bluuebunny/crossref_metadata_2025 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

The 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

Primary 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

Background

Parkinson’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.

Methods

To 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 Results

Levels 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.

Conclusions

This 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 Abstract

KEY POINTS

Mouse 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

Immune 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

Plant 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.
Coordinated variation in the immune systems and microbiomes of healthy humans is linked to tonic interferon states
Authors: Babdor Joel , Patel Ravi K , Davidson Brittany , Noecker Cecilia , Rahim Maha , Bisanz Jordan E , Tenvooren Iliana , Marquez Diana , Calvo Maria , Johri Vrinda , McCarthy Elizabeth , Shaheed Avneet , Ekstrand Christina , Weakley Allison M , Yu Feiqiao B , Fiehn Oliver , Turnbaugh Peter J , Combes Alexis J , Fragiadakis Gabriela K , Spitzer Matthew H.
Published: December 2024

Human immune systems are highly variable, with most variation attributable to non-genetic sources. The gut microbiome crucially shapes the immune system; however, its relationship with the baseline immune states of healthy humans remains incompletely understood. Therefore, we performed multi-omic profiling of 110 healthy participants through the ImmunoMicrobiome study. A factor-based integrative approach identified coordinated variation, revealing that the tonic interferon response was amongst the most variable immune features in healthy participants. Microbiome composition, pathways, and stool metabolites varied concomitantly with interferon response pathways. Distinct transcriptional programs involving inflammation and TGF-β in SIGLEC-1highmonocytes and CD69highactivated MAIT and NK cells were representative of these programs. Our study provides extensive data to examine the relationship between the immune states and microbiomes of healthy individuals at steady state, which paves the way for delineating inter-individual differences relevant for disease susceptibility and responses to therapy.
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

Understanding 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

Tobacco 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

Powassan 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 summary

Powassan 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.
Functional dissection of metabolic trait-associated gene regulation in steady state and stimulated human skeletal muscle cells
Authors: Nishino Kirsten , Kitzman Jacob O. , Parker Stephen C.J. , Tovar Adelaide
Published: December 2024

Type 2 diabetes (T2D) is a common metabolic disorder characterized by dysregulation of glucose metabolism. Genome-wide association studies have defined hundreds of signals associated with T2D and related metabolic traits, predominantly in noncoding regions. While pancreatic islets have been a focal point given their central role in insulin production and glucose homeostasis, other metabolic tissues, including liver, adipose, and skeletal muscle, also contribute to T2D pathogenesis and risk. Here, we examined context-specific genetic regulation under basal and stimulated states. Using LHCN-M2 human skeletal muscle cells, we generated transcriptomic profiles and characterized regulatory activity of 327 metabolic trait-associated variants via a massively parallel reporter assay (MPRA). To identify condition-specific effects, we compared four different conditions: (1) undifferentiated, or (2) differentiated with basal media, (3) media supplemented with the AMP analog AICAR (to simulate exercise) or (4) media containing sodium palmitate (to induce insulin resistance). RNA-seq revealed these treatments extensively perturbed transcriptional regulation, with 498-3,686 genes showing significant differential expression between pairs of conditions. Among differentially expressed genes, we observed enrichment of relevant biological pathways including muscle differentiation (undifferentiated vs. differentiated), oxidoreductase activity (differentiated vs. AICAR), and glycogen binding (differentiated vs. palmitate). The results of our MPRA found broadly different levels of activity between all conditions. Our MPRA screen revealed a shared set of 7 variants with significant allelic activity across all conditions, along with a proportional number of variants showing condition-specific allelic bias and the total number of active oligos per condition. We found that a lead variant for serum triglyceride levels, rs490972, overlaps SP transcription factor motifs and has differential regulatory activity between conditions. Comparison of MPRA activity with paired gene expression data allowed us to predict that regulatory activity at this locus is mediated by SP1 transcription factor binding. While several of the MPRA variants have been previously characterized in other metabolic tissues, none have been studied in these stimulated states. Together, this work uncovers context-dependent transcriptomic and regulatory dynamics of T2D- and metabolic trait-associated variants in skeletal muscle cells, offering new insights into their functional roles in metabolic processes.
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

In 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

Sex 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

Proteins 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.
Is the nematodeStrongyloides stercoralisa zoonosis from dogs? – a population genetics approach
Authors: Liu Yuchen , Raihan Sarker A. H. M. , Sripa Banchob , Tangkawatta Sirikachorn , Khieu Virak , Nevin William , Paterson Steve , Viney Mark
Published: December 2024

