Biology subjects

Johnson, C.

Publications and source records attributed to Johnson, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Fine-tuning neuron number: Lzts as a key regulator of neurogenesis and cell proliferation in Ciona

How progenitor mitotic timing is coupled to the number of neurons in a nervous system remains poorly understood, in part because most model systems have large, variable progenitor pools that obscure this relationship. The non-vertebrate chordate Ciona robusta offers a tractable alternative: its larval nervous system arises from an invariant lineage, including four Bipolar Tail Neurons (BTNs) that are reproducibly generated from the caudal neural plate border. Here we investigate the developmental function of the single Ciona ortholog belonging to the leucine zipper tumor suppressor (Lzts) gene family, whose vertebrate members are implicated in cell-cycle regulation and tumor suppression. In Ciona, Lzts is expressed in several embryonic tissues, including differentiating BTNs. Tissue-specific CRISPR/Cas9 knockout of Lzts in the BTN lineage produced supernumerary BTNs, without expanding the embryonic Neurog+ domain, indicating that Lzts acts downstream of BTN specification to limit neuron number. Lzts1 promotes Cdk1 activity via stabilization of Cdc25C, co-expression of Ciona Cdc25C or a non-phosphorylatable Cdk1/2/3 mutant rescued normal BTN number in Lzts crispants, proving the existence of an ancestral Lzts-Cdc25-Cdk1 circuit controlling neural cell cycle. These findings establish Ciona Lzts as a regulator of mitotic tempo determining the BTN number and suggest that this cell-cycle regulatory axis links proliferation to neurogenesis across chordates in vivo.

developmental biology↗

bioRxiv2026

Modelling human haematopoietic stem cell commitment ex vivo identifies IL-33 as a regulator of megakaryopoiesis

Commitment events to specific blood lineages arise from single hematopoietic stem cells (HSCs) and are influenced by stress, inflammation and disease. However, the understanding of how such events are regulated in human haematopoiesis is limited by the lack of tractable in vitro models. In this study, we introduce a novel Early Progenitor Differentiation (EPD) assay to study the initial lineage commitment of human 49+ HSCs, in a system faithfully recapitulating cell states observed in vivo. Combining single cell -omics approaches and single cell functional assays, we show that IL-33 acts directly on human 49f+ HSCs activating the MAPK pathway to enhance their commitment towards Megakaryocytic-Erythroid-Mast cell Progenitors and subsequently megakaryopoiesis. This occurs without affecting HSC self-renewal via accelerated establishment of chromatin programmes associated with Erythroid and Megakaryocyte and mast cells lineages. Our findings demonstrate the utility of the EPD model to identify molecular regulators of human HSC differentiation and uncover a new role of IL-33 in haematopoiesis.

cell biology↗

bioRxiv2026

Genetic drivers of protein changes over time: Findings, considerations, and approaches in TOPMed cohorts and UK Biobank

Age is a major risk factor for many diseases, but the biological processes driving aging are heterogeneous across individuals. Efforts to untangle differences between chronological and biological age have focused on identifying age-associated markers, such as omics clocks. Many omics features, including proteins, are strongly associated with age, and genetics contribute to variance in these measures. However, few studies have identified genetic drivers of interindividual variability in omics changes over time. Using longitudinal proteomics data (Olink 3k) from the Multi-Ethnic Study of Atherosclerosis (MESA), we calculated a protein slope for each individual (n=2,007) and protein (n=2,737) across 3 visits spanning 14-18 years, then conducted a genome-wide analysis for each slope, both with and without adjusting for baseline protein level. Subsets in UK Biobank (UKB; n=948) and CARDIA (n=1,328) with longitudinal proteomics data were used for replication. We considered additional methods for modeling of protein change and variability, including linear mixed models, SNP-by-age interactions, and variance quantitative trait loci. Without baseline adjustment, only 19 proteins (20 credible sets) had a slope pQTL in MESA, with poor replication in UKB and CARDIA. With baseline adjustment, 607 proteins (698 credivle sets) had a slope pQTL and over 70% replicated in CARDIA and/or UKB; such baseline adjusted models may, however, be subject to collider bias. Longitudinal and cross-sectional interaction models identified fewer than 14 pQTLs, suggesting they were generally underpowered; but 73% of proteins with a variance pQTL also had a slope pQTL. By examining effect direction concordance, replication rate, directed acyclic graphs, and signal overlap with other models we demonstrate that many baseline-adjusted slope pQTLs may be arising due to model misspecification or regression to the mean. Overall, our results highlight considerations for modeling strategies of change phenotypes and build on understanding of potential genetic mechanisms influencing interindividual proteome changes over time.

genetics↗

bioRxiv2026

Bacterial histone-like proteins released during antibiotic treatment mediate vascular injury in meningococcal sepsis.

