Biology subjects

Patel, V.

Publications and source records attributed to Patel, V..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Modular evolution and strain-specific partnerships: how Hamiltonella defensa shapes defense and symbiont communities in aphids

Insects frequently carry maternally-transmitted endosymbionts that mediate ecological interactions, including resource acquisition and host defense. All pea aphids (Acyrthosiphon pisum), for example, carry the obligate nutritional symbiont Buchnera, while most have one or more of the seven heritable facultative symbionts, which play diverse roles. A common symbiont, Hamiltonella defensa, confers protection against the parasitic wasp Aphidius ervi via a toxin-bearing bacteriophage called APSE, with strain-level variation in protection best predicted by APSE variant. Yet, little is known about Hamiltonella/APSE strain variation in the field, resulting in an incomplete understanding of the full arsenal of symbiont defenses and how these change over space and time. Here, we characterized Hamiltonella/APSE diversity in over 3,000 field-collected aphids from two North American populations across multiple years. We identified bacterial strains representing five Hamiltonella clades, seven APSE variants, and numerous toxin alleles, resulting in at least 38 distinct combinations. We found that APSEs moved laterally among Hamiltonella strains more readily than toxins among phage backbones, together generating modular defensive diversity. Hamiltonella strains exhibited strain-specific coinfection preferences with other symbionts, particularly Fukatsuia, Rickettsia, and Rickettsiella, indicating strain-level structuring of heritable bacterial communities. Geographic and temporal analyses revealed dramatic regional differences and rapid population turnover, with combinations conferring intermediate laboratory protection dominating despite the decline of highly protective strains, suggesting ecological success goes beyond parasitoid resistance alone. This extensive cryptic diversity provides standing genetic variation enabling rapid evolutionary responses to biological control efforts and anthropogenic stressors, including climate change, with implications for pest management and host adaptation.

evolutionary biology↗

bioRxiv2025

Disruption of a six-nucleotide miRNA motif improves PKD1 dosage and ameliorates polycystic kidney disease

Disrupting microRNA interactions to restore protein expression from haploinsufficient genes offers a promising precision-therapy strategy for monogenic disorders. PKD1 heterozygosity underlies autosomal dominant polycystic kidney disease (ADPKD), a disorder affecting nearly 12 million people worldwide, where reduced PKD1 dosage drives progressive cyst formation and kidney failure. We previously identified a 55-bp cis-repressive element in the PKD1 3'UTR. Here, we define a six-nucleotide miR-17 seed match within this element that is sufficient to reproduce PKD1 repression. In vivo base substitution of this motif stabilizes Pkd1 mRNA and increases polycystin-1 (PC1) protein levels, producing a robust reduction in cyst growth and preservation of kidney function in mouse models. To therapeutically recapitulate this effect, we developed a steric-blocking oligonucleotide that occludes the motif, stabilizes PKD1 transcript levels, increases PC1 expression, and mitigates cyst-pathogenic events in both murine and patient-derived ADPKD cells. Together, these findings establish a minimal, targetable cis-regulatory motif and provide proof-of-concept for oligonucleotide-mediated PKD1 derepression, while offering a potentially generalizable strategy to restore other haploinsufficient genes.

genetics↗

bioRxiv2025

Gene-centric metagenomic analyses reveal microbiome functional insights into diseases

The microbiome encodes millions of genes; however, understanding their role in human health remains challenging. Here, we developed MetaGEAR, a gene-centric analysis framework for metagenomic data. MetaGEAR constructs cohort-specific databases for efficient retrieval of gene annotations, abundances, and co-localization, while providing enhanced taxonomic resolution by integrating reference- and assembly-based approaches. This is combined with a Metagenomic Assembled Graph (MAGraph) capturing gene neighborhood information. Using MetaGEAR, we built a multi-cohort database comprising >33 million gene families to investigate microbiome functionality across 24 cohorts of inflammatory bowel disease, colorectal cancer, and healthy populations and identified disease signature genes. Furthermore, the MAGraph revealed mobile genetic elements acting as hubs for tetracycline resistance spreading among Enterococcus, Streptococcus, and Veillonella species. Also, a duplicated nitrate reduction operon in Klebsiella pneumoniae was linked to differential gene expression under stress and virulence-inducing conditions. In summary, gene-centric metagenomic analyses reveal important insights into microbiome functionality in diseases.