Gut nematode worms are important parasites of people and other animals. The parasitic nematodeStrongyloides stercoralisinfects an estimated 600 million people worldwide, and is one of the soil-transmitted helminthiases, a WHO-defined neglected tropical disease. It has long been suggested that humanS. stercoralisinfection may be a zoonosis from dogs. We investigated this by whole genome sequence analysis ofS. stercoralisfrom sympatric human and dog populations in Asia. We find that human- and dog-derivedS. stercoralishave genetically distinct nuclear genomes, but we also find evidence of rare cross infection. Analysis of theS. stercoralismitochondrial genome reveals evidence of historical introgression between human- and dog-derived parasites. Based on these data we suggest thatS. stercoraliswas originally a parasite of canids, that began to infect humans when people domesticated dogs, since when human- and dog-derived parasites have differentiated, but have not become separate species.

Significance Statement

Nematode worms infect approximately a quarter of the world’s human population;Strongyloides stercoralisinfects some 600 million people. It has been suggested thatS. stercoralisin people and dogs is the same parasite, such that some human infection is acquired zoonotically from dogs. It is important to understand the source of humanStrongyloidesinfection to be able to control it and the harm that it causes. Our population genomic analyses of human- and dog-derivedS. stercoralisin Asia show that these parasites are distinct, but also reveal rare cross infection events. Our results are consistent withS. stercoralisancestrally being a parasite of dogs that began infecting people when dogs became domesticated.
Untangling the contribution of adaptiveversusnon-adaptive processes in the evolution of reproductive isolation betweenCoenonymphabutterflies
Authors: Capblancq Thibaut , Roux Camille , Boyer Frédéric , Legeai Fabrice , Joron Mathieu , Després Laurence
Published: December 2024

Speciation is a key evolutionary process which has been studied in numerous organisms and at multiple scales, from lineage radiation to gene expression. However, the factors explaining the rise of new species are not yet fully understood, and the relative contribution of neutralversusselective evolutionary processes in triggering and maintaining reproductive isolation between lineages is still debated. To explore this question, we study the divergence of two butterfly species,Coenonympha arcaniaandC. gardetta(Nymphalidae), which diverged relatively recently but show strong ecological differences. Whole genome sequence data reveal high overall differentiation between the two lineages, best explained by a long period of isolation at the early stage of their divergence. Demographically explicit approaches identify that 6.6% of the genome (32.7 Mbp) is impermeable to gene flow between the two species. Lots of these barrier loci are located on the Z chromosome, potentially spanning 75% of its length which would indicate that a large Z effect is at play in this speciation. Moreover, only a small proportion of barriers showed signatures of selection, suggesting that non-adaptive processes largely contributed to the build-up of reproductive isolation. Therefore, although genes involved in stress response and response to hypoxia are interesting candidates under selection, the adaptation ofC. gardettato alpine conditions may not to be the main driver of speciation. Our study brings an original example of intertwined adaptive and non-adaptive processes leading to reproductive isolation in a speciation with secondary contact and improves our understanding of the genomic underpinnings of species divergence.
Increased NFAT and NFκB signalling contribute to the hyperinflammatory phenotype in response toAspergillus fumigatusin cystic fibrosis
Authors: Bercusson Amelia , Williams Thomas J , Simmonds Nicholas J , Alton Eric WFW , Griesenbach Uta , Shah Anand , Warris Adilia , Armstrong-James Darius
Published: December 2024

Aspergillus fumigatus(Af) is a major mould pathogen found ubiquitously in the air. It commonly infects the airways of people with cystic fibrosis (CF) leading toAspergillusbronchitis or allergic bronchopulmonary aspergillosis. Resident alveolar macrophages and recruited neutrophils are important first lines of defence for clearance ofAfin the lung. However, their contribution to the inflammatory phenotype in CF duringAfinfection is not well understood. Here, utilising CFTR deficient mice we describe a hyperinflammatory phenotype in both acute and allergic murine models of pulmonary aspergillosis. We show that during aspergillosis, CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in CF, accompanied by impaired fungal control. Utilising CFTR deficient murine cells and primary human CF cells we show that at a cellular level there is increased activation of NFκB and NFAT in response toAfwhich, as inin vivomodels, is associated with increased cell death and reduced fungal control. Taken together, these studies indicate that CFTR deficiency promotes increased activation of inflammatory pathways, the induction of macrophage cell death and reduced fungal control contributing to the hyper-inflammatory of pulmonary aspergillosis phenotypes in CF.

