Biology subjects

Mathur, A.

Publications and source records attributed to Mathur, A..

At least 19 recordsLinked to original sources

bioRxiv2026

A Novel Biofilm Amyloid Ligand for Caspase-11 Drives Hyperactivation in Dendritic Cells

Bacterial biofilms drive persistent infection and chronic inflammation, yet host sensing of biofilm-derived ligands remains poorly understood. Here we identify curli amyloid, an integral component of Enterobacteriaceae biofilms, as a novel activator of the non-canonical inflammasome in human and mouse dendritic cells (DCs). Curli both primes and activates the inflammasome, directly binding caspase-11 to engage NLRP3 and drive robust IL-1{beta} maturation without pyroptosis, establishing curli as a previously unrecognized trigger of DC hyperactivation. Mechanistically, this non-lytic signaling is marked by limited gasdermin D oligomerization without mitochondrial localization and NINJ1-dependent membrane rupture. Functionally, curli-hyperactivated DCs show enhanced migration to the draining lymph nodes in vivo, suggesting consequent augmented adaptive immunity. Finally, curli-containing biofilms also elicit IL-1{beta} secretion without cell death, identifying bacterial amyloid as a central driver of non-lytic inflammasome activation during immune recognition of biofilms.

immunology↗

bioRxiv2026

Unsupervised anomaly detection for tumor delineation in a preclinical model of glioblastoma using CEST MRI

IntroductionGlioblastoma is characterized by heterogeneous tumor characteristics and infiltrative tumor boundaries, making accurate delineation difficult with extensive manual annotations. Chemical exchange saturation transfer (CEST) is a non-invasive MRI technique used for in vivo assessment of metabolic and macromolecular information through a Z-spectrum. CEST may provide insight into metabolic changes present in early-stage disease that are not visible in routine clinical imaging, thereby improving tumor delineation. In this work, we use an unsupervised anomaly detection (UAD) strategy to learn the distribution of features present in Z-spectra of healthy tissue and capture their deviations in pathology, foregoing the need for extensive labels. The approach leverages the metabolic information provided by CEST to improve the detection and delineation of glioblastoma and inform further treatment planning. MethodsA 1D convolutional autoencoder (CAE) was implemented to reconstruct Z-spectra from individual tissue voxels. The network was trained on Z-spectra acquired at 9.4T from healthy Sprague-Dawley rats and tested on data acquired from F98 glioma-bearing rats post Gd-administration. For baseline comparisons, Isolation Forest and Local Outlier Factor, which have shown success in anomaly detection, were implemented. For the CAE, our anomaly score was determined to be the mean squared reconstruction error. To facilitate clinical translation and evaluate the robustness of our model for under sampled Z-spectra, acceleration factors of 2x and 7x were performed with two sampling schemes: uniformly skipping frequency offsets and selecting offsets based on feature importance identified by Shapley value analysis and Integrated Gradients (IG). Binarization was performed by determining an optimal anomaly threshold, followed by comparison to ground truth tumor masks. Metrics related to model performance were assessed for baseline anomaly detectors on the fully sampled dataset and for the CAE on fully and under sampled datasets. ResultsThe best baseline anomaly detector was Isolation Forest, with an ROC-AUC of 0.967 and an F1-score of 0.584. Our method, the CAE, accurately reconstructed Z-spectral features, achieving Dice scores of up to 0.72 and outperforming the baseline model with an ROC-AUC of 0.968 and F1-score of 0.642. This model performance remained robust across sampling schemes and acceleration factors, with ROC-AUCs of [~]0.96 and similar Dice scores (up to 0.7). Feature importance analysis indicated that offsets in the range of {+/-}3.0 to 5.0ppm contributed most to the anomaly score. DiscussionThis study successfully demonstrated a UAD pipeline utilizing the Z-spectrum from CEST MRI for metabolically informed tumor delineation. The framework captures biochemical deviations that may precede or extend beyond morphologic abnormalities, enabling sensitive detection of tumor regions and intra-tumoral heterogeneity that previous methods may fail to capture. The offsets from the feature analysis indicated a strong contribution from the magnetization transfer (MT) pool to the spectral deviations captured by the model, with additional contributions from relayed nuclear Overhauser effect (rNOE) and amide proton transfer (APT). Model robustness with under sampling further highlights the pipelines potential in accelerated acquisitions, thus improving clinical practicality. While there is a need for validation on larger cohorts and clinical datasets, the current results demonstrate that this label-free, Z-spectral anomaly mapping can serve as an interpretable and scalable tool for monitoring tumor heterogeneity and progression, with potential applicability to other diffuse or metabolically subtle pathologies.

