bluuebunny/crossref_metadata_2025_split huggingface dataset:
VBayesMM: Variational Bayesian neural network to prioritize important relationships of high-dimensional microbiome multiomics data
Authors: Dang Tung , Lysenko Artem , Boroevich Keith A. , Tsunoda Tatsuhiko 
Published: December 2024

AbstractThe analysis of high-dimensional microbiome multiomics datasets is crucial for understanding the complex interactions between microbial communities and host physiological states across health and disease conditions. Despite their importance, current methods such as the microbe–metabolite vectors (MMvec) approach, often fail to efficiently identify keystone species. This arises from the vast dimensionality of metagenomics data which complicates the inference of significant relationships, particularly the estimation of co-occurrence probabilities between microbes and metabolites. Here we propose the variational Bayesian microbiome multiomics (VBayesMM) approach, which enhances MMvec by incorporating a spike-and-slab prior within a Bayesian neural network. This allows VBayesMM to rapidly and precisely identify crucial microbial species, improving the accuracy of estimated co-occurrence probabilities between microbes and metabolites, while also robustly managing the uncertainty inherent in high-dimensional data. Moreover, we have implemented variational inference to address computational bottlenecks, enabling scalable analysis across extensive multiomics datasets. Our comparative evaluation of large-scale human and mouse multiomics datasets demonstrates that VBayesMM not only outperforms existing methods in accuracy but also provides a scalable solution for analyzing massive datasets. VBayesMM enhances the interpretability of the Bayesian neural network by identifying a core set of influential microbial species, thus facilitating a deeper understanding of their probabilistic relationships with the host.
Single-cell multi-omic analysis of post-transplant mesenchymal cells reveals molecular signatures and putative regulators of lung fibrosis
Authors: Lu Lu , McLinden A. Patrick , Walker Natalie M. , Vittal Ragini , Wang Yichen , Combs Michael P. , Welch Joshua D. , Lama Vibha N. 
Published: December 2024

AbstractPrimary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) are critical challenges in lung transplantation. Dysregulated gene expression and epigenomic states in lung mesenchymal cells (MCs) play a key role in these conditions, but further work is needed to elucidate the biomarkers and molecular drivers. Single-cell multi-omic technologies offer an unprecedented opportunity to address this gap by jointly measuring gene expression and chromatin accessibility in diseased and healthy cells. We performed single-cell multi-omic profiling and genetic demultiplexing on MCs isolated from human bronchoalveolar lavage samples of lung transplant recipients with CLAD and PGD, compared with time-matched controls. A classification model trained on these profiles classified the disease status of individual cells with > 98% accuracy using a small set of signature genes. We further identified 8 subtypes of MCs each characterized by distinct transcriptomic and epigenomic signatures, including a CLAD-enriched subtype and a PGD-enriched subtype. The CLAD-enriched subtype expresses markers of fibrosis, while the PGD-enriched subtype expresses pro-inflammatory genes. Finally, we used co-accessibility and co-expression to identify C/EBPD, SOX4, and FOXP2 as key regulators of the genes and chromatin accessibility peaks that are dysregulated in the CLAD-enriched cell population. Knocking down C/EBPD with siRNA partially reverted the CLAD gene expression signature, confirming the importance of this factor in the dysregulated molecular state of CLAD-associated MCs. Additional scRNA-seq analysis of MCs from human lung autopsy samples showed that cultured MCs retained key transcriptomic signatures from theirin vivocounterparts. Sub-clustering analysis identified a CLAD-enriched MC sub-cluster with high C/EBPD expression, further linking these cells to the fibrotic state seenin vitro. Our results provide deeper insights into the transcriptomic and epigenomic changes in post-transplant MCs, nominating biomarkers and disease-associated factors with implications for future therapeutic efforts.
Sex specific effects of environmental toxin-derived alpha synuclein on enteric neuronal-epithelial interactions
Authors: Templeton Hayley N , Ehrlich Alexis T , Schwerdtfeger Luke A , Sheng Julietta A , Tjalkens Ronald B , Tobet Stuart A 
Published: December 2024

