bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of reactive balance training on cardiorespiratory fitness and muscle strength: a pilot randomized controlled trial
Authors: Devasahayam Augustine J. , Barzideh Azadeh , Jagroop David , Danells Cynthia , Inness Elizabeth L. , Marzolini Susan , Mathur Sunitha , Oh Paul , Mansfield Avril
Published: December 2024

Background

Reactive balance training (RBT) may improve multiple components of physical fitness, including aerobic capacity and muscle strength. However, there have been no studies examining its effects on these factors in people with stroke.

Objectives

The objectives of this pilot study were to determine the feasibility of a non-inferiority randomized controlled trial, comparing aerobic and strength training (AST) and RBT, considering sample size (primary objective), rates of accrual and withdrawal, intervention adherence, missing data, preliminary effects, and harms (secondary objectives).

Methods

People who were at least six months’ post-stroke and could stand independently for >30 seconds were recruited. Peak oxygen consumptionwas measured by cardiopulmonary exercise test. Peak isokinetic torques for knee extension and flexion were measured by dynamometer.

Results

Twenty-three participants (6 women) were randomized into AST and RBT groups. Four-hundred participants per group were estimated to be required for the main trial consideringand peak isokinetic torque as primary outcomes. Rates of accrual and withdrawal were 2 participants for every quarter and 30%, respectively. On average, AST participants attended 29.6/36 sessions (range: 18-36) and RBT participants attended 23.5/36 sessions (range: 1-35). Data were missing for(n=2) and ABC scale (n=1) as participants declined testing.and peak knee extension torque of more-affected legs improved post-intervention in both groups. Ten adverse events related to study interventions resolved without medical attention.

Conclusion

Progressing to a definitive single-site trial is not feasible given the large required sample size, low accrual, and high withdrawal rates.

Trial registration

NCT04042961
Clinical Biomarker-Based Biological Aging and the Risk of Abdominal Aortic Aneurysm: A Prospective Cohort Study
Authors: Zhou Xinyi , Yu Zaixin , Juaiti Mukamengjiang , Zha Lihuang , Peng Baohua , Xiao Chengshuang , Tang Yiyang
Published: December 2024

Background: Compared to chronological age, biological age (BA), a concept introduced in recent years, more accurately reflects the true aging status of the body. While biological aging has been found to be associated with various cardiovascular diseases, its relationship with abdominal aortic aneurysm (AAA) remains unclear. Methods: This study utilized data extracted from UK Biobank for analysis. Telomere length (TL), and BA acceleration calculated using the Klemera-Doubal (KDM) and PhenoAge methods, were employed as surrogate measures to assess biological aging. Cox regression was primarily performed to explore the association between biological aging and AAA risk. Genetic susceptibility was assessed by constructing a polygenic risk score (PRS). Results: This study included 311,646 participants, predominantly women and White, with a median age of 58 years. During a median follow-up of 12.54 years, 1,339 new cases of AAA (4.3‰) were reported. Each standard deviation (SD) decrease in TL was associated with a 20% increased risk of AAA (HR=1.20, 95% CI=1.14-1.27); each SD increase in KDM-BA acceleration was associated with a 21% increased risk (HR=1.21, 95% CI=1.12-1.29); and each SD increase in PhenoAge acceleration was associated with a 40% increased risk (HR=1.40, 95% CI=1.32-1.48). These associations were independent of genetic risk, as assessed by the PRS, and demonstrated a joint effect with genetic predisposition on the long-term risk of AAA. Conclusion: Accelerated biological aging was longitudinally associated with an increased risk of AAA, suggesting it may be a significant factor and potential biomarker for the occurrence of the condition.
2-D organoids demonstrate specificity in the interactions of parasitic nematodes and their secreted products at the basal or apical intestinal epithelium
Authors: White Ruby , Bermúdez-Barrientos Jose Roberto , Robertson Elaine , Duque Correa María A. , Buck Amy H.
Published: December 2024

The intestinal epithelium is a selectively permeable barrier that absorbs water and nutrients, senses the luminal environment, and orchestrates submucosal immune responses. Some gastrointestinal nematodes occupy both submucosal and luminal niches and can cause profound changes in epithelial cells. Yet, there is little understanding of the specificity of parasite-host interactions with epithelial cells and the differential responses at the apical or basal sides. Organoids enable uncoupling of parasite-driven responses from immune-driven effects on the epithelium, and two-dimensional (2-D) organoids allow for controlled access to both sides. Here we used 2-D enteroids to modelin vivolocalisation ofHeligmosomoides bakeri(H. bakeri) fourth-larval (L4) and adult stages and identify localisation-specific effects on gene expression. Using bulk RNA sequencing, we found an enhanced upregulation of IFN-stimulated genes (ISGs) during basal co-culture and an overall stronger response to L4 parasites than adults. Further,H. bakerilive worms induced much stronger effects on gene expression than their isolated excretory-secretory (ES), but cells that internalisedH. bakeriextracellular vesicles (EVs) displayed up-regulation of ISGs, repair genes, and YAP/TAZ signalling. Our results demonstrate that nematodes and their products, including EVs, modify the host epithelium in a localisation-dependent and cell-specific manner.
Early endosome disturbance and endolysosomal pathway dysfunction in Duchenne muscular dystrophy
Authors: Chassagne Julie , Silva Nathalie Da , Akrouf Ines , Cadot Bruno , Julien Laura , Barthélémy Ines , Blot Stéphane , Le Guiner Caroline , Bui Mai Thao , Romero Norma B. , Lainé Jeanne , Pietri-Rouxel France , Meunier Pierre , Mamchaoui Kamel , Lorain Stéphanie , Bitoun Marc , Benkhelifa-Ziyyat Sofia
Published: December 2024

