Biology subjects

Bhatnagar, A.

Publications and source records attributed to Bhatnagar, A..

At least 19 recordsLinked to original sources

bioRxiv2025

Improvement in Orchard Nutrient Status and Productivity Through Integrated Nutrient Management in Mango (Mangifera indica L.) Under Medium-Density Planting

AbstractBalanced nutrient management is essential for sustaining productivity and soil health in perennial fruit crops. A two-year field study (2022-2024) was conducted to evaluate the effects of integrating soil and foliar micronutrient applications with reduced recommended doses of fertilizers (RDF) on vegetative growth, nutrient status, yield, fruit quality, and economic performance of mango (Mangifera indica L.) cv. Dashehari under medium-density planting. Nine nutrient modules combining 25-100% RDF with soil- and foliar-applied Fe, Zn, B, Cu, and Ca were compared using ANOVA, PCA, and PLS-SEM. Integrated treatments significantly enhanced canopy height, spread, and volume, with the 75% RDF + two foliar micronutrient sprays producing the greatest vegetative growth. Yield attributes, fruit size, retention, and shelf life improved markedly under micronutrient-enriched treatments. The highest fruit yield and benefit-cost ratio was obtained with 75% RDF + two foliar sprays, outperforming the conventional 100% RDF. Soil pH and EC were moderated, and organic carbon improved slightly under integrated nutrient management. Soil and leaf macro- and micronutrient concentrations were consistently higher with combined soil-foliar approaches. PCA clustered high-performing nutrient modules with yield and canopy variables, while PLS-SEM identified plant nutrient status as the strongest predictor of fruit yield. Overall, integrating micronutrient supplementation with 75% RDF improved nutrient-use efficiency, productivity, and economic returns while reducing dependence on full-dose fertilizers. The study highlights 75% RDF + foliar micronutrient sprays as an effective and sustainable nutrient management strategy for enhancing yield and orchard performance in mango. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/697138v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@227e25org.highwire.dtl.DTLVardef@87b769org.highwire.dtl.DTLVardef@1a73b2org.highwire.dtl.DTLVardef@a1cf12_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗

bioRxiv2025

E1: Retrieval-Augmented Protein Encoder Models

Large language models trained on natural proteins learn powerful representations of protein sequences that are useful for downstream understanding and prediction tasks. Because they are only exposed to individual protein sequences during pretraining without any additional contextual information, conventional protein language models suffer from parameter inefficiencies in learning, baked-in phylogenetic biases, and functional performance issues at larger scales. To address these challenges, we have built Profluent-E1, a family of retrieval-augmented protein language models that explicitly condition on homologous sequences. By integrating retrieved evolutionary context through block-causal multi-sequence attention, E1 captures both general and family-specific constraints without fine-tuning. We train E1 models on four trillion tokens from the Profluent Protein Atlas and achieve state-of-the-art performance across zero-shot fitness and unsupervised contact-map prediction benchmarks - surpassing alternative sequence-only models. Performance scales with model size from 150M to 600M parameters, and E1 can be used flexibly in single-sequence or retrieval-augmented inference mode for fitness prediction, variant ranking, and embeddings for structural tasks. To encourage open science and further development in retrieval-augmented protein language models, we release three models for free research and commercial use at https://github.com/Profluent-AI/E1.

synthetic biology↗

bioRxiv2025

Systems-level Plant Responses Reveal Pseudomonas-Mediated Growth Promotion in Brachypodium Under Nitrogen Limitation