cancer biology↗

bioRxiv2025

Human hepatic stellate cells orchestrate the accumulation and function of CD103+ tissue-resident CD8+ T-cells in liver fibrosis

Tissue-resident memory cells (TRM) contribute to protective and pathogenic responses in the liver, yet precisely how hepatic TRM adapt and integrate cues from the underlying stroma and extracellular matrix (ECM) in chronic liver disease (CLD) has yet to be fully defined. Here we describe a role for activated myofibroblast-like hepatic stellate cells (HSCs) in the accumulation and in situ localisation of CD8+ TRM in the CLD liver. Activated HSCs drive a program of tissue residence in activated, tissue-infiltrating CD8+ T-cells in a TGF{beta}-dependent manner. We show upregulation of CD103, ECM-binding integrins and adhesion molecules driven by TGF{beta} which together contribute to the sequestration of TRM within the ECM-rich fibrotic niche. Ex vivo, hepatic CD103+ TRM correlate with the extent of ECM deposited, express an altered repertoire of co-stimulatory and co-inhibitory receptors, transcriptional regulators of cellular exhaustion and produce less proinflammatory mediators upon TCR engagement in CLD than in health. Through expression of several co-inhibitory ligands, we further demonstrate the potential for activated HSCs to acquire an immunomodulatory phenotype and limit the capacity of CD103+ TRM to produce anti-viral and anti-tumour mediators upon antigen encounter. Finally, we demonstrate that strategies to block such regulatory pathways, including the PD1:PD-L1/PD-L2 axis, have the potential to restore the antigen-specific effector function of tissue-compartmentalised CD103+ TRM and thus contribute to improving the effectiveness of local immunosurveillance in CLD. One Sentence Summary: Activated hepatic stellate cells characteristic of liver fibrosis orchestrate an accumulation of a CD103+ TRM population with a reduced capacity for antigen-specific effector function in human CLD.

immunology↗

bioRxiv2025

Torque-based immune cell chemotaxis in complex environments

Directed migration in chemical gradients is crucial to the immune response, yet how immune cells navigate complex tissues remains incompletely understood. Using in vitro migration assays and theoretical modeling, we uncover distinct chemotactic strategies in two key immune cell types: neutrophils and dendritic cells (DCs). DCs actively steer toward chemokine gradients via a deterministic torque-like reorientation, while neutrophils bias movement by modulating angular noise and speed. A quantitative Fokker-Planck framework decomposes these behaviors into deterministic and stochastic components. Cytoskeletal perturbations show that microtubules enable torque-based navigation in DCs in collagen gels, whereas actomyosin contractility is required for noise modulation employed by neutrophils and DCs in 2D confined migration assays. Despite both achieving directed migration, the two strategies result in opposing macroscopic outcomes: torque-driven cells minimize dispersion, while noise-biased migration enhances population spread. These results reveal distinct navigation aligned with immune function and demonstrate that immune cell chemotaxis is tuned by cytoskeletal architecture and environmental context.