Duchenne muscular dystrophy (DMD) is a lethal dystrophy characterized by the progressive loss of muscle fibers caused by mutations inDMDgene and absence of the dystrophin protein. While autophagy and lysosome biogenesis defects have been described in DMD muscles, the endosomal pathway has never been studied. Here, we showed that impaired lysosome formation is associated with altered acidification and reduced degradative function of the endolysosomal pathway in muscle cells derived from DMD patients. Our data demonstrated that early endosomes are increased in these cells as well as in muscle biopsies from DMD patients and two animal models of DMD,mdxmice and GRMD dogs. We determined that these abnormalities are due to the lack of dystrophinper se and could be correlated with disease progression and severity. We further identified an abnormal upregulation of the Rab5 GTPase protein, one key actor of early endosomal biogenesis and fusion, in the three DMD models which may underlie the endosomal defects. Finally, we demonstrated that Rab5 knock-down in human DMD muscle cells as well as dystrophin restoration in GRMD dogs, normalize Rab5 expression levels and rescue endosomal abnormalities. This study unveils a defect in a pathway essential for muscle homeostasis and for efficacy of adeno associated virus vectors and antisense oligonucleotides-mediated therapies.
PinkyCaMP a mScarlet-based calcium sensor with exceptional brightness, photostability, and multiplexing capabilities
Authors: Fink Ryan , Imai Shosei , Gockel Nala , Lauer German , Renken Kim , Wietek Jonas , Lamothe-Molina Paul J. , Fuhrmann Falko , Mittag Manuel , Ziebarth Tim , Canziani Annika , Kubitschke Martin , Kistmacher Vivien , Kretschmer Anny , Sebastian Eva , Schmitz Dietmar , Terai Takuya , Gründemann Jan , Hassan Sami , Patriarchi Tommaso , Reiner Andreas , Fuhrmann Martin , Campbell Robert E. , Masseck Olivia Andrea
Published: December 2024

Genetically encoded calcium (Ca2+) indicators (GECIs) are widely used for imaging neuronal activity, yet current limitations of existing red fluorescent GECIs have constrained their applicability. The inherently dim fluorescence and low signal-to-noise ratio of red-shifted GECIs have posed significant challenges. More critically, several red-fluorescent GECIs exhibit photoswitching when exposed to blue light, thereby limiting their applicability in all-optical experimental approaches. Here, we present the development of PinkyCaMP, the first mScarlet-based Ca2+sensor that outperforms current red fluorescent sensors in brightness, photostability, signal-to-noise ratio, and compatibility with optogenetics and neurotransmitter imaging. PinkyCaMP is well-tolerated by neurons, showing no toxicity or aggregation, bothin vitroandin vivo. All imaging approaches, including single-photon excitation methods such as fiber photometry, widefield imaging, miniscope imaging, as well as two-photon imaging in awake mice, are fully compatible with PinkyCaMP.
Long-read sequencing of hundreds of diverse brains provides insight into the impact of structural variation on gene expression and DNA methylation
Authors: Billingsley Kimberley J. , Meredith Melissa , Daida Kensuke , Alvarez Jerez Pilar , Negi Shloka , Malik Laksh , Genner Rylee M. , Moller Abraham , Zheng Xinchang , Gibson Sophia B. , Mastoras Mira , Baker Breeana , Kouam Cedric , Paquette Kimberly , Jarreau Paige , Makarious Mary B. , Moore Anni , Hong Samantha , Vitale Dan , Shah Syed , Monlong Jean , Pantazis Caroline B. , Asri Mobin , Shafin Kishwar , Carnevali Paolo , Marenco Stefano , Auluck Pavan , Mandal Ajeet , Miga Karen H. , Rhie Arang , Reed Xylena , Ding Jinhui , Cookson Mark R. , Nalls Mike , Singleton Andrew , Miller Danny E. , Chaisson Mark , Timp Winston , Gibbs J. Raphael , Phillippy Adam M. , Kolmogorov Mikhail , Jain Miten , Sedlazeck Fritz J. , Paten Benedict , Blauwendraat Cornelis
Published: December 2024