Plant molecular adaptation to plant growth promoting bacteria (PGPB) under nutrient stress remains unclear, yet is essential for advancing PGPB use in agriculture. The model grass Brachypodium dystachion was studied together with Pseudomonas koreeensis (Pk) at two nitrogen (N) conditions. Non-invasive shoot phenotyping showed an immediate response to low-N, while beneficial effects of Pk became quantifiable after day 19. Increased N content in inoculated plants, along with Pks ability to grow on N-free media, suggests bacterial N contribution at deficient N. In low-N conditions, Pk-inoculated plants showed 33.2% more N than uninoculated controls and biomass comparable to high-N plants. Pk had no effect under sufficient N. Proteomics and lipidomics revealed that lipid profiles were primarily shaped by N availability, while protein abundance responded to both Pk and N status. Inoculated low-N plants displayed protein profiles resembling those of high-N controls, with some distinct exceptions. The plant-microbe interaction is dynamic and developed over 3 weeks, leading to increased biomass and N content. Root proteins strongly induced by Pk under low-N included lipid degradation enzymes, N transporters, and regulatory proteins, suggesting a coordinated remodelling of energy metabolism supporting whole-plant biomass and increased abundance of N uptake proteins.

plant biology↗

bioRxiv2025

Carnosinylation of Cardiac Antigens Attenuates Immunogenic Responses and Improves Function in Failing Hearts

ObjectiveTo investigate the effects of carnosine on heart failure and to examine whether this is associated with reduced immunogenicity of oxidatively-generated aldehyde modified proteins. BackgroundHeart failure is associated with the accumulation of lipid derived aldehydes that form immunogenic protein adducts. However, the pathological impact of these aldehydes and aldehyde-modified proteins in heart failure has not been assessed. Histidyl dipeptides, such as carnosine found in the heart, bind to aldehydes, and their protein adducts. However, the effects of carnosine on heart failure or the antigenicity of aldehyde modified proteins have not been studied. MethodsMale, wild type C57BL/6J mice were subjected to either sham or transverse aortic constriction (TAC) surgery. To increase carnosine levels, they were placed on drinking water with or without {beta}-alanine prior to surgery, and for the remainder of the study. Cardiac function was evaluated by echocardiography, and the levels of histidyl dipeptides, immune cell populations, and CD4+ T cell activation were assessed via LC-MS/MS and flow cytometry, respectively. ResultsMyocardial levels of histidyl dipeptides decreased at both 3- and 8-weeks post-TAC. Supplementation with {beta}-alanine increased myocardial histidyl dipeptide levels, attenuated adverse cardiac remodeling, and reduced aldehyde stress. Carnosine formed covalent bond with protein-bound aldehydes in the failing heart, reducing their antigenic potential and decreasing activation of dendritic cells and CD4+ T cells in vitro. {beta}-alanine supplementation decreased the population of CD11b+CD64-Ly6G+ neutrophils and CD4+ CD44+ effector T cells in the failing heart. ConclusionsIncreasing myocardial carnosine levels reduces aldehyde stress, dampens maladaptive immune responses, and preserves cardiac function during heart failure. HIGHLIGHTSO_LILevels of endogenous dipeptide carnosine are depleted in failing hearts, while supplementation of the carnosine precurson {beta}-alanine increases myocardial carnosine and preserves cardiac function during heart failure. C_LIO_LIHeart failure is associated with increased activation and infiltration of CD4+ T cells and generation of aldehyde modified protein adducts in failing hearts. C_LIO_LIThe free aldehyde moiety of aldehyde modified protein adducts activates CD4+ T cells through dendritic cell presentation and capping this moiety with carnosine diminishes their antigencity. C_LIO_LIIncreasing myocardial carnosine levels diminishes aldehyde stress and activation of CD4+ T cells during heart failure. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/671840v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@28fc7corg.highwire.dtl.DTLVardef@d851ccorg.highwire.dtl.DTLVardef@1e24a5dorg.highwire.dtl.DTLVardef@18023b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Genetic parameters and genome-wide association analysis of service sire effect on litter size and its relationship with boar semen quality in three terminal sire lines