biophysics↗

bioRxiv2025

Multimodal MR Imaging for quantification of brain lipid in mice at 9.4T

BackgroundAdvanced MR imaging techniques like steady state Nuclear Overhauser enhancement (ssNOE), transient NOE (tNOE), and myelin water fraction (MWF) provide a non-invasive way to assess the biochemical and structural integrity of brain tissue. Their sensitivity to endogenous lipids and macromolecules allows for the early detection of neuropathological changes, making them valuable tools in studying brain health and disease progression. In this study, we systematically evaluate the repeatability and sensitivity of NOEMTR, tNOE, and MWF for quantifying lipid and myelin content in the brains of wild-type (WT) mice, correlating the results with immunohistochemistry (IHC). MethodsFive 6-month-old C57BL6/J mice were imaged using 3D-NOE, and four mice underwent imaging with 2D tNOE and MWF across four repeated sessions using a 9.4T Scanner. For ssNOE imaging, CEST-weighted images at 56 frequency offsets were acquired using B1rms of 1.0 T and 3s saturation duration. For tNOE, 52 offsets were acquired with a hyperbolic secant inversion pulse (bandwidth = 400Hz, duration = 44ms) and a mixing time of 200ms. For MWF, a multi-echo spin-echo (MESE) sequence was acquired with 40 evenly spaced echoes from 5.5ms to 200ms. For both ssNOE and tNOE, B0 correction was performed using WASSR. Repeatability was quantified using intra- and inter-subject coefficients of variation (COV%). Pearson correlation was performed to see the association between imaging matrices and IHC measures, Luxol fast blue (LFB) stained sections, and myelin basic protein (MBP). ResultsAll techniques demonstrated high repeatability across the whole brain (WB) and selected regions of interest (ROIs). Whole-brain intra-subject COV% for NOEMTR ranged from 1.92% to 3.40%, with corresponding inter-subject COVs of 1.50%. tNOE exhibited improved intra-subject repeatability with COVs ranging from 0.75% to 5.57%, but a reduced inter-subject COV of 2.97%. MWF imaging showed the highest stability overall, with an intra-subject COV ranging from 0.47% to 2.03% and an inter-subject COV of 0.75%. Visually, tNOE offers superior contrast in myelin-rich areas compared to NOEMTR and MWF imaging, showing greater sensitivity to myelinated regions. tNOE strongly correlates with histological markers: r = 0.83 with MBP staining and r = 0.72 with LFB staining (both p < 0.001). MWF and NOEMTR showed correlations with MBP (r = 0.63 and r = 0.57, respectively). ConclusionNOEMTR, tNOE, and MWF imaging are reliable and repeatable methods for quantifying macromolecules in the brain. Among these, tNOE emerges as the most sensitive for detecting myelin lipids as confirmed by histological validation. These findings highlight the translational potential of tNOE for studying demyelinating disorders and neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Splenic granulopoiesis and S100A9 drive resistance to checkpoint inhibitors conferred by liver metastases

Here, we investigate why liver metastases reduce the efficacy of immune checkpoint inhibitors (CPI). The poor prognosis of patients with liver metastases is associated with a systemic increase in neutrophils. Using experimental models, we confirm that mice with liver metastases respond poorly to CPI, have elevated neutrophils and suppress the response of subcutaneous lesions to CPI. We demonstrate that liver metastases, acting partly via IL-6, boost granulopoiesis in the spleen and promote the generation of immature S100A9hi neutrophils that suppress T-cell proliferation. Human liver metastases exhibit a similar increase in S100A9hi neutrophils. Neutrophil depletion attenuates the growth of liver metastases, but not subcutaneous metastases. Moreover, genetic deletion of S100A9 enables liver metastases to be effectively treated with CPI, and prevents liver metastases from suppressing the response in subcutaneous metastases. Thus, we document how liver metastases specifically change splenic granulopoiesis leading to changes in the microenvironment of non-hepatic lesions, and how targeting a key neutrophil protein restores the efficacy of CPI.

immunology↗

bioRxiv2025

Riboflavin metabolism shapes FSP1-driven ferroptosis resistance

Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. Deficiencies in these protective systems lead to an increased propensity to phospholipid peroxidation and ferroptosis. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor acting via regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterised, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here, we conducted a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a new modulator of ferroptosis sensitivity. We demonstrate that riboflavin, unlike other vitamins that act as radical-trapping antioxidants, supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitises cancer cells to ferroptosis. Thus, we uncover a direct and actionable role for riboflavin in maintaining membrane integrity by promoting membrane tolerance to lipid peroxidation. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients and their contributions to a cells antioxidant capacity.

cell biology↗

bioRxiv2025

Engineering B cells to Express Fully Customizable Antibodies with Enhanced Fc Functions