Structural variants (SVs) drive gene expression in the human brain and are causative of many neurological conditions. However, most existing genetic studies have been based on short-read sequencing methods, which capture fewer than half of the SVs present in any one individual. Long-read sequencing (LRS) enhances our ability to detect disease-associated and functionally relevant structural variants (SVs); however, its application in large-scale genomic studies has been limited by challenges in sample preparation and high costs. Here, we leverage a new scalable wet-lab protocol and computational pipeline for whole-genome Oxford Nanopore Technologies sequencing and apply it to neurologically normal control samples from the North American Brain Expression Consortium (NABEC) (European ancestry) and Human Brain Collection Core (HBCC) (African or African admixed ancestry) cohorts. Through this work, we present a publicly available long-read resource from 351 human brain samples (median N50: 27 Kbp and at an average depth of ∼40x genome coverage). We discover approximately 234,905 SVs and produce locally phased assemblies that cover 95% of all protein-coding genes in GRCh38. Utilizing matched expression datasets for these samples, we apply quantitative trait locus (QTL) analyses and identify SVs that impact gene expression in post-mortem frontal cortex brain tissue. Further, we determine haplotype- specific methylation signatures at millions of CpGs and, with this data, identify cis-acting SVs. In summary, these results highlight that large-scale LRS can identify complex regulatory mechanisms in the brain that were inaccessible using previous approaches. We believe this new resource provides a critical step toward understanding the biological effects of genetic variation in the human brain.
Isolation of a novelSphingomonasstrain able to degrade the pleuromutilin tiamulin: omic analysis reveals its transformation pathway
Authors: Perruchon Chiara , Tagkalidou Niki , Kalogiouri Natasa , Katsivelou Eleni , Karas Panagiotis , Menkissoglu-Spiroudi Urania , Vasileiadis Sotirios , Karpouzas Dimitrios G
Published: December 2024

Tiamulin (TIA) is a commonly used veterinary antibiotic, persistent in the animal digestive system and downstream receiving environments like soil after manuring. We aimed to isolate and characterize TIA-degrading bacteria for bioaugmentation strategies towards mitigating TIA environmental pressure. A strain able to degrade TIA and use it as sole C source was isolated from a soil exhibiting enhanced biodegradation of the antibiotic. The isolate degraded TIA at concentrations up to 100 μg ml-1, with pH and temperature optima of 6.5-7.5 and 16-25°C respectively. Phylogenomic analysis deemed the isolate to be a new Sphingomonas species (83.87 % ANI with S. laterariae, ≤ 95 %), which was named Candidatus Sphingomonas perruchonii. Genomics and transcriptomics revealed the TIA-driven induction of features conducive with its antiotrophic character; genes encoding for drug efflux pumps and the catabolism of xenobiotics. These included ribosome protective ABC-F transporters and efflux pumps able to protect the ribosome and microbial cells from TIA, oxygenases (e.g. P450 cytochrome) and hydrolases (e.g. alpha/beta hydrolases and amidohydrolases) possibly contributing to its degradation. LC-MS/MS analysis detected putative transformation products (TPs) of TIA, leading us to propose a transformation pathway. This involved a primary oxidation of the tricyclic moiety of TIA to a mono-hydroxylated derivative (TIA-O), potentially mediated by the highly upregulated monoxygenases, which was either further oxidized to TIA-O2or hydrolysed, by the upregulated hydrolase or amidohydrolases, to 2-diethylamino-ethyl-thio acetic acid, both not degrading further. Further tests and in vitro functional analysis will verify the role of these genes in the transformation of TIA.
An opioid efficacy switch for reversible optical control of peripheral analgesia
Authors: Posa Luca , Romano Giovanna , Ji Xiang , Khan Saif , Paz Bruno Matos , Han Gye Won , Nazarova Antonina L. , Zaidi Saheem A. , Ranjbar Mohsen , Pleil Kristen , Katritch Vsevolod , Gati Cornelius , Trauner Dirk , Levitz Joshua
Published: December 2024

The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic administration of opioid agonists makes it both very difficult to decipher their underlying circuit mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse side effects. Here we design, synthesize, and characterize a reversibly photoswitchable morphinan agonist termed “azo-morphine-3” (AM-3) which interconverts from low to high efficacy in response to different wavelengths of light to enable optical control of MOR signaling. Cryo-EM structures of the low efficacy “trans” and high efficacy “cis” states ofAM-3bound to the MOR reveal distinct binding modes of the photoswitchable azobenzene moiety, each inducing unique structural dynamics, providing insight into the molecular basis of agonist efficacy. In mice,AM-3drives reversible and repeatable optical control of anti-nociception with a reduced side effect profile owing to its restriction to the periphery and its ability to be locally activated at the site of pain.
BACH2-driven tissue resident memory programs promote HIV-1 persistence
Authors: Wei Yulong , Ma Haocong Katherine , Wong Michelle E. , Papasavvas Emmanouil , Konnikova Liza , Tebas Pablo , Morgenstern Ricardo , Montaner Luis J. , Ho Ya-Chi
Published: December 2024

Transcription repressor BACH2 redirects short-lived terminally differentiated effector into long-lived memory cells. We postulate that BACH2-mediated long-lived memory programs promote HIV-1 persistence in gut CD4+ T cells. We coupled single-cell DOGMA-seq and TREK-seq to capture chromatin accessibility, transcriptome, surface proteins, T cell receptor, HIV-1 DNA and HIV-1 RNA in 100,744 gut T cells from ten aviremic HIV-1+ individuals and five HIV-1– donors. BACH2 was the leading transcription factor that shaped gut tissue resident memory T cells (TRMs) into long-lived memory with restrained interferon-induced effector function. We found that HIV-1-infected cells were enriched in TRMs (80.8%). HIV-1-infected cells had increased BACH2 transcription factor accessibility, TRM (CD49a, CD69, CD103) and survival (IL7R) gene expression, and Th17 polarization (RORC,CCR6). In vitro gut CD4+ T cell infection revealed preferential infection and persistence of HIV-1 in CCR6+ TRMs. Overall, we found BACH2-driven TRM program promotes HIV-1 persistence and BACH2 as a new therapeutic target.
Nanocoding: Lipid Nanoparticle Barcoding for Multiplexed Single-Cell RNA Sequencing
Authors: Feng Yujun , Chen Donglai , Applegate Catherine C. , Gonzalez Medina Natalia Y. , Kuo Chia-wei , Arogundade Opeyemi H. , Wright Chris L. , Xu Fangxiu , Drnevich Jenny , Smith Andrew M.
Published: December 2024

