential to further alter offspring traits. Studies rarely examine maternally derived hormones and contaminants along with offspring phenotypes, and we know little about their interrelationships and potential interactions. Here, we measure yolk concentrations of 24 endocrine-disrupting compounds (EDCs) and 28 steroid hormones along with gonadal transcriptomes from two populations of the American alligator (
Alligator mississippiensis
) that differ in reproductive development and exposure to EDCs. Using a network-based approach, we identify gene expression modules associated with hormones and contaminants independently, in combination, or by potential indirect influences of EDCs on maternal hormone deposition. We find that yolk concentrations of both 17β-oestradiol and etiocholanolone differ across populations and explain substantial variation in gene expression. We further provide evidence for the indirect effect of the pesticide, methoxychlor, on gonadal gene expression through its relationship with 17β-oestradiol. Our results reveal novel pathways by which maternal exposure to environmental contaminants interacts with hormone provisioning to affect offspring sexual development.
The perceptual effects of signal components: black sword margins are crucial for signal size discrimination in green swordtails
Xiphophorus hellerii
Authors: Caves Eleanor M. , Kelley Laura A.
Published: January 2025

The signals that mediate mate choice can be complex, comprising multiple components, and understanding how complex signals evolve under sexual selection has been the focus of much study. However, open questions still remain about the role of the female’s sensory and perceptual processes in shaping the evolution of complex signals. Male green swordtails
Xiphophorus hellerii
have an elongated caudal fin that comprises colour, length and a black melanic margin; females prefer males with larger bodies, longer swords and complete black sword margins. Here, we used a two-choice assay to quantify female preferences for animations of courting males of different sizes with or without sword margin coloration, and found that, when a black melanic margin was present, females exhibited preferences for larger males. However, when the margin was absent, females did not show size-based mate preference, though females spent equal time assessing males in both treatments. Our results suggest that the presence/absence of the black sword margin is an important predictor of female preference, specifically a female’s ability to discriminate between potential mates of different sizes, pointing to a novel size discrimination function of black margins in animal signals, which in many species involve patterns or structures with dark edges.
Social vocalizations indicate behavioural type in
Glossophagine
bats
Authors: Schabacker Theresa , Castiglione Raffaella , Snijders Lysanne , Knörnschild Mirjam
Published: January 2025

Vocalizations play a crucial role in the social systems of many animals and may inadvertently reveal behavioural characteristics of the sender. Bats, the second largest mammalian order, rely extensively on vocalizations owing to their nocturnal lifestyle and complex social systems, making them ideal for studying links between vocalizations and consistent behavioural traits. In this study, we developed a new testing regime to investigate whether consistent individual vocalization differences in nectarivorous bats are associated with specific behavioural types. We exposed 60 wild, male
Glossophaga soricina handleyi
bats to novel and risky stressors and assessed their behavioural and vocal responses. Proactive, exploratory and bold bats were more likely to produce social calls, and among the vocalizing bats, more agitated bats produced higher numbers of social calls. We thus show that bat vocalization behaviour can be indicative of a certain behavioural type, potentially allowing conspecifics to assess personalities from a distance, which in turn could impact subsequent social interactions, group dynamics and reproductive success. Our results, in combination with previous findings in birds, suggest that advertent or inadvertent long-distance broadcasting of personality may be widespread, thus opening up new exciting questions about the links between vocalizations and sociality.
Pollination ecotypes and the origin of plant species
Authors: Johnson Steven D.
Published: January 2025

