bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiation of pain: psychophysical evidence for a population coding mechanism in humans
Authors: Adamczyk Wacław M. , Ramu Vishwanath , Jackson Catherine , Schulze Geraldine , Goldschneider Kenneth R. , Kashikar-Zuck Susmita , King Christopher D. , Coghill Robert C.
Published: December 2024

The spread of pain across body locations remains poorly understood but may provide important insights into the encoding of sensory features of noxious stimuli by populations of neurons. In this psychophysical experiment, we hypothesized that more intense noxious stimuli would lead to spread of pain, but more intense light stimuli would not produce perceptual radiation. Fifty healthy volunteers (27 females, 23 males, ages 14-44 years) participated in this study wherein noxious stimuli (43, 45, 47, and 49°C) were applied to glabrous (hand) and hairy skin (forearm) skin with 5-second and 10-second durations. Also, visual stimuli displayed on the target bodily area were used as a control. Participants provided pain (and light) spatial extent ratings as well as pain (and light) intensity ratings. In the extent rating procedure, participants adjusted the extent of the square displayed on the screen with the extent of pain (or light) that they experienced. Pain extent ratings showed statistically significant radiation of pain indicated by 12.42× greater spatial spread of pain (pain extent) than the area of the stimulation with 49°C (P < 0.001), in contrast to visual ratings, which closely approximated the size of the stimulus (1.22×). Pain radiation was more pronounced in hairy than glabrous skin (P < 0.05) and was more pronounced with longer stimulus duration (P < 0.001). Pain intensity explained only 14% of the pain radiation variability. The relative independence of the pain radiation from pain intensity indicates that distinct components of population coding mechanisms may be involved in the spatial representation of pain vs intensity coding.
Horner Syndrome in a Pediatric Patient: A Case Report of Lymphatic Malformation Induced Presentation in a 7-year-old Boy
Authors: Merino-Mateo Lara , Redondo Sedano Jesús Vicente , Gallego Herrero María Del Carmen
Published: December 2024

Lymphatic malformations are low-flow vascular anomalies that predominantly affect the cervicofacial region in the pediatric population. We describe a case of a 7-year-old healthy boy who presented to the emergency department with the classic triad of miosis, ptosis, and anhidrosis. Initial evaluation, including a cervicocranial computed tomography scan, revealed no intracranial space-occupying lesion. Subsequent diagnostic work-up, involving ultrasound and cervicothoracic magnetic resonance imaging, identified a cystic lesion in the upper mediastinum, consistent with the diagnosis of lymphatic malformations. The integration of a multidisciplinary team proved essential in reaching a definitive diagnosis and selecting the optimal treatment (ultrasound-guided sclerotherapy) mitigating the risk of life-threatening and cosmetic complications.
Decisional Control Preferences in Managing Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: England Bryce , Habib Joseph R. , Sharma Acacia R. , Hewitt D. Brock , Bridges John F.P. , Javed Ammar A. , Wolfgang Christopher L. , Braithwaite R. Scott , Sacks Greg D.
Published: December 2024

Objectives

To evaluate patient preferences for decision-making role in the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and to identify individual characteristics associated with those preferences.

Background

Management of IPMNs is rooted in uncertainty with current guidelines failing to incorporate patients’ preferences and values.

Methods

A representative sample of participants aged 40-70 were recruited to evaluate a clinical vignette where they were given the option to undergo surveillance or surgical resection of their IPMN. Their preferred role in the decision-making process for the vignette was evaluated using the Control Preference Scale. The relationship between control preference and variables including cancer anxiety, health literacy, and education level was analyzed.

Results

Of the 520 participants in the study, most preferred an active role (65%), followed by shared (29%), and passive roles (6%) in the decision-making process. Lower health literacy was significantly associated with a more passive control preference (p = 0.003). Non-active preference was significantly associated with Latino race compared to White race (odds ratio = 0.52, p = 0.009) in multivariate analysis. We found no significant association between control preference and education level or cancer anxiety.

Conclusions

Most patients preferred an active role in IPMN treatment decisions. Lower health literacy and Latino race were associated with a preference for non-active decision roles. Clinicians should strive to align patient involvement in IPMN treatment decisions with their patient’s preferred role.
Perceptions and Needs for a Technology-Based Dyadic Intervention on Symptom Management Among Patients With Colorectal Cancer and Their Caregivers: A Qualitative Study
Authors: Epari Amruta , Kim Kevin , Xiao Canhua , Porter Laura S. , Alese Olatunji B. , Northouse Laurel , Liu Darren , Graetz Ilana , Lin Yufen
Published: December 2024

Background

Colorectal cancer (CRC) patients and their caregivers often experience multiple co-occurring symptoms (eg, fatigue, depression, anxiety, and sleep disturbance). There is a noticeable gap in research regarding symptom management for patient-caregiver dyads, particularly using technology-based tools.

Objective

This study aimed to describe the needs and perceptions of patient-caregiver dyads regarding a technology-based tool to manage their multiple symptoms.

Methods

This study utilized a qualitative descriptive design with purposive sampling. Semistructured interviews were conducted with CRC patients undergoing chemotherapy and their caregivers. Thematic analysis was performed to identify key themes.