microbiology↗

bioRxiv2025

Microbial oral-gut translocation in advanced chronic liver disease is linked to exacerbation of intestinal barrier dysfunction and hepatic fibrosis

While microbiome perturbations are associated with advanced chronic liver disease (ACLD), microbial disease mechanisms are poorly understood. Using multi-omics analyses of paired saliva and faecal samples from an ACLD cohort, we identified next-to-identical oral and gut bacterial strains (including Veillonella and Streptococcus spp.) which increased in absolute abundance in the gut of ACLD patients. These translocators uniquely encoded a collagenase-like proteinase (prtC) with the potential for gut barrier disruption and prtC faecal abundance was a robust ACLD biomarker (auPR=0.91). CCl4-treated mice inoculated with Veillonella and Streptococcus prtC-encoding patient isolates showed exacerbation of gut barrier impairment and hepatic fibrosis. Furthermore, faecal collagenase activity was increased in ACLD patients and experimentally confirmed for the prtC gene from translocating Veillonella parvula. Overall, our study establishes mechanistic links between oral-gut translocation and ACLD pathobiology, and identifies the oral microbiome as an important contributing factor with potential for microbial diagnostics and therapeutics.

microbiology↗

bioRxiv2025

The molecular basis of coordinated antigen switching enabling chronic infection by human malaria parasites

The exceptional virulence of the human malaria parasite, Plasmodium falciparum, is in large part attributed to the adhesive properties of infected red blood cells and the parasites ability to avoid antibody recognition through antigenic variation. Both properties are derived from a hypervariable protein placed on the infected cell surface called PfEMP1, different versions of which are encoded by members of the multi-copy var gene family. Over the course of an infection, rising and falling waves of parasitemia correspond to transcriptional switching between var genes, with parasites expressing alternative PfEMP1 isoforms replacing those eliminated by antibodies targeting the previously expressed PfEMP1. var gene expression is controlled epigenetically, however what triggers transcriptional switching and determines which genes are activated is largely unknown. Previous work implicated a unique, universally conserved gene called var2csa as a central component in transcriptional switching, however the molecular basis for its role was obscure. Here we describe how noncoding RNAs, an upstream open reading frame and the nonsense mediated mRNA decay pathway interact to enable var2csa to function as a transiently activated "switching hub" that unifies the var gene family into a single coordinated network, thereby perpetuating chronic infections.

microbiology↗

bioRxiv2025

Divergent Effects of Ultra-High Dose Arachidonic Acid versus Docosahexaenoic Acid on MYCN-Driven Neuroblastoma Progression in a Syngeneic Mouse Model

Neuroblastoma (NB) represents the most common extracranial solid tumor in children, where high-risk cases have particularly poor prognosis. We used a syngeneic mouse model to investigate the effects of ultra-high dose highly unsaturated fatty acids (HUFA) on NB progression. Following tumor establishment, mice were randomized to receive daily oral gavage with omega-6 ({omega}6) arachidonic acid (ARA) at 4.7 g/d human equivalent (hEq), or omega-3 ({omega}3) docosahexaenoic acid (DHA) at 24 g/d hEq, and controls did not receive gavage. We observed strikingly divergent effects: ARA significantly promoted tumor growth, resulting in 100% tumor survival and 4-fold larger tumors compared to controls, with enhanced vascularization and invasive morphology. In contrast, DHA administration reduced tumor survival (40% versus 92% in controls) and significantly suppressed the progression of remaining tumors, with remaining DHA-treated tumors approximately 4.5-fold smaller than controls and 18-fold smaller than ARA-treated tumors. In a separate lipid mediator analysis, ARA supplementation significantly increased pro-inflammatory/pro-tumorigenic mediators including PGE2, TXB2, and epoxyeicosatrienoic acids in liver, spleen, brain and skeletal muscle. DHA supplementation increased anti-inflammatory/anti-tumor mediators, particularly EPA-derived 17,18-EpETE, 18-HEPE, and DHA-derived 14-HDHA in these same tissues. No significant differences in body weight were observed among treatment groups, indicating the treatments were well-tolerated. These findings build upon our previous research demonstrating that ultra-high dose {omega}3 supplementation can completely block tumor formation in MYCN-driven NB. The profound tumor-suppressive effects of DHA suggest that dietary modulation of {omega}3 and {omega}6 HUFA intake may offer a complementary, low-toxicity approach to high-risk NB standard of care (SoC). Our findings suggest that dietary intervention may be an effective primary or adjunctive strategy in pediatric oncology, enabling reduced SoC dosing while improving outcomes and survivorship.