Ecological niche shifts are a key driver of phenotypic divergence and contribute to isolating barriers among lineages. For many groups of organisms, the history of these shifts and associated trait–environment correlations are well-documented at the macroevolutionary level. However, the processes that generate these patterns are initiated below the species level, often by the formation of ecotypes in contrasting environments. Here, I review the evidence in plants for ‘pollination ecotypes’ as microevolutionary responses to environmental gradients in pollinator availability. Pollinators are critical for population establishment and persistence in most species, thereby forming part of their fundamental niche. Novel floral trait combinations allow species to exploit particular pollination opportunities in local habitats and evolve primarily through sexual selection due to their effects on mating success. I examine selected case studies on the evolution of pollination ecotypes, including self-pollinating forms, and use these to illustrate challenging practical and conceptual issues. These issues include the paucity of reliable natural history data, the problem of implementing and interpreting reciprocal translocation experiments, and establishing criteria for when allopatric ecotypes should be considered species.
Evaluation of p16/Ki- 67 cytology as triage test for high-risk HPV-positive women in a “see and treat strategy”
Authors: Onyango Calleb George , Ogonda Lilian , Guyah Bernard
Published: January 2025

Background

Although high risk human papilloma virus DNA (hr-HPV-DNA) test is the primary tool for cervical cancer screening, with visual inspection with acetic acid (VIA) serving as a triage test where Pap cytology is not available, the low intra-observer agreement associated with VIA means its reliability is limited and a more efficient test is still required. The aim of this study was to compare the performance of p16/Ki-67 cytology with VIA in the detection of cervical precancer and the feasibility as an alternative triage in the “see and treat strategy”.

Methods

In a hospital-based cross-sectional study, we utilized stored provider-collected specimens from a previous study of women referred with cervical abnormalities to a tertiary hospital in Kisumu County, Kenya from February 2021 to November 2023. Specimens were tested with both Xpert and p16/ki-67 Immunostain. All hr-HPV positive women with cervical lesions were triaged using VIA and p16/Ki- 67 cytology. CIN2 or worse (≥CIN2) were defined as the clinical end points.

Results

The p16/ Ki- 67 Immunostaining showed a statistically significant higher sensitivity (84.6% vs. 59.0%%), specificity (44.0% vs. 62.0%), positive predictive value (28.2% vs. 28.8%) and negative predictive value (91.7% vs. 85.3%) compared to VIA examination.

Conclusion

The p16/Ki-67 immunostaining for the detection of ≥CIN2 has shown high sensitivity and high negative predictive value in our study, which is comparable to several previous findings; implying that the assay is superior to VIA in identifying ≥CIN2 and can serve as an alternative tool for triaging primary HPV-positive women in the current “see and treat” strategy.
The Association between Mental Health and Cognitive Ability: Evidence from The UK Household Longitudinal Study
Authors: Iqbal Syka , Waqas Muhammad , Yong Min Hooi , McGarrigle Ronan , Vaportzis Eleftheria
Published: January 2025

The relationship between poor mental health and cognitive impairments in older age is well- established. Social engagement also influences cognitive ability; however much of the research on this relationship has not accounted for the impact of mental health and demographic factors. This study examined the associations between cognitive ability and mental health in older adults, controlling for social interaction and socio-demographic factors. In total, 7,685 individuals aged 65 or older were drawn from the UK Household Longitudinal Study Understanding Society (1). Cognitive abilities were assessed using self-reports and performance on five tasks (immediate and delayed word recall, subtraction, number series and numerical ability). Mental health scores were derived from the General Health Questionnaire (GHQ-12). We controlled for social interaction, gender, ethnicity, educational background, marital status, number of children, and geographic location. We found positive relationships between mental health and all measures of cognitive ability except performance on subtraction and number series tasks. These relationships remained after controlling for social interaction. Demographic factors that contributed to the relationship between mental health and cognitive ability included being White, having higher education, being male for numerical tasks only, and being female, married or divorced for verbal memory tasks only. Overall, our results suggest that the relationship between mental health and cognitive abilities persists when controlling for social interaction alongside socio- demographic factors in older adults, underscoring the importance of addressing these factors in policies and interventions for healthy ageing.
Image-based Explainable Artificial Intelligence Accurately Identifies Myelodysplastic Neoplasms Beyond Conventional Signs of Dysplasia
Authors: Eckardt Jan-Niklas , Srivastava Ishan , Schulze Freya , Winter Susann , Schmittmann Tim , Riechert Sebastian , Schneider Martin , Reichel Lukas , Gediga Miriam Eva Helena , Sockel Katja , Sulaiman Anas Shekh , Roellig Christoph , Kroschinsky Frank , Asemissen Anne-Marie , Pohlkamp Christian , Haferlach Torsten , Bornhaeuser Martin , Wendt Karsten , Middeke Jan Moritz
Published: January 2025