This study aimed to estimate the genetic parameters for service sire effects on the number born alive (NBA) and its relationship with semen quality traits. Data of 6,416, 23,188, and 48,890 litter size records collected between 2020 and 2024 from three purebred terminal sire lines were analyzed. The number of sows was 3,071, 11,819, and 24,089, with 197, 554, and 891 service sires for the three respective lines. There were 1,424,858, 4,344,630, and 2,146,583 animals in the pedigree of which 67,990, 259,250, and 365,392 were genotyped and imputed up to 50K SNPs. The service sire and dam effects were modeled as additive genetic effects, considering a covariance structure among them, given by the relationship matrix. The model also included fixed effects of contemporary group and parity group with random permanent environmental effects for service sire and dam. Genetic parameters were estimated using the AIREML option in the BLUPF90+ software, and GEBVs were generated by ssGBLUP with the algorithm for proven and young (APY). Heritability for the service sire effect ranged from 0.01 to 0.03, and the heritability for the dam effect ranged from 0.09 to 0.15, with genetic correlations ranging from -0.20 to 0.37. A single-step genome-wide association study (ssGWAS) was also performed, and no strong signals were detected for service sire effects on NBA. Sperm motility (MOT) and total abnormal morphology (ABN_MOR) GEBVs from the three lines were estimated based on about 57,500 to 608,996 ejaculates recorded using the computer-assisted semen analysis (CASA) system from 1,698 to 29,095 boars collected from 2013 to 2025. Heritability estimates ranged from 0.10 to 0.12 for motility and from 0.17 to 0.28 for total abnormal morphology. The correlations between service sire GEBV for NBA and semen quality were low but in the favorable direction. Results suggest that although paternal genetic contributions to litter size were small compared to maternal genetic contributions, selecting on service sire effects on litter size in addition to semen quality traits will improve overall reproductive success.

genetics↗

bioRxiv2025

Comparative toxicity of menthol- and tobacco-flavored electronic cigarette constituents causing inflammation, epithelial barrier dysfunction, and nicotinic acetylcholine receptor modulation in the absence of nicotine.

BackgroundMenthol and tobacco-flavored nicotine delivery systems (ENDS) are widely used as safer alternatives to combustible cigarettes. These flavored products include constituents such as propylene glycol/vegetable glycerin (PG/VG), benzoic acid, acetoin, L-menthone, 98% menthone, 2-isopropyl-N,2,3-trimethylbutanamide (WS-23), vanillin, and carvone. However, little is known about the potential adverse effects of the constituents in these flavored products. Rationale and hypothesisWe hypothesized that exposure to common constituents in tobacco- and menthol-flavored ENDS constituents could elicit a lung-injurious response mediated by nicotinic acetylcholine receptor (-nAChR or CHRNA) modulation. MethodsHuman bronchial epithelial cells, BEAS-2B, cells were treated with commonly used menthol and tobacco constituents on trans well inserts. Transepithelial barrier resistance (TEER) and millivolts (mV) across epithelial cells were measured over a 24-hour time. To assess the elicited inflammatory response, cytokines IL8 and IL6 were quantified in the conditioned media. Cytotoxicity caused by these constituents was evaluated by acridine orange/propidium iodide (AO/PI) staining of the cells after 24 hrs. alpha nicotinic receptor protein abundance (1, 4, 5, and 7) was quantified by immunoblotting. ResultsEpithelial integrity was decreased over time with a significant decrease in TEER and voltage by ENDS constituents. A significant increase in IL6 in conditioned media was observed in PG/VG, carvone, and WS-23 treated cells. Carvone-treated cells also elicited significantly elevated IL8 in conditioned media. Further, increased 1, 4, 5, and 7 nAChR were seen in cells treated with PG/VG, Acetoin, Carvone, and WS-23. ConclusionThese findings suggested that common constituents in menthol- and tobacco-flavored ENDS induce lung inflammation, epithelial barrier dysfunction, and lung injury. Further, our data implicate potential lung disease pathogenesis via nAChR modulation-mediated inflammation by exposure to these ENDS constituents, even in the absence of nicotine.

pharmacology and toxicology↗

bioRxiv2025

Evaluation of Enterobacterales carrying Acinetobacter-associated blaOXA genes--United States, 2017-2022