ABSTRACTBackgroundParkinson’s Disease (PD) is a neurodegenerative disorder with prodromal gastrointestinal (GI) issues often emerging decades before motor symptoms. Pathologically, PD can be driven by accumulation of misfolded alpha synuclein (aSyn) protein in the brain and periphery, including the GI tract. Disease epidemiology differs by sex, with men twice as likely to develop PD. Women, however, experience faster disease progression, higher mortality, and more severe GI symptoms. Gut calcitonin gene related peptide (CGRP) is a key regulator of intestinal contractions and visceral pain. The current study tests the hypothesis that sex differences in GI symptomology in PD are the result of aSyn aggregation altering enteric CGRP signaling pathways.MethodsTo facilitate peripheral aSyn aggregation, the pesticide rotenone was administered intraperitoneally once daily for two weeks to male and female mice. Mice were sacrificed two weeks after the last rotenone injection and immunohistochemistry was performed on sections of proximal colon.Key ResultsLevels of aSyn were heightened in myenteric plexus neurons and a subset of neurons immunoreactive to CGRP in rotenone treated mice. Female mice exhibited 153% more myenteric aSyn, 26% more apical CGRP immunoreactivity, and 66.7% more aSyn in apical CGRP+fibers after rotenone when compared to males. Goblet cell numbers were diminished but the individual cells were larger in the apical regions of crypts in the colons of rotenone treated mice.ConclusionsThis study used a mouse model of PD to uncover sex specific alterations in enteric neuronal and epithelial populations, underscoring the importance of considering sex as a biological variable while investigating prodromal GI symptoms.Graphical AbstractKEY POINTSMouse model of Parkinson’s Disease (PD) was used to investigate sex specific impact of enteric alpha synuclein (aSyn) on colonic goblet cells and CGRP+neurons and fibers.Sex specific alterations in intestinal neuronal and epithelial signaling pathways in response to aSyn provides insight into sex differences in PD etiology and prodromal gastrointestinal symptoms.
Polyfunctional IL-21+IFNγ+T follicular helper cells contribute to checkpoint inhibitor diabetes mellitus and can be targeted by JAK inhibitor therapy
Authors: Huang Nicole , Ortega Jessica , Kimbrell Kyleigh , Lee Joah , Scott Lauren N. , Peluso Esther M. , Wang Sarah J. , Kao Ellie , Kim Kristy , Olay Jarod , Quandt Zoe , Angell Trevor E. , Su Maureen A. , Lechner Melissa G. 
Published: December 2024

ABSTRACTImmune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic beta-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+T cells, the role for CD4+T cells in ICI-T1DM is less understood. Here, we identify expansion CD4+T follicular helper (Tfh) cells expressing interleukin 21 (IL-21) and interferon gamma (IFNγ) as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFNγ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFNγ both signal through JAK-STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robustin vivoprotection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.VISUAL ABSTRACT
Light quantity impacts early response to cold and cold acclimation in young leaves of Arabidopsis
Authors: Luklová Markéta , Dubois Marieke , Kameniarová Michaela , Plačková Klára , Novák Jan , Kopecká Romana , Karady Michal , Pavlů Jaroslav , Skalák Jan , Jindal Sunita , Tubić Ljiljana , Quddos Zainab , Novák Ondřej , Inzé Dirk , Černý Martin 
Published: December 2024