Sample multiplexing is an emerging method in single-cell RNA sequencing (scRNA-seq) that addresses high costs and batch effects. Current multiplexing schemes use DNA labels to barcode cell samples but are limited in their stability and extent of labeling across heterogeneous cell populations. Here, we introduce Nanocoding using lipid nanoparticles (LNPs) for high barcode labeling density in multiplexed scRNA-seq. LNPs reduce dependencies on cell surface labeling mechanisms due to multiple controllable means of cell uptake, amplifying barcode loading 10-100-fold and allowing both protection and efficient release by dissolution. In cultured cell lines and heterogeneous cells from tissue digests, Nanocoding occurs in 40 minutes with stability after sample mixing and requires only commercially available reagents without novel chemical modifications. In spleen digests, 6-plex barcoded samples show minimal unlabeled cells, with all barcodes giving bimodal count distributions. Challenging samples containing lipid-rich debris and heterogeneous cells from adipose tissue of obese rodents show more than 95% labeling with all known subtypes identified. Using Nanocoding, we investigate gene expression changes related to aging in adipose tissue, profiling cells that could not be readily identified with current direct conjugate methods using lipid or antibody conjugates. This ease of generating and tuning these constructs may afford efficient and robust whole-sample multiplexing with minimal sample crosstalk.
AlphaFold prediction and analysis of Adhesion-family G protein coupled receptor (aGPCR) structures
Authors: Zhou Xiao Wen (Kelly) , Chen Eddie , Ramachandran Rithwik
Published: December 2024

Adhesion GPCRs (aGPCRs), a family of 33 receptors, regulate crucial physiological processes through a unique self-activation mechanism. We employed AlphaFold, a state-of-the-art AI system, to predict 3D structures of aGPCRs in active and inactive conformations. Full-length models were obtained from the AlphaFold Protein Structure Database, while tethered-ligand (TL) exposed structures were predicted using AlphaFold. Comparison with available experimentally solved structures were made to validate accuracy of Alphafold aGPCR model. For receptors without experimentally solved structures, we compare structures of inactive (TL masked) and active (TL exposed) aGPCRs. In the active structures, the tethered-ligand was docked in the transmembrane bundle for several receptors but surprisingly not all receptors. This AI driven analysis of aGPCR structures provides a framework for exploring alternative receptor activation mechanisms. These models also offer valuable insights into receptor conformational changes and TL interactions, paving the way for the development of novel pharmacological tools and accelerating drug discovery efforts targeting this important receptor family.
Hierarchical Interpretation of Out-of-Distribution Cells Using Bottlenecked Transformer
Authors: Wang Qifei , Zhu He , Hu Yiwen , Chen Yanjie , Wang Yuwei , Zhang Xuegong , Zou James , Kellis Manolis , Li Yue , Liu Dianbo , Jiang Lan
Published: December 2024

Identifying the genetic and molecular drivers of phenotypic heterogeneity among individuals is vital for understanding human health and for diagnosing, monitoring, and treating diseases. To this end, international consortia such as the Human Cell Atlas and the Tabula Sapiens are creating comprehensive cellular references. Due to the massive volume of data generated, machine learning methods, especially transformer architectures, have been widely employed in related studies. However, applying machine learning to cellular data presents several challenges. One such challenge is making the methods interpretable with respect to both the input cellular information and its context. Another less explored challenge is the accurate representation of cells outside existing references, referred to as out-of-distribution (OOD) cells. The out-of-distribution could be attributed to various physiological conditions, such as comparing diseased cells, particularly tumor cells, with healthy reference data, or significant technical variations, such as using transfer learning from single-cell reference to spatial query data. Inspired by the global workspace theory in cognitive neuroscience, we introduce CellMemory, a bottlenecked Transformer with improved generalization capabilities designed for the hierarchical interpretation of OOD cells unseen during reference building. Even without pre-training, it exceeds the performance of large language models pre-trained with tens of millions of cells. In particular, when deciphering spatially resolved single-cell transcriptomics data, CellMemory demonstrates the ability to interpret data at the granule level accurately. Finally, we harness CellMemory’s robust representational capabilities to elucidate malignant cells and their founder cells in different patients, providing reliable characterizations of the cellular changes caused by the disease.
Mapping of suitable release areas for the parasitoidDolichogenidea gelechiidivoris(Marsh) for the classical biocontrol ofTuta absoluta(Meyrick) using temperature-dependent phenology models
Authors: Mujica Norma , Carhuapoma Pablo , Kroschel Jürgen , Kreuze Jan
Published: December 2024