Through their ability to hydrolyze carbapenems, Ambler class D beta-lactamases endanger patients by limiting the clinical efficacy of beta-lactam antimicrobials. Further, plasmid-mediated transmission can increase mobility of carbapenemase genes between bacteria and facilitate their spread between patients. In the United States and elsewhere, the plasmid-mediated Ambler class D carbapenemase genes blaOXA-23-like, blaOXA-24/40-like, and blaOXA-58-like are commonly associated with Acinetobacter species and have rarely been reported outside of this genus. However, multiple recent international reports indicate detection of Enterobacterales isolates carrying Acinetobacter-associated class D carbapenemase genes. This evaluation aimed to provide insight into whether Enterobacterales harboring these class D genes may be circulating undetected in the United States, thereby signaling a need for adapting testing strategies to prioritize the detection of these potentially emerging public health threats. We analyzed whole-genome sequencing data generated through multiple Centers for Disease Control and Prevention (CDC) activities, including testing conducted across the Antimicrobial Resistance Laboratory Network, to determine whether any Enterobacterales isolates sequenced from 2017-2022 harbored Acinetobacter-associated class D carbapenemase genes. Among [~]10,000 predominantly carbapenem-resistant Enterobacterales isolates, we identified only a single Enterobacterales isolate harboring an Acinetobacter-associated class D gene - a Klebsiella pneumoniae isolate harboring a blaOXA-23-like gene. Our findings suggest that blaOXA-23-like, blaOXA-24/40-like, and blaOXA-58-like genes are rare among Enterobacterales isolates sequenced through CDC public health activities in the United States and do not warrant changes to current testing priorities at this time.

microbiology↗

bioRxiv2025

Thermotolerance in Chia (Salvia hispanica L.) is Mediated by Rapid Heat-Induced Transcriptomic Reprogramming and Lipid Remodelling in Leaves

Heat stress poses a significant threat to crop productivity; however, the thermotolerance mechanisms in underutilised oilseed crops, such as chia (Salvia hispanica L.), remain poorly understood. Despite the growing interest in chia as a rich source of {omega}-3 fatty acids, its molecular response to heat stress, particularly in vegetative tissues, has not been explored. We conducted transcriptomic and lipidomic profiling to examine how chia leaves respond to short-term (3 h) and prolonged (27 h) heat stress, followed by recovery under ambient conditions. Heat stress induced differential expression in over 20% of transcripts in chia leaves, with distinct patterns involving Ca{superscript 2} signalling, heat shock factors, and other biological pathways contributing to cellular homeostasis. Gene expression and lipid profiles in chia leaves responded dynamically to both short-term (3 h) and prolonged (27 h) heat stress (38{degrees}C/20{degrees}C). An almost complete return to baseline was observed, with all but 0.3% of heat-responsive genes reverting to control expression levels after 24 h. Our analysis confirms the role of Ca{superscript 2}-mediated signalling pathways and molecular chaperones, including heat shock proteins and heat shock factors, which have been previously shown to contribute to maintaining cellular function during heat stress in other plant species. Among 287 annotated lipid species, TGs exhibited the most significant and reversible changes (>2-fold), suggesting their involvement in membrane remodelling. Our findings reveal adaptive mechanisms in chia that may open avenues for enhancing thermotolerance in other heat-sensitive oilseed crops. SIGNIFICANCE STATEMENTUnderstanding how crops respond to heat stress is crucial as global temperatures rise. This study indicates that in chia (Salvia hispanica), pathways responding to heat stress, like calcium signalling and heat shock proteins, are rapidly activated, and leaf triacylglycerol levels rise under heat stress before returning to baseline during recovery. By demonstrating near-complete recovery of gene expression following heat exposure, these findings highlight mechanisms of thermotolerance that may support improved stress tolerance in other crops.

plant biology↗

bioRxiv2025

Scaling unlocks broader generation and deeper functional understanding of proteins

