Search bioRxiv⌕ Search

Biology subjects

Smith, A.

Publications and source records attributed to Smith, A..

At least 37 records · Page 2Linked to original sources

Survival across habitats and sizes explains ontogenetic habitat shifts in juvenile blue crabs

Juvenile organisms often shift habitat usage during ontogeny to balance changing needs for growth and refuge, yet fine-scale habitat shifts within narrow size classes remain understudied. We conducted a manipulative tethering experiment to quantify size-specific survival of juvenile blue crabs across three habitats - seagrass meadows (seagrass), salt marsh edge (SME), and unvegetated sand flats (sand) - in the York River, Chesapeake Bay, USA. We also accounted for spatial orientation, seasonality, and turbidity. Results were analyzed using Bayesian hierarchical logistic regression models. Survival varied with crab size, habitat, and time of year, with an interaction between size and habitat. Smaller juveniles had the highest survival in seagrass, but survival increased more rapidly with size in SME and sand habitats. By 33 mm carapace width (CW), relative survival rates in seagrass and SME were statistically indistinguishable. Meanwhile, survival in sand approached that of seagrass at approximately 45 mm CW. When considered alongside previous growth rate studies, these results suggest that seagrass offers a growth-survival advantage for crabs < 15 - 20 mm CW, while salt marsh and sand habitats become increasingly favorable for larger juveniles due to comparable survival and faster growth. Consequently, even across a relatively small size range of the juvenile phase, size-specific patterns in survival differ substantially across structured and unstructured habitats. Our findings align with observed patterns of size-specific habitat use and underscore the complementary nursery roles of seagrass and salt marshes, reinforcing their joint importance in habitat restoration and conservation strategies for juvenile blue crabs.

ecology↗

Trajectory-matching ABC-MCMC for simulating heterogeneous dynamics in mechanistic models

The inherent heterogeneity of complex biological systems makes it difficult to experimentally and clinically explore individual outcomes. Mechanistic mathematical models are essential tools for studying such heterogeneity. Thus, there is increasing interest in integrating newer mechanistic model-based techniques, like virtual patient cohorts and virtual clinical trials, within experimental and regulatory pipelines to probe relationships that may be difficult or impossible to ascertain through traditional wet-lab or clinical experimentation alone. Approximate Bayesian Computation (ABC) is an attractive method for generating virtual patient cohorts and running virtual clinical trials. However, ABC-based approaches can become computationally demanding when stringent acceptance criteria are imposed. In response, we developed a model-based technique called trajectory-matching random-walk feasibility sampling (TM-RWFS) that captures the variability of complex biological systems by constraining model trajectories between the upper and lower bounds of available data to generate heterogeneity. By testing the method's performance on existing mechanistic models, we show that TM-RWS generates parameter sets whose simulated trajectories reproduce the observed variability in biological systems of varying complexity while maintaining computational efficiency. Thus, TM-RWFS is a fast, new approach for generating heterogeneity in mechanistic mathematical models with implications for model-based experimental design, virtual patient cohorts, and virtual clinical trials.

systems biology↗

Anabolic and catabolic responses to different modes of exercise in patients with chronic kidney disease