Genome editing within the constant region of the immunoglobulin Heavy chain locus (IGH) can reprogram B cells to express Heavy chain only antibodies (HCAbs) containing custom antigen-recognition domains. HCAb-engineered cells express both surface B cell receptor (BCR) and secreted antibody isoforms and respond to antigen. By selecting alternate editing sites within IGH, we extended this approach to also allow customization of the constant (Fc) domain of the Heavy chain, producing HCAbs with enhanced effector functions or containing mutations to extend antibody half-life. We also introduced mutations to force obligate HCAb homodimers and prevent unwanted pairing with endogenous antibody chains. Finally, we showed that additional domains could be accommodated at the HCAb C-terminus and preferentially expressed in the secreted isoform. Together these data demonstrate the flexibility of the HCAb editing platform to express fully customized molecules that take advantage of the properties of B cells.

immunology↗

bioRxiv2025

Developmental Immunotoxicity of Low-dose Inorganic Arsenic Reprograms Macrophages Inducing Tumor-promoting Phenotypes

In many regions around the world, including the United States, inorganic arsenic (iAs) contaminates groundwater used for drinking, food production, and irrigation. Although the World Health Organization has set a safety limit of 10 {micro}g/L for arsenic in drinking water, an estimated 200 million people worldwide are still exposed to arsenic concentrations above this threshold. Eliciting a broad range of adverse health effects, arsenic is a known carcinogen classified by the International Agency for Research on Cancer (IARC) and causes increased susceptibility to infectious diseases, highlighting its role as an immunotoxicant. The purpose of this study is to elucidate the effects of arsenic on the innate immune system, namely macrophages, using in vitro exposure models. Bone marrow-derived macrophages (BMDMs) were cultured from adult male and female C57/BL6 mice. These naive macrophages ("M0" BMDMs) were exposed in vitro to a non-cytotoxic dose of iAs (0.1 {micro}M sodium (meta)arsenite) during the 7 day period of macrophage differentiation and stimulated for 24 hrs with LPS and IFN{gamma} (to induce "M1" pro-inflammatory activation) or IL-4 and IL-13 (to induce "M2" anti-inflammatory activation). In a parallel chronic exposure model, RAW 264.7 (RAW) macrophages were cultured in vitro with iAs for 70 days. Culture supernatant analysis for nitric oxide and cytokine secretion revealed sex-dependent differences in immune response between exposure models, as well as between iAs-exposed and nonexposed macrophages, with and without stimulation. Additionally, iAs-exposed macrophages exhibited increased lipid droplet formation and altered lipidomic and metabolomic profiles, as determined by LC/MS. Flow cytometric analysis further revealed changes in macrophage polarization markers in a sex- and stimulation-dependent manner, with M2-related markers being upregulated in iAs-exposed conditions. Finally, to assess the effects of iAs on macrophages in the context of cancer, we demonstrated that iAs-exposed macrophages displayed increased migration toward cancer cell-conditioned media, and promoted cancer cell proliferation. These results suggest that dysregulated macrophage polarization due to iAs exposure could impact susceptibility to diseases. This research contributes to our understanding of the full spectrum of adverse health effects of iAs exposure and may aid in the development of therapeutics for iAs-induced diseases, including cancer.

immunology↗

bioRxiv2024

Prenatal Arsenic Exposure and Gene Expression in Fetal Liver, Heart, Lung, and Placenta

Prenatal arsenic exposure has been linked to a myriad of negative health effects. There is relatively little insight into the mechanisms and signaling alterations across different fetal organs that drive long-term immune-related issues following prenatal arsenic exposure. Therefore, the effects of this exposure window on gene expression in the liver, placenta, heart, and lung of gestation day (GD) 18 C57BL/6 mouse fetuses were investigated. From two weeks prior to mating until tissue collection at GD18, mice were exposed to 0 or 100 ppb sodium (meta) arsenite in drinking water. Genes of interest were analyzed by RT-qPCR, complemented with untargeted Agilent 44K microarray analysis. Data cleanup and analysis was performed in RStudio. Differentially expressed mRNAs were queried in the String Database and using Cytoscape to create interaction networks and identify significantly enriched biological pathways. A total of 251, 165, 158, and 41 genes were significantly altered in the liver, placenta, heart, and lung, respectively, when treated samples were compared to controls. Many altered pathways were immune-related, supporting prior research. Most notably, gene expression of Gbp3, a key player in the cellular response to interferon gamma, was found to be reduced in placentas of female fetuses exposed to arsenic compared to controls (p=0.0762). ImpactThis is the first study comparing alterations in gene expression across multiple organs following prenatal exposure to environmentally relevant levels of arsenic. These findings, elucidating the multi-organ impact of prenatal arsenic exposure on predominantly immune-related pathways, further our mechanistic understanding of the long-term health effects observed in early-life arsenic-exposed populations.