AbstractPlant reactions to stress vary with development stage and fitness. This study assessed the relationship between light and chilling stress in Arabidopsis acclimation. By analyzing the transcriptome and proteome responses of expanding leaves subjected to varying light intensity and cold, 2251 and 2064 early response genes and proteins were identified, respectively. Many of these represent as yet unknown part of early response to cold, illustrating development-dependent response to stress and a duality in plant adaptations. While standard light promoted photosynthetic upregulation, plastid maintenance, and increased resilience, low light triggered a unique metabolic shift, prioritizing ribosome biogenesis and lipid metabolism and attenuating expression of genes associated with plant immunity. The comparison of early response in young leaves with that in expanded ones showed striking differences, suggesting a sacrifice of expanded leaves to support young ones. Validations of selected DEGs in mutant background confirmed a role of HSP90-1, transcription factor FLZ13, and Phospholipase A1 (PLIP) in response to cold, and the PLIP family emerged as crucial in promoting acclimation and freezing stress tolerance. The findings highlight the dynamic mechanisms that enable plants to adapt to challenging environments and pave the way for the development of genetically modified crops with enhanced freezing tolerance.
In vivo, online label-free monitoring of heterogenous oxygen utilization during phototherapy with real-time ultrasound-guided photoacoustic imaging
Authors: Langley Andrew , Sweeney Allison , Shethia Ronak T. , Bednarke Brooke , Wulandana Faizah , Xavierselvan Marvin , Mallidi Srivalleesha 
Published: December 2024

AbstractUnderstanding the tumor microenvironment, particularly the vascular density and the availability of oxygen, is key in individualizing treatment approaches and determining their efficacy. While there are many therapies including radiotherapy that are ineffective in hypoxic tumor microenvironments, here we demonstrate the heterogeneous oxygen consumption during photodynamic therapy (PDT), a non-invasive treatment method using localized light to activate a photosensitive drug in the presence of oxygen that has shown high effectiveness in the treatment of various types of tumors, including those presented in head and neck cancer (HNC) patients. While our previous work has demonstrated that blood oxygen saturation (StO2) mapped before and after treatment with ultrasound-guided photoacoustic imaging (US-PAI) can be used as a surrogate marker for the regionalized long-term efficacy of PDT, real-time monitoring of StO2during PDT could provide additional insights on oxygen consumption and inform dose design for “on the spot” treatment decisions. Specifically, in this work, we integrated the US-PAI transducer probe with PDT light delivery fibers. We tested the setup on murine tumor models intravenously injected with liposomal benzoporphyrin derivative (BPD) photosensitizer at 0.5 mg/kg dose and photodynamic illumination at 100 and 400 mW/cm2fluence rate. As expected, we observed with our US-PAI StO2images that the rate of oxygen utilization increases when using a high fluence rate (HFR) light dose. Particularly in the higher fluence rate group, we observed StO2reaching a minimum mid-light dose, followed by some degree of re-oxygenation. US-PAI added the advantage of spatial information to StO2monitoring, which allowed us to match regions of re-oxygenation during therapy to retained vascular function with immunohistochemistry. Overall, our results have demonstrated the potential of US-PAI for applications in online dosimetry for cancer therapies such as PDT, using oxygen changes to detect regionalized physiological vascular response in the tumor microenvironment.
Tobacco smoke alters the landscape of mutation, selection, and epistasis in lung adenocarcinoma
Authors: Dasari Krishna , Alfaro-Murillo Jorge A. , Townsend Jeffrey P. 
Published: December 2024

AbstractTobacco smoke elevates mutagenesis. Its physiological effects may additionally influence the adaptive benefits of specific mutations to oncogenesis. However, the relative contributions of these mutagenic and physiological effects to oncogenesis have not been quantified. Here we deconvolved the prevalence of 21 driver mutations into components of mutation and selection in ever-smoker (ES) and never-smoker (NS) lung adenocarcinoma (LUAD). Mutagenesis was broadly elevated in ES-LUAD. Moreover, mutations of some genes experienced stronger selection in ES-LUAD (KRAS,KEAP1, andSTK11) or NS-LUAD (TP53,EGFR,PIK3CA,SMAD4, and more). Analyzing the influence of somatic genotype, we found widespread antagonistic epistasis and strong synergistic epistasis, with more frequent synergy and substantially less frequent antagonism in ES-LUAD. When multiple mutations were present, higher-order epistasis exhibited strong effects on the oncogenic adaptive landscape. This disambiguation of the mutagenic and selective effects of smoking facilitates quantitative prediction of treatment response based on smoking history and tumor somatic genotype.
The TLR7/8 agonist INI-4001 enhances the immunogenicity of a Powassan virus-like-particle vaccine
Authors: Crawford Michael W. , Abdelwahab Walid M. , Siram Karthik , Parkins Christopher J. , Harrison Henry F. , Osman Samantha R. , Schweitzer Dillon , Evans Jay T. , Burkhart David J. , Pinto Amelia K. , Brien James D. , Smith Jessica L. , Hirsch Alec J. 
Published: December 2024