Vascular injury and coagulopathy are key drivers of mortality in bacterial sepsis. In Neisseria meningitidis infection, endothelial adhesion and thrombosis cause the characteristic petechial rash and, in the most severe cases, purpura fulminans. Although antibiotics rapidly kill bacteria, inflammation and vascular injury often persist or worsen after bacterial clearance, suggesting ongoing toxicity from released bacterial components. Here we identify bacterial histone-like proteins (HLPs), small positively charged DNA-binding proteins conserved across bacterial species, as previously unrecognized mediators of vascular damage. In vitro HLPs are released following antibiotic exposure, disrupting endothelial integrity. In patients with severe sepsis, they are detectable in plasma and tissue, colocalising with areas of vascular leak and coagulopathy. Non-anticoagulant heparins and anti-HLP antibodies neutralize HLP-induced endothelial disruption and toxicity in vitro and in vivo. These findings reveal HLPs as antibiotic-released bacterial toxins and suggest new therapeutic strategies to prevent vascular injury in sepsis. One sentence summaryAntibiotic treatment of meningococcal and other sepsis causative bacteria triggers the release of histone-like proteins (HLPs) that damage the endothelium and drive coagulopathy, but these effects can be neutralized by non-anticoagulant heparins or anti-HLP antibodies.

microbiology↗

bioRxiv2026

Interpretable decoding of cell fate from a snapshot of combinatorial signaling

How combinatorial cell signaling controls cellular decisions in the face of crosstalk is a fundamental problem in biology. A key open question is whether a single snapshot of signaling is sufficient to predict cell fate, especially given substantial evidence that signaling dynamics shape fate decisions. Here, we show that a snapshot of combinatorial signaling accurately predicts cell fate at the single-cell level in a model for human embryonic patterning. To this end, we developed Sig2Fate, a quantitative method integrating iterative immunofluorescence, information theory, and machine learning. Cell fate is encoded by combinatorial yet redundant signaling that reduces to a single angular coordinate in the high-dimensional signaling space, providing a simple interpretation of the signal-to-fate map. This map generalizes across variations in BMP concentration and pharmacological perturbations of ERK, Wnt, and YAP signaling, enabling prediction of drug responses from control data alone when signaling crosstalk is accounted for. Our findings provide a framework for predicting and explaining complex phenotypes from signaling perturbations across biological systems.

developmental biology↗

bioRxiv2026

High-speed 3D single-virus tracking reveals actin-aided viral trafficking of SARS-CoV-2 on the plasma membrane

Early interactions between viruses and live cells are difficult to resolve due to rapid extracellular motion, 3D nature of the cell membrane, and the fast, nanoscale interactions involved. While actin is a central regulator of viral entry, direct observations of actin-aided trafficking have been restricted to membrane protrusions on glass surfaces given the limitations of conventional methods. Here, high-speed 3D Tracking and Imaging microscopy (3D-TrIm) is integrated with highly photostable StayGold-labeled SARS-CoV-2 virus-like particles to capture long-term, high-resolution single-virus trajectories in live cells. This approach revealed distinct regimes of viral dynamics, including extracellular diffusion, protrusion-based surfing, and an unreported linear trafficking mode along the plasma membrane that precedes viral internalization. This work demonstrates that this membrane trafficking is actin-driven and positively correlated with ACE2 expression. These findings reveal new actin exploitation by viruses and demonstrate the utility of 3D-TrIm for dissecting dynamic virus-cell interactions at high spatiotemporal resolution.

biophysics↗

bioRxiv2026

Modulation of the human cathelicidin dimerization interface separates antimicrobial activity from mammalian membrane disruption

The human CAMP gene product LL-37 is a prototypical cationic host defense peptide with potent activity against gram-negative bacteria. The development of LL-37 and other membrane-active host defense peptides as antibiotics, however, is limited in part by their activity against mammalian membranes. To better understand the structural features underlying LL-37 functions, we reconceived of LL-37 as a small protein and systematically ablated the sidechain content of entire surfaces while preserving helical character. This approach revealed that selected modifications within surface m4 retain wild-type levels of activity against gram-negative bacteria while disrupting activity against mammalian membranes by >100-fold. Separation of antimicrobial and mammalian membrane activities mapped primarily to residues I24 and L28, and was attributable to a combination of disrupted oligomerization and decreased hydrophobic content within the dimerization interface. Modulation of the LL-37 dimerization interface thus constitutes a rational pathway by which to engineer derivatives with improved therapeutic potential.