cancer biology↗

bioRxiv2025

Privacy-Preserving Generative AI Framework for Synthetic Multimodal Eye Movement Data

Eye movements, such as nystagmus, saccades, and smooth pursuit, provide valuable information about neurological function but have limited publicly accessible datasets due to patient privacy concerns. To address this, we leverage generative AI to create realistic videos of artificial eye movement, eliminating the need for real patient data. These synthetic datasets have shown performance comparable to actual patient data in clinical tasks. Our generated videos will be openly shared, facilitating broader research and advancement in neurologic and neuro-ophthalmic AI applications.

bioengineering↗

bioRxiv2025

Noncoding RNA elements within MYCN mRNA are potent autonomous drivers of oncogenesis.

Neuroblastoma (NB) is a highly metastatic pediatric cancer arising from the neural crest lineage. Genetic amplification of the MYCN proto-oncogene is a defining feature of NB, present in about 20% of all cases. The let-7 tumor suppressor microRNA targets the 3 UTR of MYCN mRNA. We previously demonstrated that the 3 UTR of MYCN mRNA acquires the ability to sequester let-7 in MYCN-amplified (MA) disease, thus inhibiting its function. This work established that a noncoding element within an oncogenic mRNA can contribute independently to disease pathology and genetic patterning. To further investigate the roles of noncoding RNA elements within the MYCN mRNA, we engineered cells expressing either MYCN-ORF (MYCN open reading frame only), MYCN-GL (full-length MYCN mRNA from the intact genetic locus), and Null-GL (full-length MYCN mRNA variant where EGFP replaces MYCN protein). We observe that all constructs enhance growth compared to controls in vitro and in vivo. MYCN-GL-expressing cells displayed the most robust growth in vitro despite containing multiple regulatory RNA elements. Remarkably, the Null-GL construct induces cells to grow as fast or faster than MYCN-ORF-expressing cells. Animal studies further confirmed these observations, where the Null-GL-driven tumors had the highest incidence and lowest latency, followed by MYCN-GL and then MYCN-ORF. Further, through NGS analysis, let-7, miR-101, and miR-34a targets are enriched in both MYCN-GL and Null-GL expressing cells. Thus, the 3UTR of MYCN, which is also targeted by these microRNAs, may interact with them in MYCN-GL and Null-GL cells to deliver a protective effect for the mRNA targets of these microRNAs. We also observed more dynamic differential gene expression in the -GL constructs than in ORF and GFP-expressing cells. In addition, MYCN-GL and Null-GL expressing cells are similarly enriched in gene ontology pathways for cancer, RNA metabolism, and microRNA processing pathways as compared to ORF and GFP. Whole genome sequencing also revealed more similarities in copy number variation in MYCN-GL and Null-GL than in ORF and GFP, suggesting that these constructs may provide selective pressure to favor specific CNV patterns. These observations show that full-length MYCN mRNA containing noncoding regulatory elements are more robust drivers of cell growth and oncogenicity than MYCN protein alone and provide insights into the mechanisms of oncogenic contribution. These results open an exciting door for our understanding of NB pathology and genetic patterning and have broad implications for other oncogene-driven cancers.

cancer biology↗

bioRxiv2024

Nanoscale curvature of the plasma membrane regulates mechanoadaptation through nuclear deformation and rupture

Nuclear translocation of the transcription regulatory proteins YAP and TAZ is a critical readout of cellular mechanotransduction. Recent experiments have demonstrated that cells on substrates with well-defined nanotopographies demonstrate mechanoadaptation through a multitude of effects - increased integrin endocytosis as a function of nanopillar curvature, increased local actin assembly on nanopillars but decreased global cytoskeletal stiffness, and enhanced nuclear deformation. How do cells respond to local nanotopo-graphical cues and integrate their responses across multiple length scales? This question is addressed using a biophysical model that incorporates plasma membrane (PM) curvature-dependent endocytosis, PM curvature-sensitive actin assembly, and stretch-induced opening of nuclear pore complexes (NPCs) in the nuclear envelope (NE). This model recapitulates lower levels of global cytoskeletal assembly on nanopillar substrates, which can be partially compensated for by local actin assembly and NE indentation, leading to enhanced YAP/TAZ transport through stretched NPCs. Using cell shapes informed by electron micrographs and fluorescence images, the model predicts lamin A and F-actin localization around nanopillars, in good agreement with experimental measurements. Finally, simulations predict nuclear accumulation of YAP/TAZ following rupture of the NE and this is validated by experiments. Overall, this study indicates that nanotopography tunes mechanoadaptation through both positive and negative feedback on mechanotransduction. Table of Contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/619165v2_ufig1.gif" ALT="Figure 1"> View larger version (84K): org.highwire.dtl.DTLVardef@ec6d5aorg.highwire.dtl.DTLVardef@1ff6ec2org.highwire.dtl.DTLVardef@c09f46org.highwire.dtl.DTLVardef@18df50_HPS_FORMAT_FIGEXP M_FIG C_FIG This study uses experiments and biophysical modeling to examine the response and adaptation of cells to nanoscale topography of surfaces. It is shown that cytoskeletal assembly and nuclear localization of transcription regulatory factors such as YAP/TAZ can be tuned by nanoscale membrane curvature and nuclear deformation and rupture due to substrate nanotopography.

