Biology subjects

Dunn, A.

Publications and source records attributed to Dunn, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Genome-wide associations of host susceptibility to helminth and blood pathogens in spatially structured rodent populations

Parasites are ubiquitous drivers of host evolution by exerting strong selective pressure on natural populations. Understanding the genetic basis of host susceptibility to infection is important to know how host-pathogen interactions shape patterns of resistance and diversity in natural populations. We conducted a genome-wide association study (GWAS) to identify host genetic variants associated with infection by helminth and blood pathogens in spatially structured populations of Bank voles (Myodes glareolus; (Schreber, 1780). We genotyped 182 individuals sampled from ten sites in central Europe using quaddRAD sequencing, retaining 30,206 high-quality single-nucleotide polymorphisms (SNPs). Associations between SNP genotypes and parasite infection status were tested using mixed models controlling for relatedness, with host body mass included as a covariate. Across parasite taxa, we identified twelve SNPs exceeding genome-wide significance with the strongest signals detected for the intestinal nematode Heligmosomum mixtum. The variants identified are all intergenic, intronic, upstream or downstream of genes, with none predicted to alter coding sequences. These genes are not classical immunity genes but some are implicated in cytokine production, PI3K/AKT signalling and p38 MAPK pathway, suggesting that selective pressure from pathogens does not only act on known immunity genes, but on broader regulatory and metabolic networks. This finding suggests that variation in gene expression may be important for the differences in host susceptibility or resistance to parasitic infections.

evolutionary biology↗

bioRxiv2026

Species-specific responses of helminths to temperature and moisture: long-term and multi-scale analyses in a free-living rodent

Parasite infections in wildlife vary across time and space due to interactions among host biology, ecological processes, and climatic variability. Under ongoing climate change, understanding how temperature, precipitation, or humidity influences parasite dynamics is important for predicting shifts in infection patterns and host-parasite interactions. Here, we examine how variation in climatic conditions is associated with helminth infections in a free-living rodent, the bank vole (Myodes glareolus), across 17 years and multiple spatial scales. Using zero-inflated generalised linear models, we quantified the effects of climatic variables on individual parasite burden. Climatic conditions (temperature and humidity or precipitation) affected helminth infections across all analysed scales, though the strength and direction of these effects differed among parasite species and between temporal and spatial scales. In the temporal dataset, parasite load was associated with seasonal variation in weather conditions, whereas in the spatial datasets, infection levels were linked to yearly average climatic variables. The differences reflect species-specific parasites life histories and transmission strategies. Our findings highlight the importance of analysing individual parasite species rather than overall parasite load or aggregated infection indices when assessing the impacts of climatic variation on host-parasite dynamics.

ecology↗

bioRxiv2026

Generative design of intrinsically disordered protein regions with IDiom

Intrinsically disordered protein regions are ubiquitous across all kingdoms of life. These structurally heterogeneous regions play central roles in cellular processes such as transcriptional regulation, cellular signaling, and subcellular organization, yet they have remained largely inaccessible to rational design. Structure-based generative methods are not applicable to proteins that lack a stable fold, and existing sequence-based approaches for disordered regions rely on sampling methods that do not capture the evolutionary statistics of natural disordered regions. Here, we introduce IDiom, an autoregressive protein language model trained on 37 million intrinsically disordered region sequences curated from the AlphaFold Database. Trained using a fill-in-the-middle data augmentation, IDiom generates disordered region sequences conditioned on their surrounding structured context, as well as fully disordered proteins without any context. The model generates diverse sequences that recapitulate biologically relevant sequence features of natural disordered regions, and we demonstrate that post-training via reinforcement learning with a subcellular localization reward model produces sequences with features which are consistent with known sequence determinants of compartment-specific localization. These results establish IDiom as a general platform for the generative design of intrinsically disordered proteins and regions.

bioinformatics↗

bioRxiv2026

Non-invasive genomic sampling uncovers novel connectivities and origins of confiscated gorillas