pharmacology and toxicology↗

bioRxiv2023

Reprogramming human B cells with custom heavy chain antibodies

We describe a genome editing strategy to reprogram the immunoglobulin heavy chain (IgH) locus of human B cells to express custom molecules that respond to immunization. These heavy chain antibodies (HCAbs) comprise a custom antigen-recognition domain linked to an Fc domain derived from the IgH locus and can be differentially spliced to express either B cell receptor (BCR) or secreted antibody isoforms. The HCAb editing platform is highly flexible, supporting antigen-binding domains based on both antibody and non-antibody components, and also allowing alterations in the Fc domain. Using HIV Env protein as a model antigen, we show that B cells edited to express anti-Env HCAbs support the regulated expression of both BCRs and antibodies, and respond to Env antigen in a tonsil organoid model of immunization. In this way, human B cells can be reprogrammed to produce customized therapeutic molecules with the potential for in vivo amplification.

immunology↗

bioRxiv2023

Comparison of shear stress patterns by the established and advanced reconstruction method incorporating side branches to predict plaque progression

BackgroundComplete vessel reconstruction (CVR) with incorporation of side branches is essential for accurate evaluation of wall shear stress (WSS) distribution. However, CVR is time consuming and blood flow simulation is computationally expensive, while there is no evidence that WSS computed by CVR, enables better prediction of disease progression compared to WSS derived from the conventional single vessel reconstruction (SVR). We aim to compare the WSS in models reconstructed using the CVR and SVR methods and examine its ability to predict disease progression. MethodsPatients who had baseline and 13-months follow-up intravascular ultrasound (IVUS) imaging (n=19 vessels), and with neoatherosclerotic lesions (n=13 vessels) on optical coherence tomography (OCT) were included in the present analysis. All the studied vessels had at least one side branch with diameter >1mm. 3-dimensional (3D) CVR and SVR were performed and time averaged (TAWSS) and multidirectional WSS were computed using pulsatile blood flow simulation and the performance of both methods in predicting disease progression in IVUS and OCT models were assessed. ResultsThe incorporation of side branches in 3D geometry resulted in lower TAWSS in the IVUS (0.821 vs 1.698Pa, p<0.001) and OCT-based reconstructions (0.682 vs 1.325Pa, p<0.001) and influenced the multidirectional WSS distribution. In native segments, WSS metrics estimated by the CVR enabled better prediction of the lumen and plaque area and burden at follow-up than SVR and disease progression defined as decrease in lumen area and increase in plaque burden (AUC CVR 0.712 vs SVR 0.554). In stented segments, multidirectional WSS was associated with neointima area in both CVR and SVR methods, but TAWSS was only a predictor of neointima area in the CVR method. ConclusionsThe incorporation of side branches in vessel reconstruction influences WSS distribution and enables more accurate prediction of disease progression in native and stented segments than SVR modelling. HighlightsO_LIComplete vessel reconstruction (CVR) with incorporation of vessel side branches has been proposed for accurate evaluation of wall shear stress (WSS) distribution compared to the traditional single vessel reconstruction (SVR) method; however, there are no studies comparing the performance of the WSS metrics derived by these methods in predicting atherosclerotic evolution. C_LIO_LIIn vessels with large side branches, the incorporation of the side branches in the vessel geometry reconstructed from angiographic and intravascular imaging data resulted in lower time averaged wall shear stress (TAWSS) and influenced the multidirectional WSS estimations compared to the models reconstructed without the side branches. C_LIO_LIThe WSS metrics estimated in the CVR models enabled better prediction of atherosclerotic disease progression at 13-months follow-up on IVUS than the WSS derived by the SVR. C_LIO_LIIn stented vessels, all the WSS metrics in the CVR and the multidirectional WSS in SVR were associated with neointima tissue development; however, both approaches showed limited efficacy in predicting neointima proliferation. C_LI

bioengineering↗

bioRxiv2023

Deciphering the phenotypic heterogeneity and drug response in cancer cells using genome-wide activity and interaction of chromatin domains.