Author Summary

The airways of people with cystic fibrosis (pwCF) are commonly colonised withAspergillus fumigatus(Af) resulting in a persistent hyperinflammatory state and the development of allergy. Understanding how first line defence innate cells, such as alveolar macrophages and neutrophils, contribute to this hyperinflammatory phenotype is important in developing novel treatments to preserve lung function in pwCF. In this study, we report that CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in pwCF, which is associated with impaired control of infection. We identify the increased activation of the transcription factors NFκB and NFAT as the mechanism of increased inflammatory cytokine production in CFTR deficient cells. This work is the first step in describing molecular mechanisms of hyperinflammation in CF in response to fungal infection and lays the groundwork for further dissection of inflammatory pathways to target with immunotherapeutic approaches.
A powerful framework for differential co-expression analysis of general risk factors
Authors: Bass Andrew J. , Cutler David J. , Epstein Michael P.
Published: December 2024

Differential co-expression analysis (DCA) aims to identify genes in a pathway whose shared expression depends on a risk factor. While DCA provides insights into the biological activity of diseases, existing methods are limited to categorical risk factors and/or suffer from bias due to batch and variance-specific effects. We propose a new framework, Kernel-based Differential Co-expression Analysis (KDCA), that harnesses correlation patterns between genes in a pathway to detect differential co-expression arising from general (i.e., continuous, discrete, or categorical) risk factors. Using various simulated pathway architectures, we find that KDCA accounts for common sources of bias to control the type I error rate while substantially increasing the power compared to the standard eigengene approach. We then applied KDCA to The Cancer Genome Atlas thyroid data set and found several differentially co-expressed pathways by age of diagnosis andBRAFmutation status that were undetected by the eigengene method. Collectively, our results demonstrate that KDCA is a powerful testing framework that expands DCA applications in expression studies.
Selection strengthens the relationship between plant diversity and the metabolic profile ofPlantago lanceolata
Authors: Medina-van Berkum Pamela , De Giorgi Francesca , Rothe Beate , Durka Walter , Gershenzon Jonathan , Roscher Christiane , Unsicker Sybille B.
Published: December 2024

Plants growing in biodiverse communities often increase productivity, but how plant diversity impacts the metabolome and the underlying ecological and evolutionary processes remains unclear. This study investigated how plant species diversity and selection for growing in different diversity environments affects the leaf metabolome ofPlantago lanceolata.

We compared the metabolites of plants derived from those that had beenselectedin the “Jena Experiment” for 17 years in plant communities with differing plant diversity with the metabolites ofnaïveplants not subjected to this selection. The metabolic profiles ofselected P. lanceolataphytometers were also compared after growing in experimental environments varying in plant species richness, soil history, and community plant history.

Results showed volatile compound diversity inP. lanceolatadecreased with plant species richness, primarily due to phenotypic plasticity rather than selection. Soil history further strengthened this relationship. Conversely, non-volatile compound diversity increased with plant species richness, but only in phytometers subjected diversity-driven selection. These effects were more pronounced when plants shared soil-plant history with their community.

In summary, our study revealed that both plastic and adaptative responses shape the metabolome ofP. lanceolatain relation to plant diversity with these effects becoming stronger as plant and soil communities mature.
Integrated phenomenology and brain connectivity demonstrate changes in nonlinear processing in jhana advanced meditation
Authors: Potash Ruby M. , van Mil Sean D. , Estarellas Mar , Canales-Johnson Andres , Sacchet Matthew D.
Published: December 2024