Evaluation of bone marrow morphology by experienced hematologists is key in the diagnosis of myeloid neoplasms, especially to detect subtle signs of dysplasia in myelodysplastic neoplasms (MDS). The majority of recently introduced deep learning (DL) models in cytomorphology rely heavily on manually drafted cell-level labels, a time-consuming, laborious process that is prone to substantial inter-observer variability, thereby representing a substantial bottleneck in model development. Instead, we used robust image-level labels for end-to-end DL and trained several state-of-the-art computer vision models on bone marrow smears of 463 patients with MDS, 1301 patients with acute myeloid leukemia (AML), and 236 bone marrow donors. For the binary classifications of MDS vs. donors and MDS vs. AML, we obtained an area-under-the-receiver-operating-characteristic (ROCAUC) of 0.9708 and 0.9945, respectively, in our internal test sets. Results were confirmed in an external validation cohort of 50 MDS patients with corresponding ROCAUC of 0.9823 and 0.98552, respectively. Explainability via occlusion sensitivity mapping showed high network attention on cell nuclei not solely of dysplastic cells. We not only provide a highly accurate model to detect MDS from bone marrow smears, but also underline the capabilities of end-to-end learning to solve the bottleneck of time-consuming cell-level labeling.
How Users of Different Ages Rate a Mobile App for Self-Testing of Hearing
Authors: Pastucha Małgorzata , Gos Elżbieta , Kochanek Krzysztof , Skarżyński Henryk , Jedrzejczak W. Wiktor
Published: January 2025

Introduction

Traditional diagnostic methods of hearing assessment, such as pure tone audiometry, may not be equally accessible to everyone due to geographical or mobility limitations. Utilizing a mobile application (app) for self-assessment of hearing is a promising alternative. However, the effectiveness of apps, as well as their usability across different age groups, remains largely unexplored. The objective of the present study was to assess, across different age groups, the usability of the “Hearing Test” app which allows self-testing of hearing on a mobile phone.

Materials and methods

The study was conducted on 77 participants from three age groups (16–39 years, 40–59 years, 60 years and older) who self-tested their hearing thresholds using the mobile app and who later underwent pure tone audiometry with an audiologist. The usability of the app was evaluated using a questionnaire based on the Mobile App Rating Scale (MARS), which was complemented by participant observation and interview.

Results

The app generally yielded results comparable to pure tone audiometry. However, older age groups tended to report higher levels of difficulty across several usability dimensions. Specifically, the oldest group rated the app lower in terms of functionality (M = 2.30; SD = 1.27) and engagement-customization (M = 2.11; SD = 1.28). For the oldest participants, the greatest difficulties related to installation (48%), and interpretation of results (26%). None of the participants aged 60 or older were able to complete the test independently, in contrast to 67% of the youngest participants and 28% of the middle-aged who did not require assistance. All age groups expressed a preference for a conventional hearing test over an app-based assessment, although the youngest group showed the greatest openness to using mobile apps.

Conclusions

The “Hearing Test” app has demonstrated its potential as a tool for initial hearing assessment, particularly among younger users. However, older individuals often encounter difficulties with installation, interpretation of results, and overall usability. Adapting the interface to meet the specific needs of older users, including user-friendly tutorials and clear presentation of results, is crucial for enhancing its usability.
Systematic identification of context-dependent gene-essentiality in Glioblastoma: The GBM-CoDE platform
Authors: Foster Mitchell T , Ewing Ailith , Frame Margaret , Brennan Paul M , Khamseh Ava , Beentjes Sjoerd V , Carragher Neil O , Semple Colin A
Published: January 2025