biophysics↗

bioRxiv2024

Development and extensive sequencing of a broadly-consented Genome in a Bottle matched tumor-normal pair for somatic benchmarks

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first to be explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from seventeen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, and Hi-C, and karyotyping. In future publications, these data will be used by the GIAB Consortium to develop matched tumor-normal benchmarks for somatic variant detection. We expect these data to facilitate innovation for whole genome measurement technologies, de novo assembly of tumor and normal genomes, and bioinformatic tools to identify small and structural somatic mutations. This first-of-its-kind broadly consented open-access resource will facilitate further understanding of sequencing methods used for cancer biology.

genomics↗

bioRxiv2024

Engineered Nanotopographies Induce Transient Openings in the Nuclear Membrane

Materials with engineered nano-scale surface topographies, such as nanopillars, nanoneedles, and nanowires, mimic natural structures like viral spike proteins, enabling them to bypass biological barriers like the plasma membrane. These properties have led to applications in nanoelectronics for intracellular sensing and drug delivery platforms, some of which are already in clinical trials. Here, we present evidence that nanotopographic materials can induce transient openings in the nuclear membranes of various cell types without penetrating the cells, breaching the nucleo-cytoplasmic barrier and allowing uncontrolled molecular exchange across the nuclear membrane. These openings, induced by nanoscale curvature, are temporary and repaired through ESCRT-mediated mechanisms. Our findings suggest a potential for nano topographic materials for direct nuclear sensing and delivery, holding promise for improving the delivery, efficiency, and safety of therapeutic agents to the nucleus.

bioengineering↗

bioRxiv2024

Novel sex-biased outcomes in neuroblastoma are associated with distinct gene expression and chromosomal loss patterns.

The worst patient outcomes in neuroblastoma are driven by high-risk disease1,2, which is divided into similarly sized MYCN amplified and MYCN non-amplified patient subgroups3. Male patients have been reported to have slightly worse outcomes than females in all-patient analyses of multiple studies3,4. However, we show here that in MYCN non- amplified high-risk and stage 4s low-risk disease, female patients have significantly worse overall survival than males. Female MYCN non-amplified high-risk patients highly express H19 and DLK1, both of which drive cell growth in vitro and are associated with worse outcomes in females but not males. Further, chromosome-specific expression analysis of these patients reveals broad sex disparities in chromosomal patterning, including female-specific retention of chromosome 11q, a pattern typically reserved for MYCN-amplified disease5,6. Finally, we show that H19, a known let-7 microRNA target7, sequesters let-7 in females, providing a rationale for worse female survival and reconciling retention of chromosome 11q. We propose that this novel sex-based outcome disparity is driven by let-7 inhibition, expanding on a model of neuroblastoma development where let-7 mitigation is central to disease pathology8.

cancer biology↗

bioRxiv2024

High dose ω3 eicosapentaenoic acid and docosahexaenoic acid block, whereas ω6 arachidonic acid accelerates, MYCN-driven tumorigenesis in vivo