We present a neurophenomenological case study investigating distinct neural connectivity regimes during an advanced concentrative absorption meditation called jhana (ACAM-J),characterized by highly-stable attention and mental absorption. Using EEG recordings and phenomenological ratings (29 sessions) from a meditator with +20,000 hours of practice, we evaluated connectivity metrics tracking distinct large-scale neural interactions: nonlinear (WSMI and Directed Information), capturing non-oscillatory dynamics; and linear (WPLI) connectivity metrics, capturing oscillatory synchrony. Results demonstrate ACAM-J are better distinguished by non-oscillatory compared to oscillatory dynamics across multiple frequency ranges. Furthermore, combining attention-related phenomenological ratings with WSMI improves Bayesian decoding of ACAM-J compared to neural metrics alone. Crucially, deeper ACAM-J indicate an equalization of feedback and feedforward processes, suggesting a balance of internallyand externally-driven information processing. Our results reveal distinct neural dynamics during ACAM-J, offering insights into refined conscious states and highlighting the value of nonlinear neurophenomenological approaches to studying attentional states.
Hyperactive neuronal networks facilitate tau spread in an Alzheimer’s disease mouse model
Authors: Barbour Aaron J. , Hoag Keegan , Cornblath Eli J. , Chavez Abigail , Lucas Alfredo , Li Xiaofan , Zebrowitz Sydney , Hassman Chloe , Lee Edward B. , Davis Kathryn A. , Lee Virginia M.Y. , Talos Delia M. , Jensen Frances E.
Published: December 2024

Pathological tau spreads throughout the brain along neuronal connections in Alzheimer’s disease (AD), but the mechanisms that underlie this process are poorly understood. Given the high incidence and deleterious consequences of epileptiform activity in AD, we hypothesized neuronal hyperactivity and seizures are key factors in tau spread. To examine these interactions, we created a novel mouse model involving the cross of targeted recombination in active populations (TRAP) mice and the 5 times familial AD (5XFAD; 5X-TRAP) model allowing for the permanent fluorescent labelling of neuronal activity. To establish a causal role of seizures in tau spread, we seeded mice with human AD brain-derived tau lysate and induced seizures with pentylenetetrazol (PTZ) kindling. Comprehensive brain mapping of tau pathology and neuronal activity revealed that basal hyperactivity in 5X-TRAP mice was associated with increased tau spread, which was exacerbated by seizure induction through activated networks and correlated with memory deficits. Computational modeling revealed that anterograde tau spread was elevated in 5X-TRAP mice and that regional neuronal activity was predictive of tau spread to that brain region. On a cellular level, we found that in both saline and PTZ-treated 5X-TRAP mice, hyperactive neurons disproportionately contributed to the spread of tau. Further, we found that Synaptogyrin-3, a synaptic vesicle protein that interacts with tau, was increased following PTZ kindling in 5X-TRAP mice, possibly indicative of a synaptic mechanism underlying seizure-exacerbated tau spread. Importantly, postmortem AD brain tissue from patients with a history of seizures showed increased tau pathology in patterns indicative of increased spread and increased Synaptogyrin-3 levels compared to those without seizures. Overall, our study identifies neuronal hyperactivity and seizures as key factors underlying the pathobiological and cognitive progression of AD. Therapies targeting these factors should be tested clinically to slow tau spread and AD progression.
The efficacy of resting-state fMRI denoising pipelines for motion correction and behavioural prediction
Authors: Pavlovich Kane , Pang James , Holmes Alexander , Constable Toby , Fornito Alex
Published: December 2024

Resting-state functional magnetic resonance imaging (rs-fMRI) is a pivotal tool for mapping the functional organization of the brain and its relation to individual differences in behaviour. One challenge for the field is that rs-fMRI signals are contaminated by multiple sources of noise that can contaminate these rs-fMRI signals, affecting the reliability and validity of any derivative phenotypes and attenuating their correlations with behaviour. Here, we investigate the efficacy of different noise mitigation pipelines, including white-matter and cerebrospinal fluid regression, independent component analysis (ICA) – based artefact removal, volume censoring, global signal regression (GSR), and diffuse cluster estimation and regression (DiCER), in simultaneously achieving two objectives: mitigating motion-related artifacts and augmenting brain-behaviour associations. Our analysis, which employed three distinct quality control metrics to evaluate motion influence and a kernel ridge regression for behavioural predictions of 81 different behavioural variables across two independent datasets, revealed that no single pipeline universally excels at achieving both objectives consistently across different cohorts. Pipelines combining ICA-FIX and GSR demonstrate a reasonable trade-off between motion reduction and behavioural prediction performance, but inter-pipeline variations in predictive performance are modest.
Humans use overconfident estimates of auditory spatial and temporal uncertainty for perceptual inference
Authors: Hong Fangfang , Xu Jiaming , Landy Michael S. , Badde Stephanie
Published: December 2024