Results

The study included 11 patients and 8 caregivers (8 patient-caregiver dyads and 3 patients without dyads). Four main themes emerged: (1) high symptom burden experienced by CRC patients and their caregivers; (2) symptom self-management strategies, including information seeking and self-education, family and social support, and coping strategies; (3) input and suggestions for technology use, covering aspects such as content, format, and specific technology features; and (4) concerns about barriers to healthcare access, including technological literacy, geographical distance, and time constraints.

Conclusions

Our findings provide novel insights into experiences, needs, and suggestions of CRC patient-caregiver dyads for managing multiple symptoms. Participants emphasized the importance of developing a tailored, technology-based tool that includes personalized, evidence-based content; accessible and intuitive design features; and interactive social support capabilities.

Implications for Practice

Leveraging these findings, we aim to develop a technology-based dyadic intervention tool that addresses the psychosocial needs of CRC patient-caregiver dyads. This approach can also enhance health equity by making care more accessible.
Kinetic patterns of single cell gene expression discriminate between the murine cellular responses to live attenuated and inactivated Yellow Fever vaccines
Authors: Chatterjee Budha , Boughter Christopher T. , Gorga Katrina , Ohta Yuko , Blair Carly , Hill Elizabeth M. , Fasana Zachary , Atuheirwe Maxine , Adebamowo Adedola , Ammar Farah , Ayithan Natarajan , Courneya JP , Kosik Ivan , Murugan Vel , Chen Wilbur H. , Pasetti Marcela F. , Meier-Schellersheim Martin , Singh Nevil J
Published: December 2024

The success of the live attenuated Yellow Fever vaccine (YF17D) that elicits immunity lasting over thirty years has made it a widely used model to understand the generation of durable protection. We compare the early single-cell level transcriptional response in mice to YF17D and an adjuvanted-inactivated, but less effective version (InYF). Within the first week, we identify 70 kinetic patterns in 45 cellular clusters, majority of which discriminate between the two formulations, some in a tissue and sex-specific manner. Intriguingly, differential transcripts fall into two categories, one whose association with YF17D or InYF is maintained even when decoupled from their cell-type of expression and the other where such cell-plus-gene pairing is critical to maintain differential marker status. We demonstrate applications of this resource, by identifying B cells with varied interferon and antigen responsiveness in relation to each vaccine. This high-resolution dataset is amenable to further biomarker discovery and hypothesis generation.
De novo designed pMHC binders facilitate T cell induced killing of cancer cells
Authors: Johansen Kristoffer Haurum , Wolff Darian , Scapolo Beatrice , Fernandez-Quintero Monica L. , Christensen Charlotte Risager , Loeffler Johannes R. , Rivera-de-Torre Esperanza , Overath Max D. , Munk Kamilla Kjaergaard , Morell Oliver , Viuff Marie Christine , Damm Englund Alberte T. , Due Mathilde , Forli Stefano , Qingjie Andersen Emma , Fernandes Jordan Sylvester , Thumtecho Suthimon , Ward Andrew B. , Ormhoj Maria , Hadrup Sine Reker , Jenkins Timothy P.
Published: December 2024

The recognition of intracellular antigens by CD8+ T cells through T cell receptors (TCRs) is central to adaptive immunity, enabling responses against infections and cancer. The recent approval of TCR-gene-edited T cells for cancer therapy demonstrates the therapeutic advantage of using pMHC recognition to eliminate cancer. However, identification and selection of TCRs from patient material is complex and influenced by the TCR repertoire of the donors used. To overcome these limitations, we here present a rapid and robust de novo binder design platform leveraging state-of-the-art generative models, including RFdiffusion, ProteinMPNN, and AlphaFold2, to engineer minibinders (miBds) targeting the cancer-associated pMHC complex, NY-ESO-1(157-165)/HLA-A*02:01. By incorporating in silico cross-panning and molecular dynamics simulations, we enhanced specificity screening to minimise off-target interactions. We identified a miBd that exhibited high specificity for the NY-ESO-1-derived peptide SLLMWITQC in complex with HLA-A*02:01 and minimal cross-reactivity in mammalian display assays. We further demonstrate the therapeutic potential of this miBd by integrating it into a chimeric antigen receptor, as de novo Binders for Immune-mediated Killing Engagers (BIKEs). BIKE-transduced T cells selectively and effectively killed NY-ESO-1+ melanoma cells compared to non-transduced controls, demonstrating the promise of this approach in precision cancer immunotherapy. Our findings underscore the transformative potential of generative protein design for accelerating the discovery of high-specificity pMHC-targeting therapeutics. Beyond CAR-T applications, our workflow establishes a foundation for developing miBds as versatile tools, heralding a new era of precision immunotherapy.
Quantifying Pathological Progression from Single-Cell Data
Authors: Khan Samin Rahman , Rahman M. Sohel , Samee Md. Abul Hassan
Published: December 2024

The surge in single-cell datasets and reference atlases has enabled the comparison of cell states across conditions, yet a gap persists in quantifying pathological shifts from healthy cell states. To address this gap, we introduce single-cell Pathological Shift Scoring (scPSS) which provides a statistical measure for how much a “query” cell from a diseased sample has been shifted away from a reference group of healthy cells. In scPSS, The distance of a query cell to itsk-th nearest reference cell is considered as its pathological shift score. Euclidean distances in the topnprincipal component space of the gene expressions are used to measure distances between cells. The p-value of a query pathological shift score belonging to the null distribution of intra-reference cell shift scores provides a statistical significance measure of the query cell being in the reference cell group. This makes our method both simple and statistically rigorous. Comparative evaluations against a state-of-the-art contrastive variational inference model, modified for shift scores, demonstrate our method’s accuracy and efficiency. Additionally, we have also shown that the aggregation of cell-level pathological scores from scPSS can be used to predict health conditions at the individual level.
MAAPE: A Modular Approach to Evolutionary Analysis of Protein Embeddings
Authors: Wang Xiaoyu , Zhang Heqian , Huang Jiaquan , Qin Zhiwei
Published: December 2024