Background/ObjectivesNeuroblastoma is a genetically diverse, highly metastatic pediatric cancer accounting for 15% of childhood cancer deaths despite only having ~8% of childhood cancer incidence. The current standard of care for high-risk disease is highly genotoxic. This, combined with less than 50% survival in high-risk disease and an abysmal 5% survival in relapsed cases, makes discovering novel, effective, and less toxic treatments essential. MethodsA prophylactic syngeneic mouse model was used to test high-dose lipid-mediator highly unsaturated fatty acids on tumorigenesis. Wild-type mice were gavaged with 12.3-14.6 g/d (adult human equivalent) omega-3 EPA, DHA, or oxidation-resistant bis allylic deuterated DHA (D-DHA) and 4.6-6.0 g/d arachidonic acid (ARA). At seven days, MYCN-expressing murine neuro-2a cells syngeneic to the gavaged mice were injected subcutaneously. Oral gavage continued for 10-20 d post-injection when tumors and tissues were harvested. ResultsFifty percent of control (not gavaged) animals form tumors (4/8) at about 10 d. High-dose DHA, D-DHA, and EPA block tumor formation completely in n=8 or 10 animals. In contrast, {omega}6 arachidonic acid (4.6-6.0 g/d) enhances tumor formation (6/10 tumors) and reduces latency (5.5 to 10 days)compared to control. Co-delivery of ARA and EPA results in a reduced tumor burden analogous to the control group, suggesting that EPA directly opposes the mechanism of ARA-mediated tumor formation. DHA acts through a non-oxidative mechanism. ConclusionsSustained high dose {omega}3 (weeks/months) is safe and well tolerated in humans. These results suggest that {omega}3 DHA and EPA delivery at ultra-high doses may represent a viable low-toxicity therapy for neuroblastoma. Simple SummaryPediatric Neuroblastoma has an overall mortality rate above 50%, and the current standard of care consists of highly genotoxic compounds. The biological actions of omega-6 ({omega}6) and omega-3 ({omega}3) highly unsaturated fatty acids (HUFA) generally oppose one another with the {omega}6 HUFA signaling for inflammation and angiogenesis (new blood vessel formation). Prolonged use of ultrahigh dose (15-20 g/d) {omega}3 HUFA has shown efficacy in catastrophic human traumatic brain injury and is well tolerated. Tumors form in about 50% of mice in our pediatric neuro-blastoma model. We show that 12-14 g/d adult human equivalent doses of {omega}3 EPA or DHA, as well as an oxidation-resistant form of DHA (D-DHA), completely block tumor formation, whereas a dose of about 5 g/d of {omega}6 ARA enhances tumorigenesis. Our data suggest that ultra-high dose {omega}3 therapy should be carefully investigated as a low-toxicity approach to neuroblastoma intervention.

cancer biology↗

bioRxiv2024

Mammalian RNAi represses pericentromeric lncRNAs to maintain genome stability

Mammalian pericentromeric tandem repeats produce long noncoding RNAs (lncRNAs) that are dysregulated in cancer and linked to genomic instability. Identifying the basic molecular characteristics of these lncRNAs and their regulation is important to understanding their biological function. Here, we determine that the Argonaute (Ago) proteins of the RNA interference (RNAi) pathway directly and uniformly repress bidirectional pericentromeric lncRNAs in a Dicer-dependent manner in mouse embryonic and adult stem cells. Ago-dependent and Dicer-dependent autoregulatory small RNAs were identified within pericentromeric lncRNA degradation intermediates. We develop an RNase H cleavage assay to determine the relative proportions and lengths of the pericentromeric lncRNA targets. We find that 5-phosphate and non-polyadenylated bidirectional pericentromeric lncRNAs are expressed at similar proportions. These lncRNAs can span up to 9 repeats, with transcription from the reverse strand template yielding the longer products. Using pericentromeric repeat RNA reporters, we determine that Ago represses pericentromeric lncRNAs after S phase transcription. Upon loss of Ago, pericentromeric lncRNA dysregulation results in delayed cell cycle progression, a defective mitotic spindle assembly checkpoint (SAC) and genomic instability. These results show that an evolutionarily conserved Ago activity at pericentromeres contributes to mammalian genome stability.

molecular biology↗

bioRxiv2023

Integrative multiomics analysis of neointima proliferation in human saphenous vein: implications for bypass graft disease