BackgroundGorillas are a group of African great apes with two species and four subspecies that are currently critically endangered or endangered. Previous studies that analysed the genetics of wild gorillas from non-invasive samples, such as faeces or hair, analysed short mitochondrial or nuclear markers, which may not reflect the wider nuclear genome. Recent technical advances in target capture hybridisation, enrich the endogenous DNA content of non-invasive samples, allowing contiguous genomic regions to be sequenced. ResultsHere, we generated georeferenced genetic data from faecal and hair samples of 280 wild gorillas, sampled from three of the four gorilla subspecies, across large parts of their present-day distributions. With this expanded representation of gorilla genetic diversity in the wild, we detected three population clusters in western lowland gorillas, with the Sangha River and its affluents acting as significant barriers to gene flow. We reconstructed patterns of past population connectivity between western lowland gorillas in the north-eastern distribution range and Cross River gorillas, which may have been facilitated by a migration corridor also used by the Central and Nigeria-Cameroon chimpanzee subspecies. Finally, we predicted the geographic origins of wild-born gorillas, achieving a mean prediction error of 65 km, with a population-level resolution for mountain gorillas and some populations of western lowland gorillas. ConclusionOur work characterises fine-scale population structure in western lowland gorillas, which will be informative for future conservation strategies. This proof of concept in predicting geographic locations of wild gorillas, will be useful for future applications to geolocalise trafficked or rescued gorillas.

evolutionary biology↗

bioRxiv2025

LOSS OF ROR2 TYROSINE KINASE RECEPTOR IS ASSOCIATED WITH ENDOTHELIAL DYSFUNCTION IN PAH VIA INAPPROPRIATE INTEGRIN BETA 1 ACTIVATION

RationaleEndothelial dysfunction is a key feature of pulmonary arterial hypertension (PAH). We previously identified Wnt7a, a ligand of the Wnt planar cell polarity (PCP) pathway, as essential for pulmonary angiogenesis, with its loss linked to PAH. Given the importance of Wnt/PCP to lung endothelial function and angiogenesis, our goal is to elucidate how Wnt/PCP regulates angiogenic responses in pulmonary microvascular endothelial cells (PMVECs). ROR2, a tyrosine kinase receptor specific to Wnt/PCP, is crucial for cardiovascular development, but its role in PAH is unclear. We hypothesized that ROR2 supports endothelial homeostasis, and its loss would impair angiogenesis, contributing to PAH. MethodsEndothelial-specific ROR2 knockout (ROR2 ECKO) and wild-type (WT) mice were studied under normoxia and chronic hypoxia using echocardiography, hemodynamics, and lung morphometry. PMVECs from healthy and PAH lungs were transfected with ROR2 siRNA/constructs for functional and molecular studies. Focal adhesion (FA) activation and force generation were assessed via FRET-based methods. Bulk and single-cell transcriptomic analyses were performed on siROR2 PMVECs and ROR2 ECKO lungs. ResultsROR2 ECKO mice exhibited worsened pulmonary hypertension, right ventricular remodeling, microvascular loss, and muscularization in hypoxia. Single-cell RNA sequencing of lung endothelial cells showed dysregulation of pathways involved in barrier formation and angiogenesis. Evans blue dye extravasation confirmed reduced endothelial barrier integrity in ROR2 ECKO mice. ROR2-deficient PAH PMVECs displayed increased adhesion, permeability, and FA numbers, with reduced VE-cadherin at cell junctions. Confocal imaging revealed ROR2 localization in FAs, interacting with integrin {beta}1 (ITGB1). FRET analysis showed that ITGB1 remained in an active, adhesion-promoting state in ROR2-deficient cells. Restoring ROR2 in PAH PMVECs normalized adhesion, barrier function, and FA abundance. Transcriptomic analysis identified Rab12 as a key mediator of ROR2-ITGB1 crosstalk, with Rab12 knockdown mimicking ROR2 deficiency in PMVECs. ConclusionsROR2 regulates pulmonary angiogenesis by maintaining endothelial barrier integrity and facilitating integrin recycling. Restoring ROR2 signaling could be a potential therapeutic approach for PAH.