The South American tomato leafminer,Tuta absoluta(Meyrick) is a major invasive pest of tomato (Lycopersicum esculentumMill.) worldwide. Among the different integrated pest management strategies, biological control is most promising.Dolichogenidea gelechiidivoris(Marsh) is a larval endoparasitoid native to the Neotropics, where it is the dominant biological agent ofT. absolutaalong the Peruvian coast. The determination of the parasitoid’s temperature-dependent development is crucial for better predicting the potential of the parasitoid to establish in new regions and to control the target pest. Therefore, the effect of temperature on the development and reproduction ofD. gelechiidivoriswas studied at five constant temperatures ranging from 10 to 30°C in its main hostT. absoluta. The Insect Life Cycle Modeling (ILCYM) software was used to fit nonlinear equations to collected life table data and to establish an overall phenology model to simulate life table parameters based on temperature. The parasitoid completed its life cycle at constant temperatures from 15 to 30°C; the temperature of 10°C was lethal to pupae. The theoretical lower threshold temperatures for the development of egg-larvae and pupae were 7.6°C and 10.9°C respectively. The egg-larval and pupae stages had the lowest mortality between the temperature range of 20-30°C. The lowest senescence rates for females and males were observed within the temperature range of 10–20°C. Oviposition time decreased significantly with increasing temperature from 16.7 days (10°C) to 1.6 days (35°C). Mean fecundity was highest at 20°C (74.4 eggs/female). Maximum population growth is expected around 24.3°C with a finite rate of increase, λ of 1.1088, which corresponds to a population doubling time of 6.7 days. The highest values for gross reproduction rate (GRR) and net reproduction rate (R0) were found between 20 and 21°C, and the shortest mean generation time (T) was observed at 30°C (19.9 d). Suitable release areas with a very high probability of establishment and potentially good control efficacy of the parasitoid are tropical and subtropical regions (e.g., countries in Southern Europe; Spain, Portugal). The potential use of the parasitoid in the context of classical biological control ofT. absolutais discussed.
Personalizing chemotherapy drug selection using a novel transcriptomic chemogram
Authors: Lin-Rahardja Kristi , Scarborough Jessica , Scott Jacob G
Published: December 2024

Gene expression signatures predictive of chemotherapeutic response have the potential to greatly extend the reach of precision medicine by allowing medical providers to plan treatment regimens on an individual basis for patients with and without actionable mutations. Most published gene signatures are only capable of predicting response for individual drugs, but currently, a majority of chemotherapy regimens utilize combinations of different agents. We propose a unified framework, called the chemogram, that uses predictive gene signatures to rank the relative predicted sensitivity of different drugs for individual tumor samples. Using this approach, providers could efficiently screen against many therapeutics to identify the drugs that would fit best into a patient’s treatment plan at any given time. This can be easily reassessed at any point in time if treatment efficacy begins to decline due to therapeutic resistance.

To demonstrate the utility of the chemogram, we first extract predictive gene signatures using a previously established method for extracting pan-cancer signatures inspired by convergent evolution. We derived 3 signatures for 3 commonly used cytotoxic drugs (cisplatin, gemcitabine, and 5-fluorouracil). We then used these signatures in our framework to predict and rank sensitivity among the drugs within individual cell lines. To assess the accuracy of our method, we compared the rank order of predicted response to the rank order of observed response (fraction of surviving cells at a standardized dose) against each of the 3 chemotherapies. Across a majority of cancer types, chemogram-generated predictions were consistently more accurate than randomized prediction rankings, as well as prediction rankings made by randomly generated gene signatures. In addition to the chemogram’s ability to rank relative sensitivity for any given tumor, this framework is easily scalable for any number of drugs for which a predictive signature exists. We repeated the process described above for 10 drugs and found that the accuracy of the predicted sensitivity rankings was maintained as the number of drugs in the chemogram’s screen increased.

Our proposed framework demonstrates the ability of transcriptomic signatures to not only predict chemotherapeutic response but correctly assign rankings of drug sensitivity on an individual basis. With further validation, the chemogram could be easily integrated in a clinical setting, as it only requires gene expression data, which is less expensive than an extensive drug screen and can be performed at scale.
HAIRpred: Prediction of human antibody interacting residues in an antigen from its primary structure
Authors: Sahni Ruchir , Kumar Nishant , Raghava Gajendra P. S.
Published: December 2024

1.

In the past, several methods have been developed for predicting conformational B-cell epitopes in antigens that are not specific to any host. Our primary analysis of antibody-antigen complexes indicated a need to develop host-specific B-cell epitopes. In this study, we present a novel approach to predict conformational B-cell epitopes specific to human hosts by focusing on human antibody-interacting residues in antigens. We trained, test and evaluate our models on 277 complexes of human antibody-antigen complexes. Initially, we employed machine learning models based on the binary sequence profile of antigens, achieving a maximum area under the receiver operating characteristic curve (AUC) of 0.61. Performance of model improved significantly AUC from 0.61 to 0.67, when evolutionary profiles are used instead of binary profiles. Models developed using embeddings from fine-tuned large language models reached an AUC of 0.61. Additionally, models utilizing predicted surface relative solvent accessibility achieved an AUC of 0.67. Our ensemble model, which combined relative surface accessibility with evolutionary profiles, achieved highest precision with an AUCROC of 0.72. All models in this study were trained using five-fold cross-validation on a training dataset and evaluated on an independent dataset not used for training or testing. Our method outperforms existing approaches on the independent dataset. Furthermore, we used SHAP eXplainable AI (XAI) method to interpret the importance of individual features contributing to the predictions made by our models. To support the scientific community, we have developed a standalone software, and web server, HAIRpred, for predicting human antibody-interacting residues in proteins.https://webs.iiitd.edu.in/raghava/hairpred/.