BackgroundMuscle wasting is a common complication in individuals with chronic kidney disease (CKD) and contributes to reduced physical function and poor clinical outcomes. While exercise is recommended for CKD patients, the molecular responses to different exercise modalities remain poorly understood. This study aimed to investigate the anabolic, catabolic, and myogenic responses of skeletal muscle to aerobic exercise (AE) and combined exercise (CE; aerobic plus resistance) in people with CKD. MethodsMuscle biopsies were collected from participants in a 12-week randomized controlled trial of supervised exercise training, the ExTRA CKD trial. Samples were obtained at baseline, 24 hours after an initial bout of exercise (untrained), and 24 hours after the final training session (trained). Western blotting and RT-qPCR were used to assess changes in key markers of protein synthesis, degradation, and regeneration. To complement these data, in vitro experiments using mechanically stretched primary skeletal muscle cells from CKD and healthy control donors were used to explore the time course of anabolic signalling. ResultsIn vivo, Akt phosphorylation was blunted following unaccustomed CE but significantly upregulated following training, indicating partial restoration of anabolic signalling. No change was observed in response to AE. Myostatin expression was significantly downregulated following both AE and CE in the untrained state, while Pax7 and myogenic gene expression were upregulated only in response to CE after training. In vitro, mechanical stretch induced significant phosphorylation of Akt and p70S6K in both CKD and control cells, with no group difference in Akt response and a trend toward faster return to baseline of p70S6K phosphorylation in CKD cells. ConclusionThese findings demonstrate that CE, but not AE, induces beneficial anabolic and myogenic responses in skeletal muscle in CKD, and highlight the value of combining in vivo and in vitro models to explore temporal dynamics and mechanistic insight into muscle adaptation. What was knownO_LIPeople with CKD often have impaired skeletal muscle responses to exercise, termed anabolic resistance, which may contribute to muscle wasting and poor outcomes. C_LIO_LIResistance exercise activates anabolic and myogenic pathways in healthy muscle, but the extent of these responses in CKD is unclear. C_LIO_LILimited studies have compared molecular responses to different exercise modalities in CKD, particularly combining in vivo and in vitro approaches. C_LI This study addsO_LICombined aerobic-resistance exercise, but not aerobic exercise alone, restored aspects of anabolic signalling (Akt phosphorylation) in CKD skeletal muscle after training. C_LIO_LIMyogenic gene expression was upregulated following combined exercise but not aerobic exercise, indicating a modality-specific regenerative response. C_LIO_LIIn vitro, primary muscle cells from CKD and healthy donors showed similar early anabolic responses to mechanical stretch, though CKD cells may return to baseline more rapidly. C_LI Potential ImpactO_LISupports inclusion of resistance-based modalities in exercise prescriptions for people with CKD to enhance muscle anabolic and regenerative responses. C_LIO_LISuggests that exercise prescriptions for CKD should prioritise combined modalities to maximise muscle anabolic and regenerative potential. C_LIO_LIProvides mechanistic evidence to inform tailored exercise interventions aimed at preserving muscle health in CKD patients. C_LI

molecular biology↗

Loss of HMGCS2-mediated intestinal stem cell ketogenesis is a metabolic barrier to mucosal healing in Ulcerative colitis

Human colonic epithelial cells express high levels of 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the crucial mitochondrial enzyme responsible for the production ketone bodies, predominantly beta-hydroxybutyrate ({beta}HB). Ketogenesis is an important metabolic pathway responsible for energy production in states of fasting and in the intestine ketone bodies are also important in regulating intestinal stem cell (ISC) homeostasis and regeneration. Using combined single-cell and spatial transcriptomics, organoids and prospective longitudinal mucosal analysis, we demonstrated a profound loss of ISC HMGCS2-mediated ketogenesis with consequential detrimental effect on Ulcerative colitis (UC), a chronic inflammatory bowel disease that affects [~]4 million individuals worldwide. We show that {beta}HB restores UC ISC metabolic function, reduces cellular stress with further evidence of epigenetic programming key for restoration of ISC function. Furthermore, low colonic HMGCS2 expression is associated with treatment failure of multiple biological immune therapies in UC. Our findings reveal the crucial role for HMGCS2 and loss of ketogenesis as the tipping point for pathogenic epithelial dysfunction and importantly, a promising metabolic therapeutic target for UC.

cell biology↗

Multi-omic analysis of vaginal bacteria:host immune and metabolic interactions in adverse early pregnancy outcomes