biochemistry↗

bioRxiv2026

Impaired Associative Memory, Inference, and Theta Dynamics in Postictal Psychosis of Epilepsy

Postictal psychosis (PIP) is a severe complication occurring in 2% of people with epilepsy (PWE) whose underlying pathophysiology remains poorly understood. Although historically considered separate from other forms of psychosis, newer evidence demonstrates a shared genetic susceptibility. People with schizophrenia are typically impaired at both associative learning and inferring connections between overlapping associations. Successful associative encoding, retrieval, and inference can each be predicted by changes in frontotemporal theta band activity, which is impaired in rodent models and people with schizophrenia. Here, we recorded high-density scalp EEG from PWE with history of PIP and well-matched control participants while they undertook a memory inference task. We found that associative memory and inference were both impaired in the PIP group, despite no difference in item recognition. Moreover, we found disrupted theta activity during memory encoding and the retrieval of inferred associations in PWE with PIP that likely originated from the medial temporal and frontal lobes. These results suggest a pattern of behavioural deficits and altered neural dynamics common to both PIP and schizophrenia. Interpreted in conjunction with previous genetic studies, they may reflect shared neural mechanisms contributing to psychopathology in both conditions and argue that PIP is a model of more general psychoses.

neuroscience↗

bioRxiv2026

NR4A1 limits CD8⁺ T Cell effector responses and protection in tuberculosis

During Mycobacterium tuberculosis (Mtb) infection, CD8+ T cells exhibit dysfunction with impaired cytotoxicity and limited localization to granuloma cores. Using knockout mice, adoptive-transfer models and validation in macaque and human datasets, we identified the nuclear receptor NR4A1 as a key restrainer of CD8+ T cell immunity in tuberculosis (TB). Mtb-infected Nr4a1-/- mice displayed reduced bacterial burden, attenuated pathology, higher lung CD8+/CD4+ T cell ratios, and enhanced CD8+ T cell effector functions. Bulk and single-cell RNA sequencing revealed suppression of gene expression program linked with exhaustion, and expansion of Nkg7+ and Granzyme+ cytotoxic CD8+ T cell subsets in Nr4a1-/- mice. Spatial analyses demonstrated increased infiltration of Nkg7+ activated CD8+ T cells in Nr4a1-/- lesions. ChIP-qPCR showed NR4A1 binding to Nkg7 promoter, and Nkg7 knockdown abrogated the enhanced cytotoxicity of Nr4a1-/- CD8+ T cells. Pharmacologic inhibition of NR4A1 reduced Mtb burden and pathology, and restored Nkg7 expression and CD8+ T cell infiltration in the lung. Together, these findings identify NR4A1 as a negative regulator of CD8+ T cell-mediated immunity in TB and suggest the NR4A1-NKG7 axis as a novel host-directed therapeutic target. A one-sentence summary of your paperNR4A1 suppresses CD8+ T cell infiltration and cytotoxicity in TB lesions, and its inhibition enhances host resistance to Mtb infection.

immunology↗

bioRxiv2025

Tuning a Genetic Circuit with Double Negative Feedforward Loops to Approximate Square Waves

Precise temporal control of gene expression is important for programming cellular functions. Existing circuits, however, often couple amplitude and duration. This prevents independent tuning of key dynamic features. We therefore set out to design a genetic system capable of generating square-wave outputs with externally programmable geometry. To achieve this, we constructed a layered regulatory design that separates production and removal into two independently controlled modules. An activating input turns expression on and builds the reporter. A repressing input stops synthesis and removes existing protein. Together, these actions confine the active window and produce square-wave outputs or pulses on demand. Waveform geometry depends on input dose and timing. Analysis of limiting cases reveals that strong repression compresses dynamic range, and finite degradation capacity restricts decay rate. Enhancing removal capacity alleviates this bottleneck and sharpens the off-transition. Together, this work establishes a general framework for programming gene-expression dynamics with independently tunable amplitude and duration.

synthetic biology↗

bioRxiv2025

Complex Patterns of Altered White Matter Structural Connectivity within a 'subjective valuation network' in Treatment-Resistant Depression