We present MAPPE, a novel algorithm integrating a k-nearest neighbor (KNN) similarity network with co-occurrence matrix analysis to extract evolutionary insights from protein language model (PLM) embeddings. The KNN network captures diverse evolutionary relationships and events, while the co-occurrence matrix identifies directional evolutionary paths and potential signals of gene transfer. MAPPE overcomes the limitations of traditional sequence alignment methods in detecting structural homology and functional associations in low-similarity protein sequences. By employing sliding windows of varying sizes, it analyzes embeddings to uncover both local and global evolutionary signals encoded by PLMs. We have benchmarked MAAPE approach on two well-characterized protein family datasets: the Als regulatory system (AlsS/AlsR) and the Rad DNA repair protein families. In both cases, MAAPE successfully reconstructed evolutionary networks that align with established phylogenetic relationships. This approach offers a deeper understanding of evolutionary relationships and holds significant potential for applications in protein evolution research, functional prediction, and the rational design of novel proteins.
Neutrophils drive sexual dimorphism in experimental periodontitis
Authors: Martin Kelsey , Mianecki Maxwell , Maglaras Victoria , Sheikh Asfandyar , Saleh Muhammad H. A. , Decker Ann M. , Decker Joseph T.
Published: December 2024

The motivating premise of this study is to improve the treatment of periodontal disease by elucidating sex-specific mechanisms of periodontal disease progression. Men and women experience inflammation in fundamentally different ways and understanding the sex-specific biology leading to inflammation and bone loss in the periodontium will inevitably improve patient outcomes. We therefore examined clinical and immunological differences in the progression of periodontal disease using the ligature-induced periodontitis model. Periodontitis was induced in male and female C57BL/6j mice by tying a 5-0 silk suture around the left maxillary second molar. The ligature was left on for 7 or 21 days at which point maxillae were characterized for bone loss by μCT or immune infiltrate by flow cytometry. Neutrophil depletion was accomplished through systemic administration of a Ly6G antibody. Conditions were compared using two-way ANOVA with Tukey’s multiple comparison correction from n≥5 animals. Ligature-induced periodontitis led to alveolar bone loss at both 7 and 21 days in both female and male mice. Males and females had approximately the same amount of linear bone loss 7 days post-ligature placement, while male mice had significantly more linear bone loss by day 21. Male mice had significantly more immune cells in their maxillae 7 days post ligature placement compared to female mice. Both male and female mice showed a shift in immune populations towards neutrophils, with no significant difference between males and females. Neutrophil counts were significantly elevated in male mice on day 7 but not day 21, while female mice did not have any statistically significant changes in neutrophil counts. Neutrophil depletion using a Ly6G antibody limited bone loss in male but not female mice relative to isotype antibody-treated controls. Analysis of single-cell sequencing data from human patients with periodontitis showed differences in neutrophil phenotypes that were also observed in a mouse model of periodontitis. Together, these data suggest a mechanistic role for neutrophil inflammation in sexual dimorphism in periodontitis.
Early exposure to Western Diet exacerbates visual outcomes in female mice
Authors: Meseguer David , Furtado Jessica , Zapadka Thomas , Rodriguez Amanda , Na Daxiang , Grajales-Reyes Jose G. , Demb Jonathan , Eichmann Anne , Schneeberger Marc
Published: December 2024

Obesity, a growing pandemic in Western societies, significantly impacts metabolic health and contributes to visual disorders. While the systemic consequences of obesity, such as chronic inflammation and insulin resistance, are well-studied in adults, its early-life effects on retinal health remain underexplored. Using a maternal Western Diet (WD) exposure model, we investigated the developmental impact of early-life metabolic disturbances on retinal and cognitive function. Our findings reveal that WD exposure from gestation to early adulthood accelerates the onset of features resembling diabetic retinopathy, including increased retinal vascularization, inflammation, and compromised blood-retina barrier integrity, observed within just four months. Females exhibited heightened vulnerability, showing pronounced ocular defects such as anophthalmia, microphthalmia, and congenital cataracts. These results underscore a critical developmental window during which metabolic disruptions predispose to sex-specific retinal and neurovascular pathologies. This work bridges the link between pediatric and adult obesity, highlighting the urgent need for early interventions to mitigate long-term visual impairments that could further impair recognition memory.
Reshaping the Landscape of Locoregional Treatments for Breast Cancer Liver Metastases: A novel, intratumoral, p21-targeted percutaneous therapy increases survival in BALB/c mice inoculated with 4T1 triple negative breast cancer cells in the liver
Authors: Margulies Bryan S. , Likhitpanichkul Morakot , Tripathy Debu
Published: December 2024