Accurate and timely diagnosis of early pregnancy outcomes remains a clinical challenge, particularly in cases classified as pregnancy of unknown location, where ultrasound fails to confirm the location of the pregnancy. Delayed diagnosis can lead to serious complications, especially in ectopic pregnancies. This prospective cohort study aimed to characterise host-microbe interactions during early pregnancy in the vaginal mucosa by exploring the relationship between the bacterial community composition, immune response, and metabolic phenotype. We analyzed vaginal swabs from 91 women with pregnancy of unknown location, including 22 with viable intrauterine pregnancies and 69 with adverse outcomes. Metataxonomic profiling, immune assays, and direct on-swab metabolomics were performed. Adverse outcomes, especially ectopic pregnancies, were associated with reduced Lactobacillus abundance, increased bacterial diversity, mucosal inflammation, and elevated lipid species. Vaginal bleeding, a common symptom in PUL, significantly impacted immune and metabolic profiles and should be considered as a confounder in studies of the lower female reproductive tract. Multi-omic data integration highlighted metabolic phenotypes of immune response in the context of bacterial community composition, underscoring the influence of microbe-host interactions on mucosal health and pregnancy outcomes. IMPORTANCEEarly detection of complications in pregnancy is essential for improving maternal health outcomes, yet current diagnostic tools often fail to identify ectopic or failing pregnancies in a timely manner. This study highlights how changes in the vaginal microbiome, inflammation, and metabolic signals are closely linked to adverse outcomes in early pregnancy. By showing that metabolic profiling can predict microbial and immune states even in the presence of vaginal bleeding, the research provides a foundation for developing rapid, non-invasive diagnostic tools. These insights could pave the way for more personalized and effective early pregnancy care.

microbiology↗

Vibrio spp. dominate the microbiome of the endosymbiotic algae in healthy coral tissues

Coral reefs are rapidly declining due to climate change, and natural recovery mechanisms can no longer keep pace. Coral probiotics have emerged as a promising restoration tool, yet their broad application is limited by our incomplete understanding of long-term microbial associations crucial to coral health. Microbes closely associated with the coral algal symbionts (Symbiodiniaceae) are particularly promising candidates, given their potential to enhance algal function and host resilience. Although recent studies have begun to characterize these Symbiodiniaceae-associated microbial communities, methodological differences in algal cell purification have led to inconsistent results. Here, we compared multiple sample processing steps to generate Symbiodiniaceae-enriched fractions from clonal fragments of Acropora nobilis, and examined the resulting microbial communities. We consistently detected members of Flavobacteraceae, Rhodobacteraceae, Rhizobiaceae, and the genus Marinobacter. Strikingly, Vibrio species dominated the Symbiodiniaceae fractions across protocols. We isolated and sequenced 11 Vibrio strains enriched in these fractions and identified genes related to both virulence and putative beneficial traits, including vitamin biosynthesis and antioxidant production. Despite confirming their high potential for virulence, the persistent association, spatial proximity to Symbiodiniaceae, and presence of genes suggesting beneficial functions point to possible mutualistic roles for these Vibrio strains within the coral holobiont. This work highlights the value of fraction-based sampling for resolving microbiome structure, and emphasizes the need to reassess the ecological roles of key microbial taxa. By advancing our understanding of Symbiodiniaceae-bacteria interactions, this work provides a foundation for exploring microbial contributions to coral health and resilience.

microbiology↗

Arf GTPases Define BST-2-Independent Pathways for HIV-1 Assembly and Release

ADP-ribosylation factor (Arf) proteins are small GTPases that regulate intracellular membrane trafficking and actin cytoskeleton remodeling through cycles of GTP binding and hydrolysis. Arf1, a central regulator of Golgi and endosomal trafficking, and Arf6, which controls plasma membranes and endosomal dynamics, have both been implicated in late stages of the HIV-1 life cycle. However, the precise mechanisms by which these GTPases support HIV-1 assembly and release remain incompletely understood. Here, we provide direct evidence that Arf1 and Arf6 are required for efficient trafficking of the HIV-1 Gag polyprotein, assembly, and virion release. Perturbation of Arf1 function with either a GTP-locked (Q71L) or GDP-locked (T31N) mutant significantly reduced virus release, impaired Gag association with membrane compartments, and blocked Gag targeting to the plasma membrane. Manipulation of Arf1 activity via the GTPase-activating protein AGAP1 further demonstrated that dynamic cycling of Arf1 between GTP- and GDP-bound states is essential for productive Gag trafficking. Similarly, expression of a constitutively active Arf6 mutant (Q67L) misdirected Gag to intracellular membranes and markedly decreased virion production. Importantly, disruption of Arf1 or Arf6 function did not affect the total expression, surface levels, or intracellular distribution of the host restriction factor BST-2. Together, these findings establish that Arf1- and Arf6-mediated trafficking pathways are critical host determinants of HIV-1 assembly and release, functioning independently of BST-2 antagonism. IMPORTANCEThe small GTPases Arf1 and Arf6 control fundamental processes in membrane trafficking and cytoskeletal dynamics, yet their roles in HIV-1 replication are not well defined. We show that both proteins are required for efficient trafficking of HIV-1 Gag polyprotein to the plasma membrane and for subsequent virus release. Disrupting either GTPase reroutes Gag to intracellular membranes and reduces virion production, independently of the antiviral host factor BST-2. These results identify Arf1- and Arf6-dependent trafficking as critical host pathways for HIV-1 assembly and egress, expanding our understanding of the cellular machinery hijacked by retroviruses to support infections.