BackgroundTreatment-resistant depression (TRD) poses a significant clinical challenge, demanding a deeper understanding of its neurobiological underpinnings to improve therapeutics. We examined white matter microstructure and structural connectivity in TRD, focusing on the subjective valuation network (SVN), which captures motivated behavior, reward processing, and emotional regulation circuits commonly altered in depression. This allowed us to identify potential neuroimaging biomarkers associated with treatment resistance. MethodsDiffusion tensor imaging (DTI) data were acquired from a sample of age-and-gender balanced individuals with TRD (n=44; female = 24, male=11, non-binary/unchecked =7) and non-depressed controls (n=42; female=27, male =12, non-binary/unchecked=5). Tract-Based Spatial Statistics were used to compare whole-brain white matter integrity differences between groups. Probabilistic tractography was then used to assess fractional anisotropy (FA) and white matter structural connectivity within the SVN across groups. SVN was defined a priori based on converging functional connectivity studies and included key regions such as the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum, and insula and their connecting white matter tracts. Additionally, correlations between clinical measures of depression severity and cognition and structural features of the networks white matter fibers (i.e. FA and structural connectivity) were explored. ResultsCompared to non-depressed controls, individuals with TRD exhibited reduced FA within the left uncinate fasciculus, left inferior fronto-occipital fasciculus, and anterior cingulum, supporting widespread white matter integrity degradations in TRD. No correlations were found between FA and depression severity, suggesting a more specific association with anhedonic features. Whole-network measures of FA and structural connectivity of the SVN did not differ between groups. However, specific subcircuits structural connectivity within the SVN differed between groups; namely, the white matter tracts connecting the insula-vmPFC, striatum-insula, and striatum-vmPFC. Hyperconnectivity emerged for patients with TRD for tracts connecting the insula-vmPFC and striatum-vmPFC region-pairs, with exhibited hypoconnectivity between the striatum-insula. Exploratory analyses for the TRD group indicated the subcircuits with altered structural connectivity within the SVN correlated with depressive severity. This indicates subcircuit network alterations may associate with greater difficulty experiencing pleasure - a core symptom of depression and a potential marker of treatment resistance. ConclusionsThis study provides evidence for wide-spread disruption of white matter microstructure and altered structural connectivity within specific subcircuits of the SVN in TRD. These findings point to an intricate pattern of structural hyper-and-hypo-connectivity within the subcircuits of the SVN which may underlie the core symptoms of TRD. The altered structural connectivity within the SVN may contribute to the pathophysiology of TRD, especially concerning the motivational and emotional deficits associated with anhedonia. Future research employing multimodal neuroimaging techniques and longitudinal designs is warranted to further elucidate the functional consequences of these structural abnormalities and their potential as predictive biomarkers for personalized treatment interventions in TRD. Specifically, investigating how these white matter alterations change with successful treatment or targeted interventions aimed at improving anhedonia could inform more effective therapies for this challenging condition.

neuroscience↗

bioRxiv2025

A live tumor fragment platform to assess immunotherapy response in core needle biopsies while addressing challenges of tumor heterogeneity

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, providing durable and even curative responses. However, most patients do not respond and current biomarkers (eg, programmed death ligand (PD-L1), mismatch repair deficiency (dMMR)/high microsatellite instability (MSI) and tumor mutational burden) lack predictive accuracy. Ex vivo profiling of patient-derived tumor fragments shows promise as a predictive biomarker but relies on substantial surgical tissue to mitigate intra-specimen heterogeneity. Innovations are needed that address these challenges, particularly where limited tissue is available in core needle biopsies (CNBs). MethodsLive tumor fragments (LTFs) were generated from 59 human tumor resections and 31 CNBs from patients enrolled in observational clinical trials (ClinicalTrials.gov identifiers: NCT05478538, NCT05520099, NCT06349642) to assess cytokine induction following ICI treatment. LTFs were encapsulated in hydrogel and cultured ex vivo for up to 72 hours. A sequential treatment strategy that applies control and treatment within the same well was used with response to ICI or CD3/CD28 assessed using a multiplex secretome assay. Viability was assessed using established metabolic assays and dynamic optical coherence microscopy. ResultsLTFs maintained viability and retained T cells responsive to stimulation throughout ex vivo culture. Multiplex immunofluorescence and immunohistochemistry showed key components of the tumor microenvironment, including relative proportions of CD4+ and CD8+ immune cell populations, were preserved. Specimens positive for PD-L1 or dMMR/MSI-high were enriched for cytokine upregulation, including T-cell response cytokines IFN{gamma} and CXCL10, after PD-1 treatment. To demonstrate clinical applicability of the sequential treatment strategy, CNBs from patients with lung, gastrointestinal or kidney cancer were profiled and differential cytokine induction in response to ICI treatment was observed. ConclusionsThe novel ex vivo platform presented is capable of detecting T-cell response to ICI treatment by using a sequential treatment strategy. This approach addresses challenges associated with cross-well heterogeneity in tissue composition and requires half as much tissue as a cross-well comparison, mitigating tissue limitations typically associated with non-surgical biopsies. Importantly, the platform is compatible with established functional assays as well as non-destructive spatial imaging, enabling researchers to characterize response to ICI longitudinally. Ongoing trials will enable clinicians to assess platform performance in predicting response to immunotherapy.