Generative protein language models (PLMs) are powerful tools for designing proteins purpose-built to solve problems in medicine, agriculture, and industrial processes. Recent work has trained ever larger language models, but there has been little systematic study of the optimal training distributions and the influence of model scale on the sequences generated by PLMs. We introduce the ProGen3 family of sparse generative PLMs, and we develop compute-optimal scaling laws to scale up to a 46B-parameter model pre-trained on 1.5T amino acid tokens. Pro-Gen3s pre-training data is sampled from an optimized data distribution over the Profluent Protein Atlas v1, a carefully curated dataset of 3.4B full-length proteins. We evaluate for the first time in the wet lab the influence of model scale on the sequences generated by PLMs, and we find that larger models generate viable proteins for a much wider diversity of protein families. Finally, we find both computationally and experimentally that larger models are more responsive to alignment with laboratory data, resulting in improved protein fitness prediction and sequence generation capabilities. These results indicate that larger PLMs like ProGen3-46B trained on larger, well-curated datasets are powerful foundation models that push the frontier of protein design.1

synthetic biology↗

bioRxiv2025

Engineering of CRISPR-Cas PAM recognition using deep learning of vast evolutionary data

CRISPR-Cas enzymes must recognize a protospacer-adjacent motif (PAM) to edit a genomic site, significantly limiting the range of targetable sequences in a genome. Machine learning-based protein engineering provides a powerful solution to efficiently generate Cas protein variants tailored to recognize specific PAMs. Here, we present Protein2PAM, an evolution-informed deep learning model trained on a dataset of over 45,000 CRISPR-Cas PAMs. Protein2PAM rapidly and accurately predicts PAM specificity directly from Cas proteins across Type I, II, and V CRISPR-Cas systems. Using in silico deep mutational scanning, we demonstrate that the model can identify residues critical for PAM recognition in Cas9 without utilizing structural information. As a proof of concept for protein engineering, we employ Protein2PAM to computationally evolve Nme1Cas9, generating variants with broadened PAM recognition and up to a 50-fold increase in PAM cleavage rates compared to the wild-type under in vitro conditions. This work represents the first successful application of machine learning to achieve customization of Cas enzymes for alternate PAM recognition, paving the way for personalized genome editing.

synthetic biology↗

bioRxiv2024

Adapting protein language models for structure-conditioned design

Generative models for protein design trained on experimentally determined structures have proven useful for a variety of design tasks. However, such methods are limited by the quantity and diversity of structures used for training, which represent a small, biased fraction of protein space. Here, we describe proseLM, a method for protein sequence design based on adaptation of protein language models to incorporate structural and functional context. We show that proseLM benefits from the scaling trends of underlying language models, and that the addition of non-protein context - nucleic acids, ligands, and ions - improves recovery of native residues during design by 4-5% across model scales. These improvements are most pronounced for residues that directly interface with non-protein context, which are faithfully recovered at rates >70% by the most capable proseLM models. We experimentally validated proseLM by optimizing the editing efficiency of genome editors in human cells, achieving a 50% increase in base editing activity, and by redesigning therapeutic antibodies, resulting in a PD-1 binder with 2.2 nM affinity.

bioengineering↗

bioRxiv2024

Design of highly functional genome editors by modeling the universe of CRISPR-Cas sequences

Gene editing has the potential to solve fundamental challenges in agriculture, biotechnology, and human health. CRISPR-based gene editors derived from microbes, while powerful, often show significant functional tradeoffs when ported into non-native environments, such as human cells. Artificial intelligence (AI) enabled design provides a powerful alternative with potential to bypass evolutionary constraints and generate editors with optimal properties. Here, using large language models (LLMs) trained on biological diversity at scale, we demonstrate the first successful precision editing of the human genome with a programmable gene editor designed with AI. To achieve this goal, we curated a dataset of over one million CRISPR operons through systematic mining of 26 terabases of assembled genomes and meta-genomes. We demonstrate the capacity of our models by generating 4.8x the number of protein clusters across CRISPR-Cas families found in nature and tailoring single-guide RNA sequences for Cas9-like effector proteins. Several of the generated gene editors show comparable or improved activity and specificity relative to SpCas9, the prototypical gene editing effector, while being 400 mutations away in sequence. Finally, we demonstrate an AI-generated gene editor, denoted as OpenCRISPR-1, exhibits compatibility with base editing. We release OpenCRISPR-1 publicly to facilitate broad, ethical usage across research and commercial applications.