Author’s Biography

Ruchir Sahni is currently studying as an integrated BS-MS student at Indian Institute of Science Education and Research (IISER) Pune, India. He is currently working as an Intern on Project position at Department of Computational Biology, Indraprastha Institute of Information Technology (IIIT), New Delhi, India.

Nishant Kumar is currently working as Ph.D. in Computational biology from Department of Computational Biology, Indraprastha Institute of Information Technology (IIIT), New Delhi, India.

Gajendra P. S. Raghava is currently working as Professor and Head of Department of Computational Biology, Indraprastha Institute of Information Technology (IIIT), New Delhi, India.
An in-depth dataset of northwestern European arthropod life histories and ecological traits
Authors: Logghe Garben , Batsleer Femke , Maes Dirk , Permentier Tristan , Berg Matty P. , Brosens Dimitri , Cooleman Stijn , De Smedt Pallieter , Hagge Jonas , Lambrechts Jorg , Pollet Marc , Verheyde Fons , Bonte Dries
Published: December 2024

In response to the ongoing biodiversity crisis among arthropods, it is essential to implement efficient conservation strategies to safeguard both species diversity and the vital ecosystem services they provide. Developing such strategies requires reliable predictive models that can identify the species that are the most vulnerable to current and future threats, including those posed by climate and land-use change. Species life histories are central to these models, as they influence both population dynamics and spread rates. To support this effort, we compiled a dataset with key traits for arthropods based on several literature sources and expert knowledge. The dataset contains data on body size, life history, thermal niche and ecology for 4874 northwestern European species across 10 different orders. By gathering these essential trait data, we aim to create a robust foundation for predicting species vulnerability and anticipating shifts in arthropod communities in response to global change.
A generalized and versatile framework to train and evaluate autoencoders for biological representation learning and beyond: AUTOENCODIX
Authors: Joas Maximilian , Jurenaite Neringa , Prascevic Dusan , Scherf Nico , Ewald Jan
Published: December 2024

Insights and discoveries in complex biological systems, e.g. for personalized medicine, are gained by the combination of large, feature-rich and high-dimensional data with powerful computational methods uncovering patterns and relationships. In recent years, autoencoders, a family of deep learning-based methods for representation learning, are advancing data-driven research due to their variability and non-linear power of multi-modal data integration. Despite their success, current implementations lack standardization, versatility, comparability, and generalizability preventing a broad application. To fill the gap, we present AUTOENCODIX (https://github.com/jan-forest/autoencodix), an open-source framework, designed as a standardized and flexible pipeline for preprocessing, training, and evaluation of autoencoder architectures. These architectures, like ontology-based and cross-modal autoencoders, provide key advantages over traditional methods via explainability of embeddings or the ability to translate across data modalities. We show the value of our framework by its application to data sets from pan-cancer studies (TCGA), single-cell sequencing as well as in combination with imaging. Our studies provide important user-centric insights and recommendations to navigate through architectures, hyperparameters, and important trade-offs in representation learning. Those include reconstruction capability of input data, the quality of embedding for downstream machine learning models, or the reliability of ontology-based embeddings for explainability. In summary, our versatile and generalizable framework allows multi-modal data integration in biomedical research and any other data-driven fields of research. Hence, it can serve as a open-source platform for several major trends and research using autoencoders including architectural improvements, explainability, or training of large-scale pre-trained models.
WITHDRAWN: Structural Enzymology, Phylogenetics, Differentiation, and Symbolic Reflexivity at the Dawn of Biology
Authors: Carter Charles W. , Tang Guo Qing , Patra Sourav Kumar , Betts Laurie , Dieckhaus Henry , Kuhlman Brian , Douglas Jordan , Wills Peter R. , Bouckaert Remco , Popovic Milena , Ditzler Mark A.
Published: December 2024

Withdrawal Statement

This manuscript was posted without the final consent of all authors. The authors have therefore withdrawn it. The authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author,carter@med.unc.edu.
Forbs in Viking lands: The effect of disturbing dominant graminoids on forb recruitment in tundra grasslands
Authors: Celis Gerardo , Ehrich Dorothee , Heskel Mary , Soininen Eeva , Ungar Peter , Bråthen Kari Anne
Published: December 2024