microbiology↗

Live and let die: lysis time variability and resource limitation shape lytic bacteriophage fitness

Bacteriophages (phages) play a critical role in controlling bacterial populations, both in nature and as potential therapeutic agents. Their ability to replicate, compete against each other, and eradicate target cell populations is usually understood through a number of life history parameters, traditionally measured by population-level assays, which implicitly average the parameters value across a large number of infection events. Recent experiments suggest that bacteriophage life history parameters are subject to considerable heterogeneity, raising the question of whether experimental and modelling efforts that do not account for this variability may overlook important factors in phages behaviour, competitive fitness or therapeutic viability. Here, using agent-based simulations, we investigate the importance of stochasticity in lysis time and burst size of lytic bacteriophages in two common laboratory competition experiments: serial passage of well-mixed populations and plaque expansion across a bacterial lawn. We find that a phages analytic growth rate in isolation can be a poor predictor of its fitness advantage in simulated competition experiments. Specifically, when lysis times are tightly distributed, we identify a novel effect we name "population resonance", through which a bacteriophage can display a significant fitness advantage over a competitor with a much greater growth rate in isolation. Our simulations also show that both serial passage and plaque expansion reward variability in lysis time more than expected, by increasing the phage resilience when resources are scarce. Author SummaryBacteriophages (viruses that infect bacteria) can be described by a set of attributes called life history parameters. Historically, these parameters could only be measured on-average over large populations. Recent experimental advancements, however, have enabled their quantification at the single-cell-single-virus level, and have revealed that these traits are subject to inherent variability, even for genetically identical viruses infecting genetically identical cells. Here, we explore whether the degree of variability in one particular life history parameter, the lysis time (the time taken for a bacteriophage to infect and kill its host bacteria) might be subject to natural selection, by quantifying its effects on phages fitness in two simulated competition experiments: serial passage and plaque expansion. Surprisingly, we find that lysis time variability is advantageous in competition even when it reduces the phages growth rate in isolation. This finding opens the door to future computational and experimental work, as it demonstrates that mean values alone are not sufficient to describe or predict a bacteriophage efficacy, and that models that ignore this variability can overlook viable evolutionary strategies.

evolutionary biology↗

IL-33 promotes transcriptional and metabolic adaptations of tissue-resident Th2 cells

The polarization of naive CD4+ T cells into Th2 cells is initiated in lymphoid organs and completed as the cells become tissue resident, where they express ST2, the receptor for the alarmin IL-33, which may be a key signal for tissue integration. Cellular metabolic requirements associated with this transition remain poorly understood. To address this, we compared the response of lymphoid tissue (LT) Th2 cells from helminth parasite-infected mice to stimulation by IL-33 versus through the T cell receptor via anti-CD3/CD28. We found that IL-33, but not anti-CD3/CD28, induced the development of tissue-resident like Th2 cells expressing ST2. This was associated with IL-33 induced changes in arginine metabolism linked to mTORC1 activation and polyamine synthesis, which were required for the development of tissue-resident like Th2 cells. Futhermore, IL-33 induced transcriptional changes in genes involved in chemotaxis and cell adhesion that may be critical for tissue integration. Our findings provide insights into adaptations of Th2 cells responding to tissue-integration cues. SummaryIL-33 promotes development of tissue-resident-like Th2 cells in vitro from lymphoid tissue Th2 cells. This requires arginine-dependent mTORC1 activation and polyamine synthesis, and is marked by transcription of genes associated with chemotaxis and cell adhesion linked to tissue integration.

immunology↗

Tryptophan and IFN-γ Differentially Modulate Cellular Uptake, Intracellular Trafficking, and Gene Expression of Messenger RNA-Loaded Lipid Nanoparticles in Dendritic Cells