The effect of co-localization of genes in the topologically associated domains (TADs) and their activity as a regulatory unit in cancer samples and cells, together with drug-response, needs comprehensive analysis. Here, we analyzed the activity of TADs using cancer-cell transcriptomes along with chromatin-interaction and epigenome profiles to understand their relationship with drug-response. Our analysis of 819 cancer cell-line transcriptomes revealed that their response to multiple drugs was more correlated with the activity of individual TADs than genes. Applying our approach to 9014 cancer patients data (20 different cancer types) also revealed a higher association between survival and the activity of thousands of individual TADs in comparison to their genes. CRISPR-mediated knock-out of regulatory sites inside a TAD associated with cisplatin-response of oral cancer cells and discovery of primate-specific gain of synteny of genes within a TAD containing EGFR gene and its contribution towards cancer malignancy demonstrate greater utility of TAD-activity based analysis.

cancer biology↗

bioRxiv2022

GBP1 promotes killing of multidrug-resistant Acinetobacter baumannii and promotes host protection via interferon signalling and inflammasome activation.

Multidrug resistant (MDR) Acinetobacter baumannii are of major concern worldwide due to their resistance to last resort carbapenem and polymyxin antibiotics. To develop an effective treatment strategy, it is critical to better understand how an A. baumannii MDR bacterium interacts with its mammalian host. Pattern-recognition receptors sense microbes, and activate the inflammasome pathway, leading to pro-inflammatory cytokine production and programmed cell death. Here, we found that MDR A. baumannii activate the NLRP3 inflammasome complex predominantly via the non-canonical caspase-11-dependent pathway. We show that caspase-11-deficient mice are protected from a virulent MDR A. baumannii strain by maintaining a balance between protective and deleterious inflammation via IL-1. Caspase-11-deficient mice also compromise between effector cell recruitment, phagocytosis, and programmed cell death in the lung during infection. Importantly, we found that cytosolic immunity - mediated by guanylate-binding protein 1 (GBP1) and type I interferon signalling - orchestrates caspase-11-dependent inflammasome activation. This exerts a bactericidal activity against carbapenem- and colistin-resistant, lipooligosaccharide (LOS)- deficient bacteria. Together, our results suggest that developing therapeutic strategies targeting GBP1 might pave the way as a host-directed therapy to overcome multidrug resistance in A. baumannii infection.

microbiology↗

bioRxiv2022

Differential activation of NLRP3 inflammasome by Acinetobacter baumannii strains

Acinetobacter baumannii is an emerging nosocomial, opportunistic pathogen with growing clinical significance globally. A. baumannii has an exceptional ability to rapidly develop drug resistance. It is frequently responsible for ventilator-associated pneumonia in clinical settings and inflammation resulting in severe sepsis. The inflammatory response is mediated by host pattern-recognition receptors and the inflammasomes. Inflammasome activation triggers inflammatory responses, including the secretion of the pro-inflammatory cytokines IL-1{beta} and IL-18, the recruitment of innate immune effectors against A. baumannii infection, and the induction programmed cell death by pyroptosis. An important knowledge gap is how variation among clinical isolates affects the hosts innate response and activation of the inflammasome during A. baumannii infection. In this study, we compared nine A. baumannii strains, including clinical locally-acquired isolates, in their ability to induce activation of the inflammasome and programmed cell death pathway in primary macrophages and mice. We found a striking variability in survival outcomes of mice and bacterial dissemination in organs among three ATCC A. baumannii strains, likely due to the differences in virulence between strains. Interestingly, we found a stark contrast in activation of the NLRP3 inflammasome pathway, the non-canonical caspase-11 pathway, plasmatic secretion of the pro-inflammatory cytokines IL-1{beta} and IL-18 between A. baumannii strains. Our study highlights the importance of utilising multiple bacterial strains and clinical isolates with differential virulence to investigate the innate immune response to A. baumannii infection.