Glioblastoma (GBM) is a heterogeneous and aggressive brain tumour that is invariably fatal despite maximal treatment. Genetic or transcriptomic ‘biomarkers’ could be used to stratify patients for treatments, however, pairing biomarkers with appropriate therapeutic ‘targets’ is challenging. Consequently, therapeutics have not yet been optimised for specific GBM patient subsets. Here we integrate genome-wide CRISPR/Cas9 knockout screening and genetic-annotation data for 60 distinct patient-derived, IDHwildtype, adult GBM cell lines, quantifying the essentiality of 15,145 genes. We describe a novel method using Targeted Learning, to estimate the effect size of GBM-relevant biomarkers on context-dependent gene essentiality (GBM-CoDE). We derive multiple target-biomarker pair hypotheses, which we release in an accessible platform to accelerate translation to biomarker-stratified clinical trials. Two of these (WWTR1 with EGFR mutation/amplification, and VRK1 with VRK2 expression suppression) have been validated in GBM, implying that our additional novel findings may be valid. Our method is readily translatable to other cancers of unmet need.
RIG-I Stimulation Enhances Effector Function and Proliferation of Primary Human CD8 T Cells
Authors: Mohamed Adham Abuelola , Wallerath Christina , Hunkler Charlotte , Hartmann Gunther , Stankovic Sanda , Brooks Andrew G , Schlee Martin
Published: January 2025

Cytotoxic CD8 T lymphocytes (CTL) are crucial in antiviral immune responses. However, their recruitment to infection sites renders them at risk of viral infection that could modulate their effector activity. CTL express RIG-I that detects cytosolic viral RNA and subsequently induce antiviral gene expression. Here, we investigated how influenza A virus (IAV) infection influence TCR-dependent effector responses. IAV infection of CTL stimulated RIG-I, and activated downstream pathways including TBK1 and NF-⍰B, resulting in type-I interferon secretion. Transfection of CTL with a pure RIG-I ligand, tri-phosphorylated double stranded RNA(3p-dsRNA), not only stimulated these pathways but also enhanced CTL proliferationin vitroand protected them from IAV infection. Analogous with a positive effect on CD8 effector function, both IAV infection and RIG-I ligand transfection enhanced CTL degranulation and cytokine secretion. Conversely, activation of CTL via CD3/CD28-crosslinking increased their susceptibility to IAV infection. Altogether, RIG-I stimulation either by IAV infection or 3p-dsRNA transfection promoted cell intrinsic antiviral pathways and enhanced CD8 effector functions. These findings suggest that RIG-I agonists could enhance and prolong CTL effector function in immunotherapy.
FastCCC: A permutation-free framework for scalable, robust, and reference-based cell-cell communication analysis in single cell transcriptomics studies
Authors: Hou Siyu , Ma Wenjing , Zhou Xiang
Published: January 2025

Detecting cell-cell communications (CCCs) in single-cell transcriptomics studies is fundamental for understanding the function of multicellular organisms. Here, we introduce FastCCC, a permutation-free framework that enables scalable, robust, and reference-based analysis for identifying critical CCCs and uncovering biological insights. FastCCC relies on fast Fourier transformation-based convolution to computep-values analytically without permutations, introduces a modular algebraic operation framework to capture a broad spectrum of CCC patterns, and can leverage atlas-scale single cell references to enhance CCC analysis on user-collected datasets. To support routine reference-based CCC analysis, we constructed the first human CCC reference panel, encompassing 19 distinct tissue types, over 450 unique cell types, and approximately 16 million cells. We demonstrate the advantages of FastCCC across multiple datasets, most of which exceed the analytical capabilities of existing CCC methods. In real datasets, FastCCC reliably captures biologically meaningful CCCs, even in highly complex tissue environments, including differential interactions between endothelial and immune cells linked to COVID-19 severity, dynamic communications in thymic tissue during T-cell development, as well as distinct interactions in reference-based CCC analysis.
Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis
Authors: Stier Matthew T. , Sewell Allison E. , Mwizerwa Erin L. , Sim Chooi Ying , Tanner Samantha M. , Nichols Casey M. , Durai Heather H. , Jennings Erin Q. , Lindau Paul , Wilfong Erin M. , Newcomb Dawn C. , Bastarache Julie A. , Ware Lorraine B. , Rathmell Jeffrey C.
Published: January 2025