Lipid nanoparticle (LNP)-mediated mRNA delivery has emerged as a powerful platform for both immunostimulatory and immunomodulatory applications. However, the influence of local immunometabolic cues on the intracellular fate and translational efficiency of mRNA-LNPs remains poorly understood. In this study, we investigated how interferon-gamma (IFN-{gamma}), a potent inducer of indoleamine 2,3-dioxygenase 1 (IDO1), and tryptophan (Trp) deprivation independently and combinatorially affect mRNA-LNP function in DC2.4 dendritic cells. These two cues are canonical drivers of immunoregulatory microenvironments, particularly those that favor tolerogenic dendritic cell programming and the induction of regulatory T cells. Using dual-reporter mRNA constructs and high-resolution confocal imaging, we show that IFN-{gamma} stimulation reduces total cellular mRNA uptake and lysosomal accumulation without affecting translation efficiency and endosomal escape efficiency. Whereas Trp deprivation also reduces the overall cellular uptake of mRNA-LNPs, it also significantly impairs protein synthesis from mRNA-LNPs and modestly reduces endosomal escape, despite having minimal impact on lysosomal mRNA levels. Spatial compartmentalization analysis revealed that IFN-{gamma} and Trp limitation disrupt distinct steps in the delivery-translation cascade, acting independently but additively to suppress the ultimate protein translation from mRNA-LNPs in DC2.4 dendritic cells. These findings highlight the importance of considering local metabolic and cytokine contexts when deploying mRNA-LNPs for immunological applications. Our work provides mechanistic insights into how immunoregulatory environments impair the delivery and translation of mRNA-LNPs, suggesting strategies to tune delivery outcomes for tolerogenic purposes.

biochemistry↗

BST-2 inhibits SARS-CoV-2 egress at intracellular membranes and is neutralized by ORF7a

Bone marrow stromal antigen 2 (BST-2, or tetherin) is an interferon-inducible host restriction factor that inhibits the release of enveloped viruses by tethering nascent virions to cellular membranes. While its antiviral function is well established in retroviral systems, its role in SARS-CoV-2 egress remains unclear. Here, we used a virus-like particle (VLP) system composed of SARS-CoV-2 structural proteins M, E, and N to investigate the impact of BST-2 on viral particle release. BST-2 significantly inhibited VLP release in HEK293T and Calu-3 lung epithelial cells. Confocal microscopy revealed that BST-2 colocalizes with viral structural proteins at the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), the main site of coronavirus assembly. We next evaluated the roles of the SARS-CoV-2 accessory proteins ORF3a and ORF7a in overcoming this restriction. ORF3a localized to endolysosomal compartments and promoted VLP release through a BST-2-independent mechanism, without altering BST-2 expression or localization. In contrast, ORF7a colocalized with both BST-2 and ERGIC markers and restored VLP release by promoting BST-2 degradation. Notably, ORF7a also relieved BST-2-mediated restriction of HIV-1 VLP release, suggesting a conserved antagonistic function. These findings identify BST-2 as an intracellular inhibitor of SARS-CoV-2 particle release and establish ORF7a as viral accessory antagonist that neutralizes this host defense.

microbiology↗

Temperature and predation alter metabolic scaling without changing size-based structure community in freshwater macroinvertebrates

Body size is a key trait that influences ecological processes such as metabolism, abundance, and species interactions. While the metabolic theory of ecology (MTE) proposes a universal scaling of metabolic rate with body mass, recent evidence shows that this relationship is not fixed. Environmental factors like temperature and predation can alter the metabolic scaling exponent, potentially reshaping size distribution. However, most research has examined these patterns within individual species, leaving open questions about how environmental drivers affect scaling at the community level. To address this, we performed a mesocosm experiment manipulating both temperature and fish predator presence in freshwater macroinvertebrate communities. We found that metabolic scaling at the community level is highly responsive to environmental context: warming steepened the scaling exponent in predator-free tanks but flattened it when predators were present. This suggests that larger individuals reduce their baseline metabolic rates under predation risk, especially at higher temperatures. Interestingly, the slope of the community size distribution remained stable across treatments, indicating that shifts in metabolic scaling occurred independently of changes in size structure. Together, these findings highlight the environmental sensitivity of metabolic scaling and suggest that links between metabolism scaling and size distribution may be more complex than MTE predicts.