cancer biology↗

bioRxiv2025

APOE4 drives widespread changes to the hepatic proteome and alters metabolic function

Apolipoprotein E (APOE) is essential for lipid homeostasis and has been extensively studied in the central nervous system, particularly in the context of Alzheimers disease (AD). Individuals carrying an APOE4 allele have an increased risk of AD and exhibit deficits in energy metabolism, including glucose utilization and mitochondrial dysfunction. While the role of APOE in the liver is well characterized, the impact of APOE genetic variation on hepatic health and metabolism remains poorly understood. We sought to investigate this using young female and male APOE3 and APOE4 targeted replacement mice. We also used APOE isogenic induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) to examine specific effects in a human-relevant cell model. Proteomic and functional assays show that APOE4 causes extensive changes to liver mitochondrial function in a sex-specific manner in mice and alters glucose and lipid metabolism. APOE4 also impairs mitochondrial function in iHLCs and shifts metabolism towards glycolysis while modifying expression of extracellular matrix proteins. Additionally, APOE4 iHLCs display a greater reliance on fatty acids as an energy source and show increased lipid accumulation. Taken together, our findings show that APOE genetic variation causes mitochondrial dysfunction and rewires hepatic metabolism.

physiology↗

bioRxiv2025

Proteomic and metabolic profiling reveals APOE4-dependent shifts in whole brain, neuronal, and astrocytic mitochondrial function and glycolysis

Apolipoprotein E (APOE) genetic variation is the strongest genetic risk factor for late onset Alzheimers disease (LOAD). Studies on APOE genotype dependent changes have largely focused on amyloid beta (A{beta}) aggregation, disease pathology, and lipid metabolism. Recently, there has been increased interest in the relationship between metabolic function and APOE genetic variation. In this study, we examined how APOE genotype can alter metabolism in the brains of young male and female APOE3 and APOE4 targeted replacement (TR) mice. In combination with this, we also examined cell type-specific differences using induced pluripotent stem cell (iPSC) derived astrocytes and neurons. We found sex and genotype dependent changes to metabolism in the brains of young APOE TR mice. Specifically, APOE4 mice show signs of metabolic stress and compensatory mechanisms in the brain. Using proteomics and stable isotope tracing metabolomics, we found that APOE4 iAstrocytes and iNeurons exhibit signs of inflammation, mitochondrial dysfunction, altered TCA cycle and malate-aspartate shuttle activity, and a metabolic shift toward glycolysis. Taken together, this data indicates APOE4 causes early changes to metabolism within the central nervous system. While this study establishes a relationship between APOE genotype and alterations in bioenergetics, additional studies are needed to investigate underlying mechanisms.

neuroscience↗

bioRxiv2025

Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis

Pancreatic cancer patients have the highest rates and most severe forms of cancer cachexia, yet cachexia etiologies remain largely elusive, leading to a lack of effective intervening therapies. Parathyroid hormone-related protein (PTHrP) has been clinically implicated as a putative regulator of cachexia, with serum PTHrP levels correlating with increased weight loss in PDAC patients. Here we show that cachectic PDAC patients have high expression of tumor PTHrP and use a genetically engineered mouse model to functionally demonstrate that loss of PTHrP blocks cachectic wasting, dramatically extending overall survival. The re-expression of PTHrP in lowly cachectic models is sufficient to induce wasting and reduce survival in mice, which is reversed by the conditional deletion of the PTHrP receptor, Pth1r, in adipocytes. Mechanistically, tumor-derived PTHrP suppresses de novo lipogenesis in adipocytes, leading to a molecular rewiring of adipose depots to promote wasting in the cachectic state. Finally, the pharmacological disruption of the PTHrP-PTH1R signaling axis abrogates wasting, highlighting that a targeted disruption of tumor-adipose crosstalk is an effective means to limit cachexia. STATEMENT OF SIGNIFICANCEPancreatic ductal adenocarcinoma (PDAC) is the prototypical cancer type associated with cancer cachexia, a debilitating wasting syndrome marked by adipose tissue loss and muscle atrophy. Herein, we establish that PTHrP is a tumor-derived factor that facilitates cachexia by downregulating de novo lipogenesis in adipocytes and that blocking PTHrP is an effective means to limit wasting in preclinical mouse models.