microbiology↗

bioRxiv2020

Measuring effects of trainee professional development on research productivity: A cross-institutional meta-analysis

PhD-trained scientists are essential contributors to the workforce in diverse employment sectors that include academia, industry, government, and non-profit organizations. Hence, best practices for training the future biomedical workforce are of national concern. Complementing coursework and laboratory research training, many institutions now offer professional training that enables career exploration and develops a broad set of skills critical to various career paths. The National Institutes of Health funded academic institutions to design innovative programming to enable this professional development through a mechanism known as Broadening Experiences in Scientific Training (BEST). Programming at the BEST awardee institutions included career panels, skill-building workshops, job-searching workshops, site visits, and internships. An initial concern was since doctoral training is lengthy and requires focused attention on dissertation research, having students participate in additional complementary training activities might lengthen time to degree and hamper student research productivity. To address this concern, using time to degree and publication records as measures of efficiency and productivity, metrics were analyzed from ten BEST awardee institutions. Comparing doctoral students who participated to those who did not, results revealed that across these diverse academic institutions, there were no differences in time to degree or manuscript output. Furthermore, a few institutions even demonstrated a positive correlation between participation in career and professional development activities and productivity. Our findings suggest that doctoral students should be encouraged to participate in career and professional development opportunities to ensure their preparedness for a variety of diverse and important careers in the workforce. Significance StatementOur study is unique in that it compiled doctoral degree durations at ten different universities, recorded individual participation in career and professional development activities in terms of dosage, and tracked individual engagement in real-time rather than relying on surveys sent to trainees after graduation. Participation in career and professional development activities, including internships, did not decrease efficiency or productivity. Our findings suggest that doctoral students should be encouraged to participate in career and professional development opportunities to ensure their preparedness for a variety of diverse and important careers in the workforce.

scientific communication and education↗

bioRxiv2020

Single cell transcriptional characterization of human megakaryocyte lineage commitment and maturation

In the current understanding of adult bone marrow hematopoiesis, megakaryocytes (MKs) originate from cells immuno-phenotypically indistinguishable from hematopoietic stem cells (HSCs), bypassing intermediate progenitors. Here, we use single cell RNA sequencing to characterize HSCs and MKs from human bone marrow, to investigate MK lineage commitment and maturation. We identify two MK primed HSC clusters exhibiting unique differentiation kinetics, at least one of which is used in steady state and stress thrombopoiesis. By analyzing transcriptional signatures we show that human bone marrow MKs originate from MK primed HSC subpopulations, supporting the notion that these display exclusive priming for MK differentiation. We show that transcriptional programs change with increasing MK ploidy, where genes upregulated in high ploidy states may have functional relevance in platelet production. Finally, we highlight the presence of a specific transcriptional signature in MKs from individuals with myocardial infarction, supporting the aberration of MK differentiation in this thrombotic state.

cell biology↗

bioRxiv2019

Specialization of phonological and semantic reading routes in early childhood

During the early period of reading development, children gain phonological (letter-to-sound mapping) and semantic knowledge (storage and retrieval of word meaning). Their reading ability changes rapidly, accompanied by their learning-induced brain plasticity as they learn to read. This study aims to identify the specialization of phonological and semantic processing in early childhood using a combination of univariate and multivariate pattern analysis. Nineteen typically developing children between the age of five to seven performed visual word-level phonological (rhyming) and semantic (related meaning) judgment tasks during functional magnetic resonance imaging (fMRI) scans. Our multivariate analysis showed that young children with good reading ability have already recruited the left hemispheric regions in the brain for phonological processing, including the inferior frontal gyrus (IFG), superior and middle temporal gyrus, and fusiform gyrus. Additionally, our multivariate results suggested that the sub-regions of the left IFG were specialized for different tasks. Our results suggest the left lateralization of fronto-temporal regions for phonological processing and bilateral activations of parietal regions for semantic processing during early childhood. Our findings indicate that the neural bases of reading have already begun to be shaped in early childhood for typically developing children, which can be used as a control baseline for comparison of children at-risk for reading difficulties.

neuroscience↗