AbstractPowassan virus (POWV) is a pathogenic tick-borne flavivirus that causes fatal neuroinvasive disease in humans. There are currently no approved therapies or vaccines for POWV infection. Here, we develop a POW virus-like-particle (POW-VLP) based vaccine adjuvanted with the novel synthetic Toll-like receptor 7/8 agonist INI-4001. We demonstrate that INI-4001 outperforms both alum and the Toll-like receptor 4 agonist INI-2002 in enhancing the immunogenicity of a dose-sparing POW-VLP vaccine in mice. INI-4001 increases the magnitude and breadth of the antibody response as measured by whole-virus ELISA, induces neutralizing antibodies measured by FRNT, reduces viral burden in the brain of infected mice measured by RT qPCR, and confers 100% protection from lethal challenge with both lineages of POWV. We show that the antibody response induced by INI-4001 is more durable than standard alum, and 80% of mice remain protected from lethal challenge 9-months post-vaccination. Lastly, we show that the protection elicited by INI-4001 adjuvanted POW-VLP vaccine is unaffected by either CD4+or CD8+T cell depletion and can be passively transferred to unvaccinated mice indicating that protection is mediated through humoral immunity. This study highlights the utility of novel synthetic adjuvants in VLP-based vaccines.Author summaryPowassan virus (POWV) is an emerging pathogenic tick-borne flavivirus for which there is no vaccine. Current tick-borne flavivirus vaccines are less than ideal and use formalin-inactivated virus adjuvanted with alum. These vaccines require thorough inactivation of the antigen and frequent boosting to maintain immunity. In this study, we describe the development of a POWV vaccine using Powassan virus-like-particles (POW-VLPs) adjuvanted with either of two novel Toll-like receptor (TLR) agonists, the TLR4 agonist INI-2002 or the TLR7/8 agonist INI-4001. We show that INI-4001 enhances the antibody response, reduces POWV neuroinvasion, and elicits full protection from lethal POWV infection in mice prime-boost vaccinated with low doses of POW-VLP. We further show that this protection is mediated by a humoral immune response which is both broader and more durable than a POW-VLP vaccine formulated with alum. These findings demonstrate the effectiveness of the novel synthetic TLR7/8 agonist INI-4001 as an adjuvant for low-dose VLP-based vaccines and the ability of this vaccine platform to improve upon current tick-borne flavivirus vaccine methodology.
Hepatocellular carcinoma-associatedAXIN1mutations drive low levels of Wnt/β-catenin pathway activity that allow for niche-independent growth and YAP/TAZ signaling
Authors: Venhuizen Anton J. , van Os Yvanka , Kaptein Milo L. , Aarts Marleen T. , Xanthakis Despina , Jordens Ingrid , Maurice Madelon M. 
Published: December 2024

AbstractIn healthy cells, AXIN1 organizes assembly of a large destruction complex that mediates proteolysis of the transcriptional co-activator β-catenin to prevent inappropriate Wnt/β-catenin pathway activation. In hepatocellular carcinoma (HCC),AXIN1mutations (11%) associate with a poor-prognosis subtype that is molecularly distinct from β-catenin-mutant HCC (28-40%). HowAXIN1deficiency drives HCC formation has remained highly debated. Here, we address this issue by introducing HCC-associatedAXIN1andCTNNB1mutations in human liver cancer cells and liver-derived organoids. We show that different mutantAXIN1classes activate varying degrees of Wnt signaling, although at lower overall levels thanCTNNB1mutations. Strikingly, premature stop codons in 5’ coding regions do not classify as knock-out mutations but drive alternative translation of an N-terminally truncated AXIN1 variant with partially retained suppressor activity. AllAXIN1variants endow liver progenitor organoids with the capacity to grow in the absence of R-spondin and Wnt, indicative of aberrant Wnt/β-catenin pathway activation. Additionally, induced Wnt/β-catenin pathway activation inversely correlates with YAP/TAZ-mediated signaling, thus leaving higher residual YAP/TAZ activity inAXIN1-mutant versusCTNNB1-mutant cells. We conclude thatAXIN1mutations drive physiologically relevant Wnt/β-catenin signaling in HCC, while providing a permissive environment for YAP/YAZ signaling, thereby distinguishingAXIN1mutations from those inCTNNB1.
Sex-biased gene expression under sexually antagonistic and sex-limited selection
Authors: Wiberg R. Axel W. , Zwoinska Martyna , Kaufman Philipp , Howie James M. , Immonen Elina 
Published: December 2024