Patients with disseminated metastatic disease from breast cancer are likely to have liver involvement in >50% of cases at some point during disease progression. These patients have a poor prognosis; and, when treated with the standard of care systemic therapy they have a median survival of <9-months. Increasing survival in breast cancer patients will likely require the administration of better therapies that are specifically targeted to treat distant metastases. One approach to increasing treatment efficacy for breast cancer liver metastases is through the application locoregional therapies. Locoregional therapies are an appealing interventional approach for breast cancer patients with liver metastases since these tumor lesions are accessible via minimally invasive procedures that can be administered using either ultrasound or CT imaging. Current locoregional therapies to treat breast cancer liver metastases are non-specific and have not produced significant increases in survival. The goal of this study was to design and test a targeted locoregional therapeutic intervention for breast cancer liver metastases. The lead candidate, a fixed-dose small-molecule drug called MBC-005, was testedin vitroand then the efficacy was evaluated in a BALB/c mouse liver metastases model. A novel formulation of N-allyl noroxymorphone hydrochloride incorporated into an alginate-based gel overcomes many of the limitations associated with the administration of small-molecule drugs, which include solubility, off-target toxicity, and enzymatic degradation.In vitroresults demonstrated that MBC-005 mediated its anti-tumorigenic effect through a p21-dependent mechanism via a novel molecular pathway, in which N-allyl noroxymorphone component of MBC-005 stimulated the opioid growth factor receptor to increase p21 expression. Intratumoral administration of MBC-005 increased survival 3.9-fold in mice and significantly decreased tumor volume 4-fold. While many cytotoxic therapies increase p21 expression as a response to DNA damage, MBC-005 increased p21 expression independent cytotoxic DNA damage. MBC-005 did not induce off-target toxicity; and, as such, would be amenable to multiple rounds of administration. Nevertheless, it is notable that the positive effects of MBC-005 treatment on increasing survival and decreasing tumor volume in mice was achieved using a single dose.
Genetic Control of Prickles in Tetraploid Blackberry
Authors: Johns Carmen A. , Silva Alexander , Chizk T. Mason , Nelson Lacy , Clark John R. , Aryal Rishi , Ashrafi Hudson , Thompson Ellen , Hardigan Michael , Worthington Margaret
Published: December 2024

Prickle-free blackberry (RubussubgenusRubus) canes are strongly preferred by growers due to food and worker safety concerns and damage to fruit from mechanical injury by prickles. This project was conducted to identify the genetic region responsible for prickle-free canes derived from the recessive ’Merton Thornless’ source in autotetraploid blackberry using a genome-wide association study, develop diagnostic KASP markers for prickle-free canes, and determine the effects of allele dosage at the prickle-free locus on prickle density in two biparental populations. The prickle locus was located on chromosome Ra04 from 30.48 to 36.04 Mb in an extensive LD block, with the peak SNP located at 33.64 Mb. Two diagnostic KASP markers were developed that correctly predicted the phenotype of 97% and 96% of 626 diverse fresh-market blackberry genotypes from multiple breeding programs, respectively. Allele dosage at the prickle-free locus had a significant impact on prickle density, with duplex prickly genotypes having significantly higher prickle density than simplex genotypes in both biparental populations studied. Five potential candidate genes with functional annotations related to epidermal, trichome, and/or prickle development were identified within the prickle-free locus, but no nonsynonymous polymorphism within these genes were identified.

Article Summary

Blackberry cultivars with prickle-free canes are strongly preferred by growers and shipper marketers. The objectives of this study were to map the prickle-free locus in tetraploid fresh- market blackberries using a genome-wide association approach and develop diagnostic molecular markers that breeders can use to plan crosses and screen seedlings for prickle-free canes. The prickle-free locus was mapped to a 5.6 Mb region on chromosome Ra04. Two molecular markers developed in this region correctly predicted the phenotype of 96% or more of the breeding selections and cultivars in a large validation panel composed of germplasm from three breeding programs.
One score to rule them all: regularized ensemble polygenic risk prediction with GWAS summary statistics
Authors: Zhao Zijie , Dorn Stephen , Wu Yuchang , Yang Xiaoyu , Jin Jin , Lu Qiongshi
Published: December 2024

Ensemble learning has been increasingly popular for boosting the predictive power of polygenic risk scores (PRS), with almost every recent multi-ancestry PRS approach employing ensemble learning as a final step. Existing ensemble approaches rely on individual-level data for model training, which severely limits their real-world applications, especially in non-European populations without sufficient genomic samples. Here, we introduce a statistical framework to construct regularized ensemble PRS, which allows us to combine a large number of candidate PRS models using only summary statistics from genome-wide association studies. We demonstrate its robust and substantial improvement over many existing PRS models in both within- and cross-ancestry applications. We believe this is truly “one score to rule them all” due to its capability to continuously combine newly developed PRS models with existing models to improve prediction performance, which makes it a universal approach that should always be employed in future PRS applications.
Potential antiviral and immunomodulatory Amazonian medicinal plant compounds
Authors: Napoleão Sarah Maria da Silva , Bernardes João Paulo Romualdo Alarcão , Tenório Bernardo Guerra , Cardenas Calisto Moreno , Dallago Bruno Stéfano Lima , Çiçek Serhat Sezai , Bezerra Roberto Messias , Segovia Jorge Federico Orellana , Kanzaki Elida Cleyse Gomes da Mata , Kanzaki Isamu
Published: December 2024

Background

Novel antiretroviral drugs are in constant need for HIV/AIDS patients to face the continuous emerging resistance to the commonly prescribed combination of anti-HIV synthetic agents and their side effects.