Host immunity in sepsis has features of hyperinflammation together with progressive immunosuppression, particularly among CD4 T cells, that can predispose to secondary infections and ineffectual organ recovery. Metabolic and immunologic dysfunction are archetypal findings in critically ill patients with sepsis, but whether these factors are mechanistically linked remains incompletely defined. We characterized functional metabolic properties of human CD4 T cells from critically ill patients with and without sepsis and healthy adults. CD4 T cells in critical illness showed increased subset-specific metabolic plasticity, with regulatory T cells (Tregs) acquiring glycolytic capacity that stabilized suppressive markers FOXP3 and TIGIT and correlated with clinical illness severity. Single-cell transcriptomics identified differential kynurenine metabolism in Tregs, which was validatedex vivoas a mechanism of Treg glycolytic adaptation and suppressive rewiring. These findings underscore immunometabolic dysfunction as a driver of CD4 T cell remodeling in sepsis and suggest therapeutic avenues to restore an effective immune response.
Kinesin-8/Kip3 requires beta tubulin tail for depolymerase activity
Authors: Alemany Kaitlin , Johnson Samantha , Moore Jeffrey K.
Published: January 2025

Carboxy-terminal tails (CTTs) of tubulin proteins are sites of regulating microtubule function. We previously conducted a genetic interaction screen and identified Kip3, a kinesin-8 motor, as potentially requiring the β-tubulin CTT (β-CTT) for function. Here we use budding yeast to define how β-CTT promotes Kip3 function and the features of β-CTT that are important for this mechanism. We find that β-CTT is necessary for Kip3 depolymerase activity, but not for microtubule binding and motility. Mutant yeast cells lacking β-CTT show increased accumulation of Kip3 at plus ends and along microtubules, but no increase in catastrophe when Kip3 is overexpressed.In vitroexperiments show that the β-CTT is necessary for Kip3 to form a tight complex with soluble tubulin but is unnecessary for Kip3 to bind tubulin in the microtubule lattice. These results suggest a model in which β-CTT promotes Kip3 depolymerase activity by supporting a Kip3-tubulin binding state that is only accessible at the microtubule plus end or in solution.
Incident Stroke in Pediatric Sickle cell Anemia Despite Overall Improved Transcranial Doppler Velocity in a Ugandan Hydroxyurea Trial: Antecedent and ongoing risks
Authors: Wambaka Bill , Mpungu Amiirah , Mboizi Vincent , Kalibbala Dennis , Nambatya Grace , Murungi Susan , Kabatabaazi Maxencia , Nakafeero Maria , Kasirye Phillip , Munube Deogratias , Namazzi Ruth , Idro Richard , Green Nancy S.
Published: January 2025

Introduction

Transcranial doppler ultrasound (TCD) screening for primary stroke prevention in children with sickle cell anemia (SCA) was established in higher-resource regions, targeting interventions for highest velocity (“abnormal”). We sought to identify additional stroke risk factors in Uganda.

Methods

We conducted a 30-month open-label single-arm Ugandan hydroxyurea trial, dose-escalated to maximum tolerated dose, aimed to test brain protection for children aged 3-9 years with SCA. Study procedures included history, clinical stroke examination and prospective TCD and laboratory assessments.

Results

Overall, 264 children received study HU, mean age 5.6±1.7, hemoglobin 7.8±1.2g/dL, fetal hemoglobin (HbF) 11.9±8.1%, enrolment TCD maximum velocity 148.4±29.3cm/second; 15 (5.7%) had abnormal TCD. Mean TAMV at trial completion was131.9±SD25.7 cm/sec. Four participants without abnormal enrolment TCD developed acute stroke within the initial 16 months (incidence 0.62 per 100 person years); Two had enrolment HbF ≤3.1%, 2 had low oxygen saturation (90%), 1 had recurring severe anemia necessitating multiple transfusions. Apparent stroke precipitants were severe malaria, acute chest syndrome, recent pain crisis or uncertain cause. At trial completion, 8 additional participants had a higher risk TCD category than at enrolment.