AbstractSex differences in gene expression are ubiquitous, evolve quickly, and are expected to underlie phenotypic sexual dimorphism. Despite long-standing interest, the impact of sex-specific selection on the transcriptome remains poorly understood. Here, we test fundamental questions on the role of constraints on gene expression evolution arising from the mode of selection and genetic architecture. We also test the relationship between sex-specific selection, sex-biased expression and sexual dimorphism (SD). We assess these using body size selection lines in the seed beetle,Callosobruchus maculatus, that have evolved variation in SD in response to sex-specific selection; either sex-limited (SL) or sexually antagonistic (SA). We find that the evolution of male-optimal smaller size is associated with an excess of expression changes of transcripts with male-biased expression, and female-optimal larger size with a deficit of changes at transcripts with female-biased expression. Expression changes are more constrained under SA selection, and especially in females, reflecting phenotypic evolution in these lines. Although SD in size has changed most under SA selection, we show that similar SL selection on males, but not females, has resulted in more sex-biased transcripts. Consequently, we find no clear transcriptome-wide association between sex-bias and SD. Overall, sex-biased transcripts show lower cross-sex correlations in expression changes than unbiased transcripts. In the light of these unique experimental insights into how sex-specific selection on size changes adult transcription, our findings have strong implications for inferring selection history and mode from patterns of sex-biased gene expression in natural populations.
Mixture of Experts Enable Efficient and Effective Protein Understanding and Design
Authors: Sun Ning , Zou Shuxian , Tao Tianhua , Mahbub Sazan , Li Dian , Zhuang Yonghao , Wang Hongyi , Cheng Xingyi , Song Le , Xing Eric P. 
Published: December 2024

AbstractProteins play a fundamental role in life. Understanding the language of proteins offers significant potential for gaining mechanistic insights into biological systems and introduces new avenues for treating diseases, enhancing agriculture, and safeguarding the environment. While large protein language models (PLMs) like ESM2-15B and xTrimoPGLM-100B have achieved remarkable performance in diverse protein understanding and design tasks, these models, being dense transformer models, pose challenges due to their computational inefficiency during training and deployment. In this work, we introduce AIDO.Protein, a pretrained module for protein representation in an AI-driven Digital Organism [1]. AIDO.Protein is also the first mixture-of-experts (MoE) model in the protein domain, with model size scales to 16 billion parameters. Leveraging a sparse MoE architecture with 8 experts within each transformer block and selectively activating 2 experts for each input token, our model is significantly more efficient in training and inference. Through pre-training on 1.2 trillion amino acids collected from UniRef90 and ColabfoldDB, our model achieves state-of-the-art results across most tasks in the xTrimoPGLM benchmark. Furthermore, on over 280 ProteinGym Deep Mutational Scanning (DMS) assays, our model achieves nearly 99% of the overall performance of the best MSA-based model and significantly outperforms the previously reported state-of-the-art models that do not utilize MSA. We also adapted this model for structure-conditioned protein sequence generation tasks and achieved new SOTA in this domain. These results indicate that AIDO.Protein can serve as a strong foundation model for protein understanding and design. Models and codes are available through ModelGenerator inhttps://github.com/genbio-ai/AIDOand onHugging Face.