IntroductionHuman saphenous veins (SV) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima proliferation (NP). NP involves complex interplay between vascular smooth muscle cells (VSMC) and fibroblasts. Little is known, however, regarding the transcriptomic and proteomic dynamics of NP. Here, we performed multi-omics analysis in an ex vivo tissue culture model of NP in human SV procured for CABG surgery. Methods and resultsHistological examination demonstrated significant elastin degradation and NP (indicated by increased neointima area and neointima/media ratio) in SV subjected to tissue culture. Analysis of data from 73 patients suggest that the process of SV adaptation and NP may differ according to sex and body mass index. RNA sequencing confirmed upregulation of pro-inflammatory and proliferation-related genes during NP and identified novel processes, including increased cellular stress and DNA damage responses, which may reflect tissue trauma associated with SV harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics detected transdifferentiating VSMC in the intima on the day of harvesting and highlighted dynamic alterations in fibroblast and VSMC phenotype and behavior during NP. Specifically, we identified new cell subpopulations contributing to NP, including SPP1+, LGALS3+ VSMC and MMP2+, MMP14+ fibroblasts. ConclusionDynamic alterations of gene and protein expression occur during NP in human SV. Identification of the human-specific molecular and cellular mechanisms may provide novel insight into SV bypass graft disease.

genomics↗

bioRxiv2023

Fecal microbial transfer and complex carbohydrates mediate protection against COPD

ObjectiveChronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DesignUsing an in vivo mouse model of cigarette smoke-induced COPD and fecal microbial transfer (FMT), we characterized the fecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology, and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in sixteen COPD patients using a randomized, double-blind, placebo-controlled pilot study of inulin supplementation. ResultsFMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in cigarette smoke-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. ConclusionThe gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically. What is already known on this topicO_LIChanges in gut microbiota are associated with COPD but the underlying host and microbial mechanisms are unclear, limiting the therapeutic applications. C_LI What this study addsO_LIMicrobiome composition and metabolism is reproducibly correlated with lung and gastrointestinal pathology in experimental COPD. C_LIO_LIMicrobiome modifying interventions effectively alleviate disease, including protective effects supplementing smoking cessation. C_LIO_LINutritional interventions targeting the microbiome in COPD patients demonstrate efficacy in a small pilot study. C_LI How this study might affect research, practice or policyO_LIMicrobiome-targeting therapeutics and nutritional interventions may be developed for COPD, including as supplements to smoking cessation. C_LI

physiology↗

bioRxiv2023

Differential evolution of cooperative traits in aggregative multicellular bacterium Myxococcus xanthus driven by varied population bottleneck sizes

Repeated population bottlenecks influence the evolution and maintenance of cooperation1,2. However, it remains unclear whether bottlenecks select all cooperative traits expressed by an organism or only a subset of them. Myxococcus xanthus, a social bacterium, displays multiple cooperative traits, including growth, predation, sporulation in multicellular fruiting bodies, and germination 3-6. Using laboratory evolution experiment, we investigated the effect of repeated stringent versus relaxed population bottlenecks on the evolution of these four cooperative traits when they were all under selection. We found that only fruiting body formation and growth were positively selected under the stringent regimen, while the other two traits were negatively selected. The pattern was reversed in the relaxed regimen. Additionally, the relaxed regimen led to a significant increase in fitness when competed against ancestors across the entire lifecycle, whereas the stringent treatment did not change competitive fitness. Genomic analysis revealed that mutations in {sigma}54 interacting protein and DNA-binding response regulator protein are linked with the changes observed in stringent and relaxed regimens respectively. Further, similar trade-offs are also seen among natural populations of M. xanthus. Overall, we demonstrate that different bottleneck sizes drive the evolution of lifecycles in distinct manners, driven by trade-offs between cooperative life history traits.

evolutionary biology↗

bioRxiv2023

Dopaminoceptive D1 and D2 neurons in ventral hippocampus arbitrate approach and avoidance in anxiety

The hippocampus 1-7, as well as dopamine circuits 8-11, coordinate decision-making in anxiety-eliciting situations. Yet, little is known about how dopamine modulates hippocampal representations of emotionally-salient stimuli to inform appropriate resolution of approach versus avoidance conflicts. We here study dopaminoceptive neurons in mouse ventral hippocampus (vHipp), molecularly distinguished by their expression of dopamine D1 or D2 receptors. We show that these neurons are transcriptionally distinct and topographically organized across vHipp subfields and cell types. In the ventral subiculum where they are enriched, both D1 and D2 neurons are recruited during anxiogenic exploration, yet with distinct profiles related to investigation and behavioral selection. In turn, they mediate opposite approach/avoidance responses, and are differentially modulated by dopaminergic transmission in that region. Together, these results suggest that vHipp dopamine dynamics gate exploratory behaviors under contextual uncertainty, implicating dopaminoception in the complex computation engaged in vHipp to govern emotional states.

neuroscience↗