Conclusion

Effectiveness of TCD screening for stroke prevention may vary by region, as no participant with incident stroke was at highest risk. Antecedent and/or ongoing SCA-related risks of anemia, low HbF, hypoxemia, infections and/or disease complications likely contributed to stroke despite trial HU. Results suggest that TCD alone may not fully identify highest stroke risk in the region, and need for primary stroke prevention from early and continuous hydroxyurea therapy.
SEXUAL MISCONDUCT AMONG HIGH SCHOOL STUDENTS IN VIETNAM
Authors: Tran Kim Tu , Leone Ruschelle M. , Swartout Kevin M , Tran Minh Hung , Trinh Oanh , Yount Kathryn M.
Published: January 2025

Background

Sexual misconduct is a global problem. Adolescents 15-19 years face the highest risk of sexual misconduct, however, studies on school-based sexual misconduct in low and middle-income countries (LMICs) are limited. We aimed to determine the prevalence of sexual misconduct, including sexual harassment, stalking, dating violence, and sexual violence experiences among students at three high schools in Vietnam since their enrollment.

Methods

Between February and May 2023, 754 students in three high schools in Ho Chi Minh City completed the adapted Administrator-Researcher Campus Climate Collaborative online.

Results

Overall, 54.5% of students reported any sexual misconduct since enrolling in high school. The prevalence of sexual harassment victimization was 40.2% perpetrated by staff and 30.2% perpetrated by students. Stalking prevalence was 18.3%, and 13.1% of students reported experiencing dating violence. Nearly 1 in 10 (8.7%) of students reported sexual violence victimization. Sexual coercion prevalence was highest in the middle-ranked school (6.2%) and lowest in the high-ranked school (1.6%) (p=0.028). Compared to girls, boys reported a higher prevalence of unwanted sexual attention (18.7% vs. 10.9%) and sexual coercion (10.1% vs 4.6%) by staff (p=0.001). Girls reported a higher prevalence of dating violence victimization than boys (14.9% vs. 9.9%, p=0.029).

Conclusion

Sexual misconduct prevalence among high school students in Ho Chi Minh City is high with notable gender differences in victimization. Awareness raising among parents, school administrators, and youth is needed to develop contextually appropriate preventive and response programs to address sexual misconduct in high schools across Vietnam.

Highlights

We assessed sexual misconduct among students in three high schools in South Vietnam

We assessed experiences of sexual harassment, stalking, dating violence, and sexual violence

Boys experienced higher sexual harassment victimization by faculty/staff than girls

Girls experienced a higher prevalence of dating violence victimization than boys

Findings inform future research and prevention efforts for high schools in South Vietnam
Towards Metacognitive Clinical Reasoning: Benchmarking MD-PIE Against State-of-the-Art LLMs in Medical Decision-Making
Authors: Esteitieh Yasma , Mandal Shaurjya , Laliotis George
Published: January 2025