cell biology↗

bioRxiv2025

Single Cell Landscape of Sex-specific Drivers of Alzheimers Disease

BackgroundSex differences in Alzheimers disease (AD) have been documented for decades, and many sex-specific molecular contributors to AD have been discovered through bulk omics analysis of brain tissues. RNA sequencing (RNAseq) at single cell resolution provides an opportunity to characterize transcript associations with AD in a cell type-specific matter. Here, we investigated sex-specific gene expression associations with neuropathology and cognitive manifestation of AD (endophenotypes) leveraging a large single-nucleus transcriptomic dataset consisting of 1.64 million nuclei from dorsolateral prefrontal cortex (DLPFC) tissue of 424 unique donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP; AD Knowledge Portal syn2580853). MethodsROS/MAP single-nucleus RNAseq data (snRNA-seq) were processed through a rigorous pipeline. In total, eight major cell types from DLPFC were identified. We first performed sex-stratified and sex-interaction association analyses by fitting negative binomial mixed models in relation to {beta}-amyloid load (A{beta}), paired helical filament tau tangle density (tau), global cognitive performance at last visit, and longitudinal cognitive trajectory. We then conducted gene-set enrichment analysis to identify functional signaling pathways enriched for sex-specific associations. Lastly, we compared differential gene expression patterns and intercellular communication profiles between sexes and diagnostic groups among major cell types. For replication, sex-specific associations were examined using snRNA-seq derived from DLPFC tissue-derived of an independent set of 84 donors from The Seattle Alzheimers Disease Brain Cell Atlas (SEA-AD) study. Results68% of the ROS/MAP participants were female, and 52% were diagnosed with AD dementia. We first identified several disease-dependent or sex-dependent cell subpopulations. Then we identified 2,660 sex-specific associations involving 2,110 genes with A{beta} (51%), tau (21%), and cognitive performance (29%). 60% female-specific associations were for A{beta}, and 49% male-specific associations were with tau. The vast majority (93%) of female protective associations were from neurons, and most (76%) of female risk associations were from glial cells. Nine of the female-specific associations involving eight unique genes were replicated in the SEA-AD cohort, including ADGRV1 and OR3A3 with A{beta}; IFI27L1, LYRM1, STAP2, and TSTD2 with tau; PDYN with global cognition; and TMEM50B with longitudinal cognitive decline. All replicated associations except TMEM50B were observed in neurons. Furthermore, the preponderance of protective female-specific associations in neurons was also recapitulated in the SEA-AD cohort. Sex-specific associations were enriched for genes in the immune, inflammation, and damage-related stress response pathways, and microglia presented the most sex-specific enriched pathways. Finally, we identified six ITGB1-mediated microglia-specific incoming signals that may play a role in female-specific risk for A{beta} accumulation. ConclusionOur study highlights the transcriptome-wide, single-cell landscape of sex-specific molecular associations with AD neuropathology and cognitive decline. We delineate the full scope of sex-specific transcript associations, differential expression, signaling pathway, and cell-cell communication network changes in each major DLPFC cell type, while identifying and replicating several female-specific gene associations in neurons to help direct future mechanistic studies.

neuroscience↗

bioRxiv2023

Wide-field Intensity Fluctuation Imaging

The temporal intensity fluctuations contain important information about the light source and light-medium interaction and are typically characterized by the intensity autocorrelation function, g2({tau}). The measurement of g2({tau}) is a central topic in many optical sensing applications, ranging from stellar intensity interferometer in astrophysics, to fluorescence correlation spectroscopy in biomedical sciences and blood flow measurement with dynamic light scattering. Currently, g2({tau}) at a single point is readily accessible through high-frequency sampling of the intensity signal. However, two-dimensional widefield measurement of g2({tau}) is still limited by camera frame rates. We propose and demonstrate a 2-pulse within-exposure modulation approach to break through the camera frame rate limit and obtain the quasi g2({tau}) map in wide field with cameras of only ordinary frame rates. HighlightsO_LIThe quasi intensity autocorrelation function can be measured at almost arbitrary time lags C_LIO_LICameras of ordinary frame rates are sufficient for the measurement C_LIO_LIIllumination within the camera exposure is modulated by an acoustic optical modulator using two short pulses C_LI

bioengineering↗

bioRxiv2023

RNA Strain-Match: A tool for matching single-nucleus, single-cell, or bulk RNA-sequencing alignment data to its corresponding genotype

When next generation sequencing is performed in large batches, there are several stages at which samples can be swapped or mislabeled. It is therefore helpful, when possible, to integrate measures into analysis pipelines to confirm that samples match their assigned metadata. Here, we introduce RNA Strain-Match (GitHub: https://github.com/jon-willcox/RNA-strain-match), a quality control tool developed to match RNA data in the form of sequence alignment files (i.e. SAM or BAM files) to their corresponding genotype without the use of an RNA variant call format file. We successfully used RNA Strain-Match in tandem with assessment of markers for sex and transgene status to identify and correct sample mismatches in 50/379 samples (13%) from two distinct recombinant inbred mouse models (BXD and Collaborative Cross). We believe this tool will be beneficial to any research group working with similar data.