Making decisions based on noisy sensory information is a crucial function of the brain. Various decisions take each sensory signal’s uncertainty into account. Here, we investigated whether perceptual inferences rely on accurate estimates of sensory uncertainty. Participants completed a set of auditory, visual, and audiovisual spatial as well as temporal tasks. We fitted Bayesian observer models of each task to every participant’s complete dataset. Crucially, in some model variants the uncertainty estimates employed for perceptual inferences were independent of the actual uncertainty associated with the sensory signals. Model comparisons and analysis of the best-fitting parameters revealed that, in unimodal and bimodal contexts, participants’ perceptual decisions relied on overconfident estimates of auditory spatial and audiovisual temporal uncertainty. These findings challenge the ubiquitous assumption that human behavior optimally accounts for sensory uncertainty regardless of sensory domain.
Ischemic Stroke Burden from Dietary Risks in China: 1990-2019 GBD Study
Authors: Duan Kui , Cheng Yongran , Wang Mingwei , Peng Shang , Zhang Min , Wang Jifeng , Ye Lan , Xu Zucai , Feng Zhanhui
Published: December 2024

Background

In China, economic growth and lifestyle shifts have made dietary risks a major public health issue for ischemic stroke. This study examines the link between six dietary risks and ischemic stroke in China from 1990 to 2019, using 2019 Global Burden of Disease (GBD) data.

Methods

Data from GBD 2019 was primarily derived from Chinese monitoring systems, and the KaiLuan study focused on trends in ischemic stroke mortality and disability-adjusted life years (DALYs) associated with six dietary risks. Age-period-cohort and join-point regression methods were utilized, accounting for age, period, and cohort effects.

Results

In 2019, deaths and DALYs attributable to six dietary risks were 283,083 and 7,082,849, respectively, marking a significant increase of 124.7% and 108.4% since 1990. Despite overall declines in mortality and DALY rates from 1990 to 2019 (annual average percentage change (AAPC): −0.5% for DALYs and −0.6% for deaths), ischemic stroke rates due to diets high in red meat (AAPC: 1.4% for DALYs and 1.3% for deaths). For five dietary risks, local drift curves indicated increasing trends with age, except for low fiber intake. DALYs rates peaked at 85–89 years for all except sodium, which peaked at 75–79 years. Mortality rates slightly increased under 79 years, but rose noticeably over 79. Men had higher numbers and rates of dietary risk-related strokes, but they experienced smaller declines than women.

Conclusions

The study reveals an increasing ischemic stroke burden due to high red meat diets and decreasing trends due to low vegetable intakes. Dietary risks associated with high sodium, low fruit, vegetable, and whole grain intakes led to increased numbers but decreased rates of ischemic stroke outcomes.
Greater host influence and promiscuity: How an invasive seaweed host has advantages over co-occurring natives
Authors: Ghotbi Marjan , Bonthond Guido , Ghotbi Mitra , Künzel Sven , Needham David M , Weinberger Florian
Published: December 2024

The surface microbiome of seaweed hosts is a multi-domain biofilm regulated by host-microbe and microbe-microbe interactions. The extent to which hosts influence these interactions, and potentially affect their resilience and invasion success, remains unclear. We experimentally tested whether hosts with invasion history exert more influence over their biofilms than native hosts. Biofilm formation on proxy surfaces adjacent to one invasive (Gracilaria vermiculophylla) and two native (Fucus serratus, Fucus vesiculosus) co-occurring hosts was monitored and compared to mature epiphytic biofilms of the same hosts. OnlyGracilaria’sproxy biofilms were significantly different in community composition compared to control surfaces.Gracilaria’s proxy biofilms also showed the highest similarity to their adjacent algae sharing certain bacterial taxa that were absent in control treatments, indicating that colonization of the proxy surface was influenced by the host.Gracilariaand its proxy biofilm showed highest similarity in microbial network variables, suggesting a higher ability of the invader to influence connectivity and microbial associations within its biofilm. MeanwhileGracilaria’s mature biofilm also showed higher variability in its prokaryotic composition over experiments, which was also reflected in a less robust microbial network in bothGracilariaand its proxy biofilms. This suggests that in addition to stronger influence in the invasive host, it was also more promiscuous towards potential symbionts from the environment. Ultimately, through examining microbial interactions, in line with previous research we found that host influence and promiscuity may play an important role in seaweed hosts to acclimate to different environmental condition and successfully thrive in new ecosystems.