The ability of large language models (LLMs) to perform clinical reasoning and cognitive tasks within medicine remains a critical measure of their overall capabilities in decision-making, with significant implications for patient outcomes and healthcare efficiency. Current AI models often face limitations in real-world clinical environments, including variability in performance, a lack of domain-specific knowledge, and black-box reasoning processes. In this study, we introduce a novel PIE framework, named MD-PIE, which emulates cognitive and reasoning abilities in medical reasoning and decision-making. We benchmark our framework and baseline methods both quantitatively and qualitatively using state-of-the-art LLMs, comparing them against OpenAI’s o1, Gemini 2.0 Flash Thinking, and DeepSeek V3 across diverse benchmarks. Our results demonstrate that MD-PIE surpasses existing models in differential diagnosis and reasoning accuracy across diverse medical benchmarks. This study underscores its potential to improve clinical decision-making through adaptive and collaborative design. Future research should focus on larger benchmarks and real-world validation to confirm its reliability and effectiveness in varied clinical scenarios.
The Utility of Ultra-Deep RNA sequencing in Mendelian Disorder Diagnostics
Authors: Zhao Sen , Sinson Jefferson C. , Li Shenglan , Rosenfeld Jill A. , Zapata Gladys , Macakova Kristina , Pena Mezthly , Maywald Becky , Worley Kim C. , Burrage Lindsay , Hubshman Monika Weisz , Ketkar Shamika , Craigen William , Emrick Lisa ,   Undiagnosed Diseases Network, Clark Tyson , Lithwick Gila Yanai , Shipony Zohar , Eng Christine , Lee Brendan , Liu Pengfei
Published: January 2025

Clinical RNA-seq has become an essential tool for resolving variants of uncertain significance (VUS), particularly those affecting gene expression and splicing. However, most reference data and diagnostic protocols employ relatively modest sequencing depths (∼50-150 million reads), which may fail to capture low-abundance transcripts and rare splicing events critical for accurate diagnoses. We evaluated the diagnostic and translational utility of ultra-high-depth (up to ∼one billion unique reads) RNA-seq in four clinically accessible tissues (blood, fibroblast, LCL, and iPSC) using Ultima sequencing platform. After validating the performance of Ultima RNA-seq, we investigated how increasing depth affects gene and isoform detection, splicing variant discovery, and clinical interpretation of VUS. Deep RNA-seq substantially improved sensitivity for detecting lowly-expressed genes and isoforms. At ∼1 billion reads, near-saturation was achieved for gene-level detection, although isoform-level coverage continued to benefit from even deeper sequencing. In two clinical cases with VUS, pathogenic splicing abnormalities were undetected at ∼50 million reads but emerged at 200 million reads, becoming even more pronounced at ∼one billion reads. Using deep RNA-seq data, we constructed a novel resource, MRSD-deep, to estimate the minimum required sequencing depth to achieve desired coverage thresholds. MRSD-deep provided gene- and junction-level guidelines, aiding labs in selecting suitable coverage targets for specific applications. Leveraging deep RNA-seq data on fibroblast, we also built an expanded splicing-variation reference that successfully identified rare splicing events missed by standard-depth data. Our findings underscore the diagnostic and research benefits of deep RNA-seq for Mendelian disease investigations. By capturing rare transcripts and splicing events, ultra-high-depth RNA-seq can facilitate more definitive variant interpretations and enrich splicing-reference databases. We anticipate that cost-effective deep sequencing technologies and robust reference cohorts will further advance RNA-based diagnostics in precision medicine.
Divergent morphologies with convergent performance in the mandible of pelagiarian fishes
Authors: Knapp Andrew , Lazaro Gizeh Rangel-de , Friedman Matt , Johanson Zerina , Evans Kory M , Giles Sam , Beckett Hermione T , Goswami Anjali
Published: January 2025

Mandibles represent a key evolutionary innovation that enabled jawed vertebrates to adapt and diversify in response to a range of food sources. Using a phylogenetic comparative approach, we explore the phenotypic disparity and mechanical properties of the lower jaw in Pelagiaria, a morphologically diverse but relatively small clade of open-ocean fishes which are hypothesized to have radiated near the Cretaceous/Paleogene (K/Pg) mass extinction event. We found that body elongation and diet are not significantly correlated with jaw shape, but that habitat depth and tooth type are. Mechanical advantage (MA) is significantly correlated with mandible shape, with jaw-closing MA being most strongly correlated. Pelagiarian jaw shapes fall broadly into six morphotypes, of which two show significantly higher closing MA than other groups, despite differing substantially in shape. The high morphological disparity of pelagiarian mandible shape was established very early in their evolutionary history, and high levels of disparity have been maintained over tens of millions of years; this is consistent with the hypothesis that Pelagiaria represents an ancient adaptive radiation. Our results demonstrate both the mechanical and morphological diversity of the pelagiarian mandible and highlight the crucial role that morphological diversification has played in the trophic radiation of this clade.
Tensor analysis of animal behavior by matricization and feature selection
Authors: Wang Beichen , Cai Jiazhang , Fang Luyang , Ma Ping , Leung Yuk Fai
Published: January 2025