bioinformatics↗

bioRxiv2023

Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis

Targeting the 4{beta}7-MAdCAM-1 axis with vedolizumab (VDZ) is a front-line therapeutic paradigm in ulcerative colitis (UC). However, mechanism(s) of action (MOA) of VDZ remain relatively undefined. Here, we examined three distinct cohorts of patients with UC (n=83, n=60, and n=21), to determine the effect of VDZ on the mucosal and peripheral immune system. Transcriptomic studies with protein level validation were used to study drug MOA using conventional and transgenic murine models. We found a significant decrease in colonic and ileal naive B and T cells and circulating gut-homing plasmablasts ({beta}7+) in VDZ-treated patients, pointing to gut-associated lymphoid tissue (GALT) targeting by VDZ. Murine Peyers patches (PP) demonstrated a significant loss cellularity associated with reduction in follicular B cells, including a unique population of epithelium-associated B cells, following anti-4{beta}7 antibody (mAb) administration. Photoconvertible (KikGR) mice unequivocally demonstrated impaired cellular entry into PPs in anti-4{beta}7 mAb treated mice. In VDZ-treated, but not anti-tumor necrosis factor-treated UC patients, lymphoid aggregate size was significantly reduced in treatment responders compared to non-responders, with an independent validation cohort further confirming these data. GALT targeting represents a novel MOA of 4{beta}7-targeted therapies, with major implications for this therapeutic paradigm in UC, and for the development of new therapeutic strategies.

immunology↗

bioRxiv2022

Anti-integrin αvβ6 autoantibodies are a novel predictive biomarker in ulcerative colitis

Background and AimsBetter biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin v{beta}6 autoantibodies (anti-v{beta}6) have been described in UC patients. Here, we tested for the presence of anti-v{beta}6 antibodies in the pre-clinical phase of UC and studied their association with disease-related outcomes after diagnosis. MethodsAnti-v{beta}6 were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense pre-clinical cohort (PREDICTS). In a distinct, external validation cohort (GEM), we tested 12 pre-UC subjects and 49 matched controls. Further, anti-v{beta}6 were measured in 2 incident UC cohorts (COMPASS n=55 and OSCCAR n=104) and associations between anti-v{beta}6 and UC-related outcomes were defined using Cox proportional-hazards model. ResultsAnti-v{beta}6 were significantly higher among individuals who developed UC compared to controls up to 10 years before diagnosis in PREDICTS. The anti-v{beta}6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Anti-v{beta}6 predicted UC development with an AUC of at least 0.8 up to 10 years before diagnosis. The presence of anti-v{beta}6 in pre-clinical UC samples was validated in the GEM cohort. Finally, high anti-v{beta}6 was associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in recently diagnosed UC. ConclusionAnti-integrin v{beta}6 auto-antibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

immunology↗

bioRxiv2022

Interpreting ICT: from Blood Flow to Vascular Network

The inverse correlation time (ICT) is a key quantity in laser speckle contrast imaging (LSCI) measurements. Traditionally, ICT is regarded as a metric of blood flow, such as speed or perfusion. However, we highlight that ICT not only contains important information about blood flow, but also reflects the underlying structure of the vascular network. In the past, ICT has been found to be correlated with vessel diameter. Here, we further report that ICT exhibits a different sensitivity to blood flow depending on vessel orientation. Specifically, ICT is more sensitive to blood flow speed changes in vessels descending from or arising to the tissue surface, compared with those laying parallel to the surface. Those findings shift our understanding of ICT from purely blood flow to a combination of blood flow and vascular network structure. We also develop theories to facilitate the study of vascular networks impact on ICT.

bioengineering↗

bioRxiv2021

Improved immunoassay sensitivity and specificity using single-molecule colocalization

Enzyme-linked immunosorbent assays (ELISAs) are a cornerstone of modern molecular detection, but the technique still suffers some notable challenges. One of the biggest problems is discriminating true signal generated by target molecules versus non-specific background arising from the interaction of detection antibodies with the assay substrate or interferents in the sample matrix. Single-Molecule Colocalization Assay (SiMCA) overcomes this problem by employing total internal reflection fluorescence (TIRF) microscopy to quantify target proteins based on the colocalization of fluorescent signal from orthogonally labeled capture and detection antibodies. By specifically counting colocalized fluorescent signals, we can essentially eliminate the confounding effects of background produced by non-specific binding of detection antibodies. We further employed a normalization strategy to account for the heterogeneous distribution of the capture antibodies, greatly improving the reproducibility of our measurements. In a series of experiments with TNF-, we show that SiMCA can achieve a three-fold lower limit of detection compared to conventional single-color assays using the same antibodies and exhibits consistent performance for assays performed in complex specimens such as chicken serum and human blood. Our results help define the pernicious effects of non-specific background in immunoassays and demonstrate the diagnostic gains that can be achieved by eliminating those effects.