Methods

Amazonian medicinal plants,Licania macrophylla(Chrysobalanaceae) andOuratea hexasperma(Ochnaceae) were assayed for antiretroviral and immunomodulatory activity, utilizing an established human leukocyte cell line and the Simian Immunodeficiency Virus. The IL-4, IL-6, IL-8, IL-10 and IFN-y cytokines were quantified after leukocyte culture stimulation with ethanolic plant extracts and challenged with lentivirus infection.

Results

Mitotic activity induced byO. hexaspermaextract was significatively more pronounced thanL. macrophyllaextract. Cytokine modulation was recorded in SIV infected cells under independent treatment withO. hexaspermaandL. macrophyllaextracts. Betulinic acid, ninuriflavone, (-)epigallocathechine, (-)gallocatechine and 4-O-methyl-epigallocatechin were isolated fromL. macrophyla.

Conclusions

Cellular proliferative activity and cytokine modulation by the extracts assayed have potential applications in the therapy of HIV/AIDS pathology, as the isolated compounds of these plants have been reported for antiviral activity.
A Comparative Review of Deep Learning Methods for RNA Tertiary Structure Prediction
Authors: Martinović Ivona , Vlašić Tin , Li Yang , Hooi Bryan , Zhang Yang , Šikić Mile
Published: December 2024

Several deep learning-based tools for RNA 3D structure prediction have recently emerged, including DRfold, DeepFoldRNA, RhoFold, RoseTTAFoldNA, trRosettaRNA, and AlphaFold3. In this study, we systematically evaluate these six models on three datasets: RNA Puzzles, CASP15 RNA targets, and a newly generated large dataset of sequentially distinct RNAs, which serves as a benchmark for generalization capabilities. To ensure a robust evaluation, we also introduce a fourth, more stringent dataset that contains both sequentially and structurally distinct RNAs. We observed that each model predicts the best structure for certain RNAs, and evaluated whether commonly used scoring functions, Rosetta score and ARES, can reliably identify the most accurate structure from the predictions. Finally, since many RNA chains in the Protein Data Bank are part of complexes, we compare the performance of RoseTTAFoldNA and AlphaFold3 in predicting RNA structures within complexes versus isolated RNA chains extracted from these complexes. This comprehensive evaluation highlights the strengths and limitations of current deep learning-based tools and provides valuable insights for advancing RNA 3D structure prediction.
Effect of levodopa/carbidopa on the progression of Machado-Joseph disease /spinocerebellar ataxia type 3 (MJD/SCA3)
Authors: Raposo Mafalda , Sárkány Zsuzsa , Damásio Joana ,   CRC-SCA Consortium, Lima Manuela , Macedo-Ribeiro Sandra , Martins Pedro M.
Published: December 2024

Background and Objectives

In Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3), ataxin-3 accumulates as neuronal nuclear inclusions in specific regions of the brain such as the substantia nigra and the dentate cerebellar nucleus. Ataxin-3 aggregation is strongly inhibited by dopamine, a neurotransmitter whose brain levels can be increased through the use of medication containing levodopa/carbidopa (LA/CA). Here we perform a retrospective study to determine whether exposition to LA/CA is associated with a decreased progression of MJD/SCA3.

Methods

We assessed the natural history of individuals with MJD/SCA3 and also SCA1, 2, 6, 7, 8, and 10 enrolled by the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA). Our initial analysis focused on individuals with all spinocerebellar ataxias (SCAs) whose ataxia progression was assessed by the Scale for the Assessment and Rating of Ataxia (SARA) between 2010 and 2023. To account for important covariates affecting the time evolution of SARA scores, our study was then limited to MJD/SCA3 cases with genetic and age information available. A linear mixed model was used to determine the effects of LA/CA and other anti-parkinsonian drugs at 6 and 13 years of MJD/SCA3 progression.

Results

Among the group of 716 individuals with SCAs with monitored SARA scores, 58 (8.1%) had taken LA/CA formulations, whereas 26 (3.6%) had taken other anti-parkinsonian drugs, mainly dopamine receptor agonists. A non-parametric analysis suggested a positive effect of LA/CA on the probability of major disease decline during the initial 6 years of patient monitoring. A multivariate analysis of 262 MJD/SCA3 cases (of which 30 were taken LA/CA) showed statistically significant effects in favor of LA/CA exposition: after adjusting for age and number of CAG repeats in the expanded allele, the yearly SARA response demonstrated a positive effect at 6 years (linear mixed model coefficientβ = −0.651[95% confidence interval−1.141 to −0.161],P = 0.009) and 13 years (β = −0.274[−0.547to−0.002],P = 0.048).