ecology↗

Electron diffraction captures high-resolution structures from in vivo protein nanocrystals of Bacillus thurigiensis

Bacillus thuringiensis is one of the most widely used biopesticides worldwide. This is owing to the highly-specific pesticidal-proteins various strains produce in the form of nanocrystals. Structure determination from such crystals remains difficult because their small size makes them unsuitable for conventional X-ray crystallography. Here we explore two emerging (cryo-) electron diffraction techniques, namely Microcrystal electron diffraction and serial electron diffraction, as tools for studying the structures of these crystals. Using the mosquitocidal protein Cry11Aa as an example, we compare electron diffraction with state of the art results obtained with an X-ray free electron laser. Our work demonstrates that electron diffraction is a viable alternative for structure determination from such challenging crystals, matching previous results obtained with X-ray free electron lasers. We present a workflow based on readily available instrumentation enabling structure determination directly from the crystals grown in vivo, unperturbed by dissolution and therefore preserved in their native state.

biophysics↗

Soil to human health continuum: Exploring ergothioneine and mycorrhizal fungi in shaping the wheat microbiome

BackgroundThe association between plants and soil microbes is critical for both soil and plant health. Studies have shown that introducing beneficial microbial inoculants can shape the soil microbiome community for plant health. Among these microbes, mycorrhizal fungi play a well-documented role in enhancing nutrient uptake in plants. Ergothioneine (ERGO), a compound well-known for its anti-inflammatory and antioxidant properties, has been linked to increased longevity in various model systems and its significance for human health. However, neither animals nor plants contain ERGO biosynthetic pathways, which are limited to fungi, including and some species of bacteria, including Actinomyceota, Cyanobacteria, and Methylobacteria. Though the leading dietary sources of ERGO for humans are fungi in the form of mushrooms or fermented foods, biofortification of crops by promoting the production and uptake of ERGO from microbial sources in the soil has promise for enhancing nutritional quality and public health outcomes. ResultsThis study explores the of interaction between soil ERGO application and arbuscular mycorrhizal fungi (AMF) in plant-symbiotic relationships to increase the ERGO content in the staple crop wheat (Triticum aestivum). We investigate how ERGO supplementation, both alone and in combination with AMF, influences the wheat root and soil microbiome in a greenhouse experiments. Our data shows that plants can take up ERGO in absence of AMF fungi. In addition, treatment with pure ERGO and ERGO in combination with AMF altered microbial diversity and community structure in both the rhizosphere and rhizoplane regions of wheat roots. ConclusionsOverall, our work reveals that plants can readily take up ERGO from soil, both with and without AMF presence, highlighting a broader role of ERGO in connecting soil health to human health, a connection that warrants further investigation.

plant biology↗

Defining conservation units in a highly diverse species: A case on Arctic charr

Defining appropriate conservation units is crucial to the protection and management of biodiversity. These delineations deliver further benefit when they include assessments of population vulnerability to extinction from pressures such as climate change. However, delineations and vulnerability assessments are particularly difficult within highly diverse species, such as the salmonid fish Arctic charr (Salvelinus alpinus), that show extensive phenotypic and genetic variation within and across locations, variable and complex life histories, and broad geographic distributions. As yet, the nature and scope of Arctic charr diversity has not been characterised at the scale needed to delineate key conservation units in Scotland. To identify evolutionarily significant and vulnerable populations to prioritise for conservation, we conducted a genomic study of Arctic charr populations across Britain and Ireland with a focus on Scottish populations (N=64 populations; 24,878 SNPs; 410 individuals). We found that most lake populations represented distinct genetic clusters, with limited gene flow between them and resulting in substantial genetic differentiation. Higher level groupings of genetic similarity across catchments likely reflect historic anadromy and migration, with populations primarily grouping east or west of the central watershed divide in Scotland. Analysing genetic offset, also known as genomic vulnerability, we identified strong inverse correlations between genetic vulnerability with latitude and distance to the sea suggesting that more southern and more inland populations are more vulnerable to loss due to climate change. Additionally, patterns of vulnerability across several additional metrics identified further populations that may be at high vulnerability to loss. We further used our genetic data, along with phenotypic and geographic information, to identify populations of greatest evolutionary significance. This highlighted the most important ones to protect are those in locations with multiple ecotypes, a key facet of functional Arctic charr biodiversity, and populations that are the only ones in their Hydrometric Area.