biophysics↗

bioRxiv2021

Allelic variation in Class I HLA determines pre-existing memory responses to SARS-CoV-2 that shape the CD8+ T cell repertoire upon viral exposure

Effective presentation of antigens by HLA class I molecules to CD8+ T cells is required for viral elimination and generation of long-term immunological memory. In this study, we applied a single-cell, multi-omic technology to generate the first unified ex vivo characterization of the CD8+ T cell response to SARS-CoV-2 across 4 major HLA class I alleles. We found that HLA genotype conditions key features of epitope specificity, TCR /{beta} sequence diversity, and the utilization of pre-existing SARS-CoV-2 reactive memory T cell pools. Single-cell transcriptomics revealed functionally diverse T cell phenotypes of SARS-CoV-2-reactive T cells, associated with both disease stage and epitope specificity. Our results show that HLA variations influence pre-existing immunity to SARS-CoV-2 and shape the immune repertoire upon subsequent viral exposure. One-Sentence SummaryWe perform a unified, multi-omic characterization of the CD8+ T cell response to SARS-CoV-2, revealing pre-existing immunity conditioned by HLA genotype.

immunology↗

bioRxiv2020

Segmentation-less, automated vascular vectorization robustly extracts neurovascular network statistics from in vivo two-photon images

Recent advances in two-photon microscopy (2PM) have allowed large scale imaging and analysis of blood vessel networks in living mice. However, extracting a network graph and vector representations for vessels remain bottlenecks in many applications. Vascular vectorization is algorithmically difficult because blood vessels have many shapes and sizes, the samples are often unevenly illuminated, and large image volumes are required to achieve good statistical power. State-of-the-art, three-dimensional, vascular vectorization approaches often require a segmented (binary) image, relying on manual or supervised-machine annotation. Therefore, voxel-by-voxel image segmentation is biased by the human annotator or trainer. Furthermore, segmented images oftentimes require remedial morphological filtering before skeletonization or vectorization. To address these limitations, we present a vectorization method to extract vascular objects directly from unsegmented images without the need for machine learning or training. The Segmentation-Less, Automated, Vascular Vectorization (SLAVV) source code in MATLAB is openly available on GitHub. This novel method uses simple models of vascular anatomy, efficient linear filtering, and low-complexity vector extraction algorithms to remove the image segmentation requirement, replacing it with manual or automated vector classification. SLAVV is demonstrated on three in vivo 2PM image volumes of microvascular networks (capillaries, arterioles and venules) in the mouse cortex. Vectorization performance is proven robust to the choice of plasma- or endothelial-labeled contrast, and processing costs are shown to scale with input image volume. Fully-automated SLAVV performance is evaluated on simulated 2PM images of varying quality all based on the large (1.4x0.9x0.6 mm3 and 1.6x108 voxel) input image. Vascular statistics of interest (e.g. volume fraction, surface area density) calculated from automatically vectorized images show greater robustness to image quality than those calculated from intensity-thresholded images. Author summarySamuel Mihelic is a PhD candidate in the Biomedical Engineering Department at the University of Texas at Austin. He graduated from Oregon State University (Chemical Engineering BS, Mathematics BS). He hosts the GitHub repository for the code used in this article: https://github.com/UTFOIL/Vectorization-Public. His research interests are in-vivo neural microvascular image analysis, anatomy, and plasticity. William Sikora graduated with a BS in Computational Biomedical Engineering from The University of Texas at Austin in May 2020. He is working with Dr. Yuan Yang and the Laureate Institute for Brain Research as a PhD student of Biomedical Engineering at the University of Oklahoma in Tulsa, researching the highly non-linear world of neural coupling and its link to common neurological pathologies such as stroke. Ahmed Hassan is a graduate of the University of California, Los Angeles and the University of Texas at Austin with a Bachelor's degree in Microbiology, Immunology, and Molecular Genetics and an MSE/PhD in Biomedical Engineering. His graduate research was concentrated in imaging and instrumentation, and his interests include developing optical and laser systems for neuroimaging, image processing and reconstruction, and advanced image analysis. Michael Williamson earned a BSc (Honours) in Neuroscience in 2016 from the University of Alberta, where he trained with Dr. Fred Colbourne. He is currently a doctoral student at the University of Texas at Austin working in the labs of Drs. Theresa Jones and Michael Drew. Theresa Jones is a Professor in the Department of Psychology and Neuroscience at The University of Texas at Austin. Her laboratory studies plasticity of neural structure and synaptic connectivity following brain damage and injury. Andrew K. Dunn is the Donald J. Douglass Centennial Professor of Engineering in the Department of Biomedical Engineering at The University of Texas at Austin and the Director of the Center for Emerging Imaging Technologies. His research focuses on the development of innovative optical imaging techniques for studying the brain.