Certain graminoids can be successful in grasslands to the extent it is a phenomenon called “the Viking Syndrome”. Nevertheless, forbs also make up a substantial part of vascular plant diversity in grasslands and are important resources of mammalian herbivores. Here we assess the hypothesis that forb recruitment is constrained by dominant graminoids, limiting access to safe sites for germination. We report on a disturbance experiment of plots with four different graminoid species in tundra grasslands of the Varanger Peninsula, Norway. Plots were selected to sample both rodent-disturbed and undisturbed areas. The dominant graminoids in each plot were removed, reducing their shading capabilities and belowground rhizome and root systems. Results show that forb recruitment one year following disturbance was significantly enhanced by manual graminoid removal. Dominant graminoid type, small rodent disturbance, initial forb abundance, and abiotic conditions had no effect on forb recruitment, whereas initial species richness had a positive relationship. Furthermore we found that manual disturbance had low impact on the species exchange ratio based on richness (SERr), suggesting that disturbance did not reduce the capacity of species to reside and move within the grassland. Our findings support the hypothesis that forb recruitment is limited by dominant graminoids.
Asymmetric Activation of Retinal ON and OFF Pathways by AOSLO Raster-Scanned Visual Stimuli
Authors: Patterson Sara S. , Cai Yongyi , Yang Qiang , Merigan William H. , Williams David R.
Published: December 2024

Adaptive optics scanning light ophthalmoscopy (AOSLO) enables high-resolution retinal imaging, eye tracking, and stimulus delivery in the living eye. AOSLO-mediated visual stimuli are created by temporally modulating the excitation light as it scans across the retina. As a result, each location within the field of view receives a brief flash of light during each scanner cycle (every 33-40 ms). Here we usedin vivocalcium imaging with AOSLO to investigate the impact of this intermittent stimulation on the retinal ON and OFF pathways. Raster-scanned backgrounds exaggerated existing ON-OFF pathway asymmetries leading to high baseline activity in ON cells and increased response rectification in OFF cells.
A Low-Cost Markerless motion capture system to automate Functional Gait Assessment: Feasibility Study
Authors: Darici Osman , Cabak Chanel , Wong Jeremy D
Published: December 2024

Functional gait assessments in older adults have traditionally required manual in-person quantification of clinically-relevant metrics such as walking speed and step placement. This reliance on skilled labour hinders the frequency with which they are performed, and reduces their generalizability and replicability. To standardize and simplify gait assessments, we here leverage recently-developed open-source tools to produce a low-cost, AI driven markerless motion capture system. Validation of data collected with a traditional marker-based system on subjects (N=3) showed strong correlation to laboratory-standard measures of step length (R2=0.989), step width (R2=0.986), and body speed (R2=0.964), suggesting that open-source markerless systems are currently sufficient to be used in gait assessments. Older adult subjects (N=5) performed the complete functional gaita assessment (FGA), and the system demonstrated data consistent with previous findings. Additional standard measurements were proposed to supplement and systematize existing FGA workflows. This markerless motion capture system demonstrates a proof-of-principle system for performing analyses of functional gait.
Temporal dynamics of energy-efficient coding in mouse primary visual cortex
Authors: Moosavi S. Amin , Pastor Antonia , Ornelas Alfredo G. , Tring Elaine , Ringach Dario L.
Published: December 2024

Sparse coding enables cortical populations to represent sensory inputs efficiently, yet its temporal dynamics remain poorly understood. Consistent with theoretical predictions, we show that stimulus onset triggers broad cortical activation, initially reducing sparseness and increasing mutual information. Subsequently, competitive interactions sustain mutual information as activity declines and sparseness increases. Notably, coding efficiency, defined as the ratio of mutual information to metabolic cost, progressively increases, demonstrating the dynamic optimization of sensory representations.
ldentify potential feature genes and immune cell infiltration of HIRI based on branched-chain amino acid-related genes by machine learning and experimental validation
Authors: Zhao Jiahui , Wu Min , Li Shuangjiang , Li Shuang , Li Mingjuan , Li Qiuyun , Pan Guangdong , Ouyang Guoqing , Xu Honglai
Published: December 2024

Background

Branched-chain amino acid metabolism is involved in the pathogenesis of various liver diseases. In this study, we investigate the potential role of branched-chain amino acid metabolism-related genes in the pathogenesis of hepatic ischemia reperfusion (HIRI).

Methods

The gene Expression profiles of HIRI were obtained from the Gene Expression Omnibu database. To determine the differential expression of branched-chain amino acid metabolism-related genes between HIRI and normal tissues. Then, the GO and KEGG analyses were performed, and the protein-protein interaction network was constructed. Next, the random forest and LASSO algorithms were used to screen hub genes, and machine learning techniques were used to build diagnostic models. immunoinfiltration was analyzed in both HIRI patients and controls and the ceRNA network was established. Finally, quantitative real-time PCR was used to verify the expression of hub gene.

Results

Based on data set GSE23649, three central DEGs (SLC7A5, SLC1A5, SLC43A2) were determined by the intersection of three machine learning algorithms and used to establish a nomogram that yielded a high predictive performance (area under the curve 0.733−0.922). In the external GSE15480 dataset, AUC value for three key genes is as high as 1.000. Further analysis of nomogram, decision curve and calibration curve also confirme the predictive efficacy of diagnosis. GSEA and GSVA suggest that these three marker genes were involved in multiple pathways associated with HIRI progression. Immunoinfiltration analysis suggest that the proportion of macrophages, neutrophils, aDCs, Treg, and Th1 cells in HIRI group is higher than that in control group, with statistical significance(P<0.05). The ceRNA network demonstrates the complex regulatory relationships among the three hub genes and these mRNA levels were further confirmed in mouse HIRI liver samples.

Conclusions

Our study have provided a comprehensive understanding of the association between branched-chain amino acid and HIRI, may provide potential target for HIRI treatment and diagnosis. And provide new insights into the mechanisms of HIRI.