Contemporary neurobehavior research often collects multi-dimensional tensor (MDT) data, consisting of time-series measurements for multiple features from multiple animals subjected to various perturbations. Proper analysis of the MDT data can facilitate the dissection of the underlying neural circuitry driving the behavior. However, many common approaches for MDT analysis, such as tensor decomposition, often yield results that are difficult to interpret and not directly compatible with standard multivariate analysis (MVA), which is designed for simpler, lower-dimensional data structures. To address this issue, dimensionality reduction techniques, including matricization methods such as Index Construction and Feature Concatenation, are applied to transform all or a subset of the features in the MDT into a lower-dimensional tensor, commonly a 2-dimensional tensor (2DT), that is compatible with MVA. However, the matricization methods may exclude information from the MDT features or create too many 2DT features that introduce spurious noise to the downstream analyses. Their impacts on the downstream MVA performance remain elusive. In this study, we systematically evaluated different approaches for matricization and feature selection and their impacts on MVA performance using an MDT dataset of zebrafish visual- motor response collected from wild-types (WTs) and visually-impaired mutants. We matricized the MDT dataset using various Index Construction and Feature Concatenation methods, then identified informative 2DT features using the filter and embedded methods. To evaluate these feature-selection approaches, we conducted a classification task distinguishing WT and visually-impaired zebrafish by multiple classifiers. We then assessed classification performance with cross-validation and holdout validation. We found that most classifiers performed the best when using all 2DT features matricized by Feature Concatenation and selected by the embedded method. The results also revealed unique behavioral differences between the WTs and visually-impaired mutants that were not identified by standard MVA or MDT analysis. Our results demonstrate the utility of analyzing MDT behavioral data by matricization and feature selection.
Leveraging Neural Network Models for Drug Repurposing: A case study on Cardiac Hypertrophy
Authors: Magnusson Rasmus , Johansson Markus , Hagvall Sepideh , Synnergren Jane
Published: January 2025

Background

Drug repurposing has emerged as an attractive strategy in contemporary pharmaceutical research, presenting an opportunity to expedite drug discovery, minimize developmental costs, and mitigate risks associated with developing new pharmaceuticals. In this study, we investigated a novel approach based on deep learning of human transcriptomic mechanisms for systematic identification of additional therapeutic potential in preexisting drugs.

Method

We trained a composite feedforward neural network model using gene expression data sourced from the ARCHS4 compilation of the GEO, encompassing extensive human datasets. Subsequently, disease-associated gene expression data were generated from our stem cell-derivedin vitromodel of cardiac hypertrophy induced by Endothelin-1 stimulation. These data were employed to identify latent variables associated with genes showing differential expression due to Endothelin-1 stimulation. By examining the differential expression profiles within the model’s latent space, we successfully correlated the disease signal with known drug targets found in pharmaceutical compounds cataloged in DrugBank.

Results

The model accurately encoded additional disease-related genes beyond the curated gene set, demonstrating its ability to generalize disease associations. Leveraging the model, we identified potential drug candidates, such as lapatinib and amiodarone showing promise in mitigating proBNP concentration associated with cardiac hypertrophy.

Conclusion

This study demonstrates the power of deep learning of human transcriptomic mechanisms in swiftly identifying new therapeutic potentials for existing drugs, highlighting the pivotal role of artificial intelligence technologies in accelerating drug development for other complex medical conditions.

Highlights

An interpretable neural network model for identification of candidate drugs for drug repurposing

Encoding expression data from our cardiac hypertrophy model highlights important disease mechanisms

Lapatinib and amiodarone experimentally validated as candidate drugs for cardiac hypertrophy therapies