bioengineering↗

bioRxiv2020

Peripheral electrical stimulation augments cerebral collateral circulation if performed within a critical time window.

Ischemic stroke is one of the leading causes of death and disability in the world. Recent advances in acute stroke care have dramatically improved clinicians abilities to reperfuse occluded blood vessels. With these advances, the importance of adjunctive therapies to supplement or complement reperfusion therapy is receiving greater interest. Cerebral collateral circulation is one of such area that is now gaining greater interest in acute stroke care. In this study, we investigate the use of peripheral electrical stimulation to induce functional hyperemia in a mouse animal model in the setting of acute stroke. Using a laser speckle contrast imaging system, we evaluated the use of peripheral electrical stimulation at 1 hour and 3 hours after stroke induction. Results demonstrated that stimulation initiated 1 hour following stroke significantly increase collateral cerebral blood flow, while stimulation at 3 hours after stroke had no appreciable effect. These results suggest that augmentation cerebral collateral circulation may be possible in the setting of acute stroke although there may be a critical time window in which this would have to be initiated.

neuroscience↗

bioRxiv2020

Biomimetic sponges improve muscle structure and function following volumetric muscle loss

Skeletal muscle is inept in regenerating after traumatic injuries such as volumetric muscle loss (VML) due to significant loss of basal lamina and the resident satellite cells. Currently, there are no approved therapies for the treatment of muscle tissue following trauma. In this study, biomimetic sponges composed of gelatin, collagen, laminin-111, and FK-506 were used for the treatment of VML in a rodent model. We observed that biomimetic sponge treatment improved muscle structure and function while modulating inflammation and limiting the extent of fibrotic tissue deposition. Specifically, sponge treatment increased the total number of myofibers, type 2B fiber cross-sectional area, myosin: collagen ratio, myofibers with central nuclei, and peak isometric torque compared to untreated VML injured muscles. As an acellular scaffold, biomimetic sponges provide a promising "off-the-shelf" clinical therapy for VML.

bioengineering↗

bioRxiv2020

Transmembrane Stem Cell Factor Protein Therapeutics EnhanceRevascularization in Ischemia without Mast Cell Activation

Stem cell factor (SCF) is a cytokine that regulates hematopoiesis and other biological processes. While clinical treatments using SCF would be highly beneficial, these have been limited by toxicity related to mast cell activation. Transmembrane SCF (tmSCF) has differential activity from soluble SCF and has not been explored as a therapeutic agent. We created novel therapeutics using tmSCF embedded in proteoliposomes or lipid nanodiscs. Mouse models of anaphylaxis and ischemia revealed the tmSCF-based therapies did not activate mast cells and improved the revascularization in the ischemic hind limb. Proteoliposomal tmSCF preferentially acted on endothelial cells to induce angiogenesis while tmSCF nanodiscs had greater activity in inducing stem cell mobilization and recruitment to the site of injury. The type of lipid nanocarrier used altered the relative cellular uptake pathways and signaling in a cell type dependent manner. Overall, we found that tmSCF-based therapies can provide therapeutic benefits without off target effects.

bioengineering↗

bioRxiv2020

Cytoskeletal tension forces mitohormesis

Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of ageing. However, the physical characteristics of the extracellular matrix are also altered in cancer and in aging tissues. We demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via SLC9A1-dependent ion exchange and HSF1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/979583v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1ecdaceorg.highwire.dtl.DTLVardef@1112c32org.highwire.dtl.DTLVardef@6c99a1org.highwire.dtl.DTLVardef@1da1e5f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