Graphical Abstract
Intraguild predation among snails drives human schistosome amplification despite susceptible host regulation
Authors: Shaw Kelsey E , Syed Raeyan , Hartman Rachel B , Mangabat Danielle , Civitello David J
Published: December 2024

Competitors and predators of hosts have the potential to alter transmission dynamics within host- parasite systems. Biocontrol aims to harness these effects to mitigate diseases of human or agricultural importance, but without a detailed understanding of the mechanisms of how hosts and non-hosts interact over time these attempts may backfire. We investigated the role that two resource competitors that have been employed in biocontrol,Melanoides tuberculataandPhysa acuta, play in theBiomphalaria glabrata-Schistosoma mansoni system. We created experimental communities with differing compositions in mesocosms and tracked resource availability, host snail abundance, size, reproduction, and parasite production over 16 weeks. We found thatMelanoidesacted as a typical, albeit weak, resource competitor ofBiomphalaria,reducing host body size and per capita cercarial production but with no appreciable influence on host abundance.Physa, however, reduced host abundance but increased resource availability and cercarial production, which represents biocontrol failure and is inconsistent with solely acting as a resource competitor. In follow-up experiments, we determined thatPhysais a voracious consumer of host eggs. We then built a model representing this intraguild predation effect, which was able to explain these initially counterintuitive results. These divergent results from two putative resource competitors of host snails underscore the importance of establishing the mechanisms through which hosts, non-hosts, and parasites interact, especially for anticipating the potential outcomes of biocontrol interventions.
Response of Serum-isolated Extracellular Vesicles to Focused Ultrasound Blood-Brain Barrier Opening
Authors: Kline-Schoder Alina R. , Tsitsos Fotios N. , Batts Alec J. , DiBenedetto Melody R. , Liu Keyu , Bae Sua , Konofagou Elisa E.
Published: December 2024

The blood-brain barrier (BBB) limits drug delivery to the brain and the movement of neurological biomarkers between the brain and blood. Focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO) noninvasively opens the BBB, allowing increased molecular transport to and from the brain parenchyma. Despite being initially developed as a drug delivery method, FUS-BBBO has shown promise both as a neuroimmunotherapeutic modality, and as a way of improving neurological disease diagnosis via amplification of disease biomarker circulation.

Recently, the role of extracellular vesicles (EVs) in modulating the neuroimmune system and in improving biomarker detection has sparked research interest. However, despite their potential role in modulating FUS-BBBO-induced neuroimmunotherapy and their ability to improve biomarker specificity after treatment, the EV response to FUS-BBBO had not been extensively characterized prior to this study.

In this study, we investigated the effect of FUS-BBBO on EV concentration and content in the serum of mice and Alzheimer’s Disease (AD) patients. We observed a 164% increase in murine EV concentration one hour after treatment, as well as an increase in EV RNA associated with FUS-BBBO neuroimmunotherapy. Patient EV concentration also increased one hour after treatment and was dependent on the volume of BBB opening three days post-treatment. Furthermore, EV isolation was found to significantly enhance the amplification of AD biomarker detection by FUS-BBBO.

Overall, we present the first evidence of altered murine and AD patient EV concentration and content in response to FUS-BBBO, providing evidence of EVs’ role within FUS-BBBO neuroimmunotherapy as well as their utility in improving FUS-BBBO biomarker amplification.
HIV-SEQ Reveals Global Host Gene Expression Differences Between HIV-Transcribing Cells from Viremic and Suppressed People with HIV
Authors: Frouard Julie , Telwatte Sushama , Luo Xiaoyu , Elphick Natalie , Thomas Reuben , Arneson Douglas , Roychoudhury Pavitra , Butte Atul J , Wong Joseph K , Hoh Rebecca , Deeks Steven G. , Lee Sulggi A. , Roan Nadia R. , Yukl Steven
Published: December 2024

“Active” reservoir cells transcribing HIV can perpetuate chronic inflammation in virally suppressed people with HIV (PWH) and likely contribute to viral rebound after antiretroviral therapy (ART) interruption, so they represent an important target for new therapies. These cells, however, are difficult to study using single-cell RNA-seq (scRNA-seq) due to their low frequency and low levels of HIV transcripts, which are usually not polyadenylated. Here, we developed “HIV-seq” to enable more efficient capture of HIV transcripts – including non-polyadenylated ones – for scRNA-seq analysis of cells from PWH. By spiking in a set of custom-designed capture sequences targeting conserved regions of the HIV genome during scRNA-seq, we increased our ability to find HIV RNA+ cells from PWH by up to 44%. Implementing HIV-seq in conjunction with surface phenotyping by CITE-seq on paired blood specimens from PWH before vs. after ART suppression, we found that HIV RNA+ cells were enriched among T effector memory (Tem) cells during both viremia and ART suppression, but exhibited a cytotoxic signature during viremia only. By contrast, HIV RNA+ cells from the ART-suppressed timepoints exhibited a distinct anti-inflammatory signature involving elevated TGF-β and diminished IFN signaling. Overall, these findings demonstrate that active reservoir cells exhibit transcriptional features distinct from HIV RNA+ cells during viremia, and underscore HIV-seq as a useful tool to better understand the mechanisms by which HIV-transcribing cells can persist during ART.