Conclusions

The use of LA/CA to treat non-cerebellar symptoms had a beneficial effect on the SARA score progression in MJD/SCA3. This observation supports the hypothesis that restoring the dopamine levels in the brains of MJD/SCA3 patients might slow down disease progression. Our findings warrant further investigation on whether individuals with MJD/SCA3, even in the absence of Parkinsonian symptoms should also be treated with LA/CA and at what doses.
Scaling Dense Representations for Single Cell with Transcriptome-Scale Context
Authors: Ho Nicholas , Ellington Caleb N. , Hou Jinyu , Addagudi Sohan , Mo Shentong , Tao Tianhua , Li Dian , Zhuang Yonghao , Wang Hongyi , Cheng Xingyi , Song Le , Xing Eric P.
Published: December 2024

Developing a unified model of cellular systems is a canonical challenge in biology. Recently, a wealth of public single-cell RNA sequencing data as well as rapid scaling of self-supervised learning methods have provided new avenues to address this longstanding challenge. However, rapid parameter scaling has been essential to the success of large language models in text and images, while similar scaling has not been attempted with Transformer architectures for cellular modeling. To produce accurate, transferable, and biologically meaningful representations of cellular systems, we develop AIDO.Cell, a pretrained module for representing gene expression and cellular systems in an AI-driven Digital Organism [1]. AIDO.Cell contains a series of 3M, 10M, 100M, and 650M parameter encoder-only dense Transformer models pre-trained on 50 million human cells from diverse tissues using a read-depth-aware masked gene expression pretraining objective. Unlike previous models, AIDO.Cell is capable of handling the entire human transcriptome as input without truncation or sampling tricks, thus learning accurate and general representations of the human cell’s entire transcriptional context. This pretraining with a longer context was enabled through FlashAttention-2, mixed precision, and large-scale distributed systems training. AIDO.Cell (100M) achieves state-of-the-art results in tasks such as zero-shot clustering, cell-type classification, and perturbation modeling. Our findings reveal interesting loss scaling behaviors as we increase AIDO.Cell’s parameters from 3M to 650M, providing insights for future directions in single-cell modeling. Models and code are available through ModelGenerator inhttps://github.com/genbio-ai/AIDOand on Hugging Face.
Superspreaders have lower gut microbial alpha-diversity and distinct gut microbial composition in a natural rodent population
Authors: Wanelik Klara M. , Begon Mike , Bradley Janette E. , Fenn Jonathan , Jackson Joseph A. , Paterson Steve
Published: December 2024

The microbiome is well-known to drive variation in host states (e.g., behaviour, or immunity) that would be expected to modulate the spread of infectious disease - but the role of microbiotal interactions in promoting superspreading by individuals is poorly understood. Superspreaders are individuals with a strongly disproportionate contribution to pathogen transmission, and they come in two forms. Supershedders transmit infection to more individuals because they shed higher levels of a pathogen. Supercontacters transmit infection to more individuals because they have a larger number of social contacts. We explore associations between the gut microbiota and these two forms of superspreading in a wild rodent model –Bartonellaspp. bacteraemia in the field vole (Microtus agrestis). We find evidence that, first, individuals fall into distinct shedding and contacting clusters, and second, that higher-contacters have lower and more variable gut microbial alpha-diversity than lower-contacters. We also show evidence that both higher-shedders and higher-contacters have distinct gut microbial composition, and identify OTUs which are differentially abundant in the gut microbiota of these two classes of individuals when compared to lower-shedders and lower-contacters respectively. We find that theMuribaculaceaeare associated with differences in both shedding and contacting, and discuss potential mechanisms by which they may be acting on these host traits.
ACE: a versatile contrastive learning framework for single-cell mosaic integration
Authors: Yan Xuhua , Chen Jinmiao , Zheng Ruiqing , Li Min
Published: December 2024

The integration of single-cell multi-omics datasets is critical for deciphering cellular heterogeneities. Mosaic integration, the most general integration task, poses a greater challenge regarding disparity in modality abundance across datasets. Here, we present ACE, a mosaic integration framework that assembles two types of strategies to handle this problem: modality-alignment based strategy (ACE-align) and regression-based strategy (ACE-spec). ACE-align utilizes a novel contrastive learning objective for explicit modality alignment to uncover the shared latent representations behind modalities. ACE-spec combines the modality-alignment results and modality-specific representations to construct complete multi-omics representations for all datasets. Extensive experiments across various mosaic integration scenarios demonstrate the superiority of ACE’s two strategies over existing methods. Application of ACE-spec to bi-modal and tri-modal integration scenarios showcases that ACE-spec is able to enhance the representation of cellular heterogeneities for datasets with incomplete modalities. The source code of ACE can be accessed athttps://github.com/CSUBioGroup/ACE-main.
A digital DNA system reveals the superiority of unidirectional inheritance over ‘Lamarckian’ inheritance
Authors: Shiju Aswathi , Arras Samantha D. M. , Rodrigo Allen G. , Poole Anthony M.
Published: December 2024