synthetic biology↗

bioRxiv2024

Drivers of Bird Communities in an Urban Neighborhood Vary by Scale

Given the accelerated pace of global biodiversity loss and rapid urbanization, it is becoming increasingly urgent to identify ways to minimize the costs and maximize the benefits of urban environments for wild flora and fauna. For instance, it has been estimated that 48% of all bird species are experiencing population declines. One of the main drivers of these declines is habitat loss and degradation associated with urbanization. Increased urbanization necessitates a better understanding of how to conserve birds in urban areas. Although relationships between urbanization and bird communities have been explored extensively, few studies have been conducted in residential neighborhoods, and the influence of urban environmental conditions, particularly air pollution, on bird communities remains unclear. In this study, we examined relationships between bird community metrics and environmental measures related to vegetation and air pollution within a residential neighborhood at multiple spatial scales. We found that bird species richness and the average number of native species were positively related to greenness (as measured by the normalized difference vegetation index; NDVI) within 50 m, and negatively associated with ambient levels of NO2 at 200 m. Similarly, we found the Hill-Shannon diversity index was positively associated with canopy cover, but negatively associated with NO2 at 200 m. The average number of invasive bird species, however, was negatively correlated with canopy cover at 50 m. The average number of native birds was negatively related to ultrafine particle (<100 nm in diameter) concentration. Unlike native bird abundances, invasive bird abundances were not sensitive to NO2 or ultrafine particles. Thus, our research suggests that reductions in air pollution, in combination with greening efforts that increase NDVI and canopy cover via the restoration of vegetation within urban neighborhoods, are likely to increase bird diversity and the abundances of native birds while reducing the abundance of invasive birds.

ecology↗

bioRxiv2023

Axis convergence in C. elegans embryos

Embryos develop in a surrounding that guides key aspects of their development. For example, the anteroposterior (AP) body axis is always aligned with the geometric long axis of the surrounding eggshell in fruit flies and worms. The mechanisms that ensure convergence of the AP axis with the long axis of the eggshell remain unresolved. We investigate axis convergence in early C. elegans development, where the nascent AP axis, when misaligned, actively re-aligns to converge with the long axis of the egg. Here, we identify two physical mechanisms that underlie axis convergence. First, bulk cytoplasmic flows, driven by actomyosin cortical flows, can directly reposition the AP axis. Second, active forces generated within the pseudocleavage furrow, a transient actomyosin structure similar to a contractile ring, can drive a mechanical re-orientation such that it becomes positioned perpendicular to the long axis of the egg. This in turn ensures AP axis convergence. Numerical simulations, together with experiments that either abolish the pseudocleavage furrow or change the shape of the egg, demonstrate that the pseudocleavage furrow-dependent mechanism is the key driver of axis convergence. We conclude that active force generation within the actomyosin cortical layer drives axis convergence in the early nematode.

biophysics↗

bioRxiv2023

Two splice forms of OsbZIP1, a homolog of AtHY5, function to regulate skoto- and photo-morphogenesis in rice

Plants possess well-developed light sensing mechanisms and signal transduction systems for regulating photomorphogenesis. ELONGATED HYOCOTYL 5 (HY5), a basic leucine zipper transcription factor, has been extensively characterized in dicot plants. In this study, we have shown that OsbZIP1 is a functional homolog of Arabidopsis HY5 (AtHY5) and is important for light-mediated regulation of seedling and mature plant development in rice. Ectopic expression of OsbZIP1 in rice reduces plant height and leaf length without affecting plant fertility, which is in contrast to OsbZIP48, another HY5 homolog we characterised earlier. OsbZIP1 is alternatively spliced and the isoform OsbZIP1.2 lacking COP1 binding domain regulates seedling development in dark; this is unique since AtHY5 lacking COP1 binding domain does not display such a phenotype. Rice seedlings overexpressing OsbZIP1 were found to be shorter than vector control under white and monochromatic light conditions whereas RNAi seedlings displayed completely opposite phenotype. While OsbZIP1.1 is light regulated, OsbZIP1.2 shows similar protein profile in both light and dark conditions. Due to its interaction with OsCOP1, OsbZIP1.1 undergoes degradation via 26S proteasome under dark conditions. Also, OsbZIP1.1 interacts with CASEIN KINASE 2 (OsCK2[a]3) and consequently undergoes phosphorylation. In comparison, OsbZIP1.2 did not show any interaction with COP1 and OsCK2[a]3. We propose that OsbZIP1.1 most likely works under low fluence of blue light (15 mol/m{superscript 2}/s) while OsbZIP1.2 becomes dominant as the fluence is increased to 30 mol/m{superscript 2}/s. Data presented in this study reveal that AtHY5 homologs in rice have undergone neofunctionalization and alternative splicing (AS) of OsbZIP1 has increased the repertoire of its functions. One sentence summaryAlternative spliced forms of OsbZIP1, an AtHY5 homolog in rice, regulate seedling development in response to light and dark