genomics↗

PIN1 Drives Cellular Plasticity and Immune Modulation in Chronic Pancreatitis

Background and AimsChronic pancreatitis (CP) is characterized by inflammation, fibrosis, and acinar-to-ductal metaplasia (ADM). PIN1, known to drive oncogenic signaling and cellular plasticity in cancer, has an unexplored role in CP. This study investigates PIN1s expression and function in CP pathogenesis using human tissues and mouse models. MethodsPIN1 expression was assessed in human CP tissue microarrays (TMAs) via immunohistochemistry (IHC) and cyclic immunofluorescence (CyCIF). Acute and chronic pancreatitis were induced in wild-type (WT) and PIN1 knockout (PIN1KO) mice using caerulein. Disease progression was monitored histologically, and immune profiling was conducted using flow cytometry. Pharmacological inhibition was performed using a small molecule PIN1 inhibitor-Sulfopin, and effects were evaluated by histology, qPCR, and cytokine analysis. Single-cell RNA sequencing (scRNA-seq) was performed on pancreatic tissues to perform pathway analysis and intercellular communication. ResultsPIN1 expression was elevated in human CP tissues, correlating with disease severity and ADM. In mice, both acute and chronic pancreatitis increased PIN1 expression, but only in our chronic PIN1KO mice displayed reduced pancreatic injury, fibrosis, ADM, and modulated immune infiltration. Pharmacological PIN1 inhibition mimicked the protective effects of genetic knockout, dampening inflammatory pathways. scRNA-seq revealed that PIN1 inhibition altered the intercellular communication networks between epithelial, immune, and stromal cells. ConclusionPIN1 drives cellular plasticity, immune modulation, and disease progression in CP. Targeting PIN1 may offer a therapeutic strategy to mitigate CP. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/653850v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@67f9fcorg.highwire.dtl.DTLVardef@4d4c1forg.highwire.dtl.DTLVardef@c099d7org.highwire.dtl.DTLVardef@b41aa5_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender. Shah, V. (2025) https://BioRender.com/undefined

cell biology↗

Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis

There is currently a public health crisis due to the rise of multi-drug-resistant tuberculosis cases, as well as the rise in number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of 49, a pre-clinical candidate that acted through inhibition of the Mycobacterium tuberculosis lysyl-tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimised lead. The work was guided by the first crystal structure of M. tuberculosis LysRS. The physicochemical and pharmacokinetic properties were optimised to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.

microbiology↗

Investigating Bacterial Contributions to Thermal Tolerance in Three Intertidal Marine Snail Tegula species

In this era of climate change there is an urgent need to better understand the mechanisms that allow organisms to thrive vs. fail in thermally stressful environments. In particular, there is growing evidence that the "holobiont" (host animal + microbiome community of bacteria, fungi, and archaea that live in an organism) affects how organisms respond to environmental stressors such as temperature and thus should be studied further. Rocky intertidal species such as Tegula snails are ideal organisms for these types of studies because closely related species exhibit variability in heat tolerance. Here, we assess potential microbiome bacterial contributions to thermal tolerance in Tegula eiseni, Tegula funebralis, and Tegula gallina that co-occur in southern California but occupy different intertidal heights that vary in thermal stress exposure. 16S sequencing of the V4 region of individuals of each species exposed to control or 5.5-hour heat stress conditions (maximum temperature = 34 {degrees}C) revealed distinct bacterial communities across species and temperature treatments. Moreover, unique bacteria of the microbiome were significantly enriched in each Tegula species. For example, Lutimonas, Polaribacter, and the exopolysaccharide (EPS)-producing bacteria Pelagicoccus was most abundant in T. gallina, the species that occupies the highest intertidal heights and thus experiences heat stress most frequently. These results suggest that microbiome-derived metabolites such as EPS could be contributing to the higher thermal tolerance of T. gallina. Overall, this study demonstrates that the bacterial microbiome should be considered when examining mechanisms of thermal tolerance in marine invertebrates.

microbiology↗