In biology, changes to a DNA sequence can impact protein sequence but changes to protein sequence (phenotype) do not flow back into DNA (genotype). A system with bidirectional information flow (i.e. both translation and ‘reverse translation’) remains a theoretical possibility for an independent origin of life or an artificial biosystem, but the recent development of digital data storage in DNA does just this: changes made to a digital file can be written back into DNA, meaning changes to ‘phenotype’ can be written back to ‘genotype’. To explore the evolutionary properties of such a system, we created an artificial system where synthetic DNA serves as genotype and music as phenotype. Audio can be output from a DNA sequence, then recorded and written to DNA as ‘codons’, enabling bidirectional information flow (DNA→music and music→DNA). Our results show that the mutation rate in a bidirectional system is much higher than for unidirectional information flow, and that, under reverse translation there is no mechanism for preservation of codon choice across generations. This has the effect of eliminating the impact of spontaneous synonymous mutations, a key the benefit of a redundant genetic code. As a result, non-synonymous mutations are the only DNA-level changes that are transmitted across generations, and, as non-synonymous mutation can emerge at both ‘genotypic’ and ‘phenotypic’ levels, these occur at a two-fold higher frequency than in a unidirectional system. Our system holds some practical insight. First, for DNA read/write systems, it may be wise to avoid designing systems with ‘de novoreverse translation’ because the opportunities for mutation are higher; tracking genotype information from the preceding generation to guide this process may reduce error. Second, our system helps clarify how a ‘Lamarckian’ biological system might operate. We conclude that, were a ‘Lamarckian’ system of inheritance a feature of early genetic systems, it would likely have been short lived as the high frequency of mutation would risk driving the system to extinction. A system based on unidirectional information flow thus appears superior as there are fewer opportunities for mutational error.
Age-dependent differential iron deficiency responses of rosette leaves during reproductive stages inArabidopsis thaliana
Authors: Ngigi Mary , Khan Mather , Remus Ricarda , Gupta Shishir K , Bauer Petra
Published: December 2024

Iron is essential for plant development throughout the life cycle. When plants lack the crucial micronutrient iron (Fe), they develop interveinal leaf chlorosis and stunted growth. To cope with this, they adjust gene expression and manage Fe and other metal ions accordingly. Rosette leaves may act as Fe sources and Fe sinks. Little is known about the dynamics of Fe deficiency (-Fe) responses in theArabidopsis thalianarosette leaves during the reproductive stages.

We studied the dynamics of Fe-dependent responses at four consecutive reproductive stages (rosette, bolting, flowering, mature silique stages, hereby named RS, BS, FS, MS). We examined the growth of rosette leaves, elemental contents and gene expression patterns of Fe homeostasis genes belonging to differently regulated groups. We determined individual leaf sizes during seven days of +Fe and -Fe treatment at the RS.

Young leaves responded rapidly to -Fe with growth inhibition and yellowing. Old and young leaves differed in gene expression patterns and elemental contents. Differences were also noted between the early and late reproductive stages (primarily RS and BS versus MS) and correlations between ionomic contents and gene expression were detected. Although all leaves had induced Fe recycling genes at -Fe, the expression patterns of “High Fe” and other Fe marker genes together with elemental contents indicate that old leaves at the RS and BS might serve as Fe sources, while young leaves might be Fe sinks at +Fe.

Our findings highlight a developmental stage-dependent modulation of +Fe and -Fe responses in leaves. We discuss possible leaf signaling mechanisms accounting for the distinct responses between old and young leaves. This insight is informative for iron management in crops.

One-sentence summary

This study explores reproductive stage-dependent responses of rosette leaves to iron availability, revealing distinct growth, elemental contents, and gene expression patterns between young and old leaves and stages.

Major findings

Young leaves but not old leaves exhibited rapid growth inhibition and chlorosis under -Fe conditions.

Significant differences in gene expression and ionomics profile were observed between old and young leaves.

Contrasts were noted between the early reproductive stages (RS, BS) and the late ones (FS, MS).

Correlations between ionomics profiles and gene expression indicated a complex interaction.
Persistent Mullerian duct syndrome in dogs – a new insight into organization ofAMHandAMHR2genes
Authors: Krzeminska Paulina
Published: December 2024

Persistent Müllerian Duct Syndrome (PMDS) is a rare congenital disorder in males, characterized by the presence of Müllerian duct derivatives despite normal testes and external genitalia. This condition is typically linked to a dysfunction in the anti-Müllerian hormone (AMH) or its receptor (AMHR2), both of which are critical for the regression of the Müllerian ducts. In dogs, PMDS is particularly frequent in the Miniature Schnauzer breed, although cases have also been reported in other breeds, such as the Yorkshire Terrier. To date, a single causative variant has been identified in theAMHR2gene, but only in Miniature Schnauzers. No deleterious variants have been found in theAMHgene; however, with the exception of one report, most studies have not sequenced the entire exon 5.

This study provides novel insights into the genomic organization of canineAMHandAMHR2genes through bioinformatics and in silico analyses of previously reported whole-genome sequencing (WGS) data from a Yorkshire Terrier affected by PMDS. The results indicate that current canine genome assemblies (ROS_Cfam_1.0; CanFam4, and CanFam6) contain a complete reference sequence for theAMHgene, unlike the earlier CanFam3.1 genome. However, next-generation sequencing technologies (WGS and RNA-seq) face challenges due to technical limitations in analyzing GC-rich repetitive elements present in exon 5 of canineAMHgene. In contrast, the genomic structure of theAMHR2gene remains inaccurately represented in the current ROS_Cfam_1.0 genome (eight instead of eleven exons), while both CanFam4 and CanFam6 contain additional and unknown nucleotide/amino acid sequences. The CanFam3.1 genome assembly still provides the most accurate annotation for canineAMHR2gene.