cancer biology↗

bioRxiv2025

Mechanisms of 10-Hydroxyoctadecanoic acid resistance in Streptococcus pneumoniae

Profiles of human nasal colonization consistently demonstrate that Staphylococcus aureus and Streptococcus pneumoniae can co-exist in the nasopharynx. Several studies have demonstrated the antagonist relationship between the two organisms via several molecular mechanisms including competition for nutrients as well as via direct killing by hydrogen peroxide. During nasal colonization, the pneumococcus is in direct contact with the fatty acid h18:0, which is released into the extracellular environment by S. aureus. We report that h18:0 is specifically toxic to the pneumococcus amongst the pathogenic streptococci, providing a unique mechanism for interspecies competition during colonization. Exposure of cells to h18:0 revealed that S. pneumoniae could rapidly adapt to and overcome the observed toxicity. Whole genome analysis revealed the mechanism underlying this resistance being linked to a truncation of a glycosyltransferase in the capsule biosynthesis locus and a genomic inversion in the phase variation locus, leading to altered cell surface charge and membrane lipid composition. These physiological differences in the resistant isolates may aid in repelling toxic, charged fatty acids such as h18:0 from the cell membrane. IMPORTANCEThe pneumococcus and S. aureus are two of the most well-characterized residents of the human nasopharynx; yet much remains unknown regarding how the two bacteria interact. Here, we describe the potential of S. aureus-produced h18:0, whose function and biological impact are still being described, to act as an inter-species competition molecule against S. pneumoniae, and how the pneumococcus can adapt to overcome its toxicity.

microbiology↗

bioRxiv2025

Climate Change, Fisheries Management, and Increases in Demersal Fish Distribution in a Southern Ocean Biodiversity Hotspot

The worlds oceans and their biodiversity are undergoing going change driven by climate change and anthropogenic impacts such as fishing. The Kerguelen Plateau is a biodiversity hotspot with many endemic fish species, furthermore the region has economic importance in supporting valuable fisheries. This region is also a climate change hotspot with known notable changes in the location of the polar front, ocean currents, and primary productivity. In this study we use data from long-term scientific trawl surveys and contemporary joint species distribution models to understand how the demersal fish assemblage of the Kerguelen Plateau has changed through time and space. The modelling indicates that most demersal species have had notable changes in their occurrence and CPUE from 2003 to 2016. This included a significant increase in species richness throughout the study period. The modelling also provides novel insights into the depth, climatic and environmental preferences for all species, including many species that were previously data limited. It is unclear whether these changes reflect shifts in the fishery, management, or the effects of climate change, but most likely a combination of all. We also found evidence of several species distributions responding to temperature variability, with species being exposed to the ongoing impacts of climate change. This new information can be used by managers and policy makers to ensure continuation of sustainable fisheries and the protection of biodiversity into the future.

ecology↗

bioRxiv2025

Separability of antibacterial and membranolytic activity in the human host defense peptide LL-37

The human CAMP gene product LL-37 is thought to exert direct antimicrobial activity against gram-negative bacteria via membrane disruption. In the course of structure-activity relationship studies of LL-37 aimed at developing peptidomimetic antibiotics, however, we incidentally noted mutations in LL-37 that globally inhibit membrane disruption in both mammalian and gram-negative bacterial cells. Despite their diminished capacity for membranolysis, these variants retained full antibacterial activity against gram-negative bacteria. While testing LL-37 and derivatives thereof against clinical isolates of Pseudomonas aeruginosa from patients with cystic fibrosis, we further noted unusually high rates of elevated minimum inhibitory concentrations for LL-37. Further evaluation of these clinical isolates revealed that they are fully permeabilized by LL-37 without being killed. Thus, we have identified variants of LL-37 that kill gram-negative bacteria without permeabilizing, and gram-negative bacteria that are permeabilized by LL-37 without being killed. This may suggest the existence of one or more mechanisms other than membrane disruption by which LL-37 can kill gram-negative bacteria, which may open up new avenues for antibiotic development based on the naturally evolved, non-membrane targets of human host defense peptides.

microbiology↗