Based on these findings, re-sequencing of theAMHgene in previously reported dogs affected by PMDS using the methodology proposed in recent literature is recommended. Further attention should be given to comparative analyses to assess whether the dog’s genome contains accurate information about genes or proteins that correspond to human orthologs.
AlphaPulldown2 – A General Pipeline for High-Throughput Structural Modeling
Authors: Molodenskiy Dmitry , Maurer Valentin J. , Yu Dingquan , Chojnowski Grzegorz , Bienert Stefan , Tauriello Gerardo , Gilep Konstantin , Schwede Torsten , Kosinski Jan
Published: December 2024

AlphaPulldown2 streamlines protein structural modeling by automating workflows, improving code adaptability, and optimizing data management for large-scale applications. It introduces an automated Snakemake pipeline, compressed data storage, support for additional modeling backends like UniFold and AlphaLink2, and a range of other improvements. These upgrades make AlphaPulldown2 a versatile platform for predicting both binary interactions and complex multi-unit assemblies.

Availability

AlphaPulldown2 is freely available athttps://github.com/KosinskiLab/AlphaPulldown.
Large-scale informative priors to better predict the local occurrence rate of a rare tree-related microhabitat
Authors: Cottais Pierre , Courbaud Benoît , Larrieu Laurent , Gouix Nicolas , Laroche Fabien
Published: December 2024

Ecological processes associated to rare events are hard to estimate from individual empirical studies. A typical example in forest ecology is the formation of tree-related microhabitats (TreMs) on trees. TreMs are key features for forest biodiversity, and their accumulation rate is a key information to design integrative management strategies. Many types of TreMs are associated to large old trees and show slow ontogenical processes. The rarity of such TreMs (particularly in intensively managed forests) hinder the estimation of their occurrence rate along tree growth. Several meta-analyses accumulated data on TreMs at continental (e.g. european) scale. However, using data accumulated at these large, heterogeneous scales to orientate management wihtin a specific site remains challenging. Here, we used a large-scale meta-analysis on TreMs occurrence rate along tree growth to build informative priors for a model of basal rot-hole occurrence on oaks within the Grésigne forest, France. We found that calibrating a model without the prior information (i.e. using only Grésigne oak trees) did not reveal any increase of occurrence with tree diameter. Estimation was hindered by confounding effects of plot and tree diameter induced by the local plot-based sampling strategy. Informative priors overcame this confounding effect, restored a positive relationship between diameter and basal rot-hole occurrence but raised the question of whether it introduced biases. A separate validation experiment suggested that it did not. The model with informative priors revealed that the high recruitment of basal rot-holes in Grésigne may be a temporary management effect in stands undergoing conversion from coppice-with-standards to high forest through sprout thinning, which will lead to conservation issues for cavicolous saproxylic species when all conversions are complete. Because using informative priors was simple and beneficial in our study, it should be further explored in other local applied contexts to orientate forest management.
A novelPGRL1paralog refined the control of photoprotection in grasses and facilitated cell specialisation in C4photosynthesis
Authors: Nix Samuel J. , Morton Craig J. , Furbank Robert T. , Ermakova Maria
Published: December 2024

One of the major events in plant history is the emergence of grasses (Poaceae), which colonised previously uninhabitable open land areas. Some grasses later evolved C4photosynthesis—operating between mesophyll and bundle sheath cells—becoming the most productive and resilient plants on Earth. We investigated whether a key regulator of photoprotection PGR5-LIKE PHOTOSYNTHETIC PHENOTYPE 1 (PGRL1), essential for survival of plants under fluctuating light, facilitated the adaptation of grasses to the open environments. We found that, in addition toPGRL1αpresent in all photosynthetic organisms, grasses evolved a new paralog,PGRL1β. AlphaFold3 modelling of predicted PGRL1 dimers suggests that the lumenal regions of PGRL1α monomers are linked by specific hydrogen bonds whereas PGRL1β’s lumenal regions show primarily hydrophobic interactions. These differences likely result in distinct modes of regulation of photoprotection offered by the two paralogs which is supported by predominant expression ofPGRL1αin mesophyll cells andPGRL1βin bundle sheath cells of NADP-ME C4grasses maize, sorghum, andSetaria viridis.We propose that the mixed PGRL1α/β system enabled a better balancing between Photosystem I protection and Photosystem II activity depending on environmental conditions. Therefore, the emergence of PGRL1β contributed to the ecological dominance of grasses and the superior efficiency of NADP-ME C4photosynthesis.
Deep-learning-enabled generative prevalent mutation prediction through host-to-herd in silico virus evolution
Authors: Liu Xudong , Nie Zhiwei , Si Haorui , Shen Xurui , Liu Yutian , Huang Xiansong , Dong Tianyi , Xu Fan , Chen Jie , Zhou Peng , Tian Yonghong
Published: December 2024

Predicting the mutation prevalence trends of emerging viruses in the real world is an efficient means to update vaccines or drugs in advance. It is crucial to develop a computational method spanning from the host level to the herd level for prevalent mutation prediction as virus evolves within and between hosts involving the impact of multiple selective pressures. Here, a deep-learning generative prediction framework for real-world prevalent mutations, GenPreMut, is developed with a novel host-to-herd selective pressure simulation strategy. Through the paradigm of host-to-herd in silico virus evolution, GenPreMut reproduces previous real-world prevalent mutations for multiple lineages with significant accuracy improvements over state-of-the-art methods. More importantly, GenPreMut correctly predicts future prevalent mutations that dominate the pandemic in the real world more than half a year in advance with in vitro experimental validation. Overall, GenPreMut demonstrates a proactive approach to the prevention of emerging viral infections, accelerating the process of discovering future prevalent mutations with the power of generative prediction.