plant biology↗

bioRxiv2022

Boolean modeling of mechanosensitive Epithelial to Mesenchymal Transition and its reversal

The significance of biophysical modulators of the Epithelial to Mesenchymal Transition (EMT) is demonstrated by experiments that document full EMT on stiff, nano-patterned substrates in the absence of biochemical induction. Yet, current models focus on biochemical triggers of EMT without addressing its mechanosensitive nature. Here we built a Boolean model of EMT triggered by mechanosensing - mitogen crosstalk. Our model reproduces epithelial, hybrid E/M and mesenchymal phenotypes, the role of autocrine TGF{beta} signaling in maintaining mesenchymal cells in the absence of external drivers, inhibition of proliferation by TGF{beta}, and its apoptotic effects on soft ECM. We offer testable predictions on the density-dependence of partial EMT, its molecular drivers, and the conflict between mitosis and hybrid E/M stability. Our model opens the door to modeling the effects of the biomechanical environment on cancer cell stemness linked to the hybrid E/M state, as well as the mutually inhibitory crosstalk between EMT and senescence.

systems biology↗

bioRxiv2021

Amoeboid-like neuronal migration ensures correct horizontal cell layer formation in the developing vertebrate retina

As neurons are often born at positions different than where they ultimately function, neuronal migration is key to ensure successful nervous system development. Radial migration during which neurons featuring unipolar and bipolar morphology, employ pre-existing processes or underlying cells for directional guidance, is the most well explored neuronal migration mode. However, how neurons that display multipolar morphology, without such processes, move through highly crowded tissue environments towards their final positions remains elusive. To understand this, we here investigated multipolar migration of horizontal cells in the zebrafish retina. We found that horizontal cells tailor their movements to the environmental spatial constraints of the crowded retina, by featuring several characteristics of amoeboid migration. These include cell and nucleus shape changes, and persistent rearward polarization of stable F-actin, which enable horizontal cells to successfully move through the crowded retina. Interference with the organization of the developing retina by changing nuclear properties or overall tissue architecture, hampers efficient horizontal cell migration and layer formation. Thus, cell-tissue interplay is crucial for efficient migration of horizontal cells in the retina. In view of high proportion of multipolar neurons, the here uncovered ameboid-like neuronal migration mode might also be crucial in other areas of the developing brain.

developmental biology↗

bioRxiv2021

Biomarkers Of Cardiovascular Toxicity Of Benzene Inhalation In Mice

Benzene is a ubiquitous environmental pollutant. Recent population-based studies suggest that benzene exposure is associated with an increased risk for cardiovascular disease. However, it is unclear whether benzene exposure is sufficient to induce cardiovascular toxicity. We examined the effects of benzene inhalation (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on the biomarkers of cardiovascular toxicity in male C57BL/6J mice. Benzene inhalation significantly increased the biomarkers of endothelial activation and injury including endothelial microparticles, activated endothelial microparticles, endothelial progenitor cell microparticles, lung endothelial microparticles, and activated lung and endothelial microparticles while having no effect on circulating levels of endothelial adhesion molecules, endothelial selectins, and biomarkers of angiogenesis. To understand how benzene may induce endothelial injury, we exposed human aortic endothelial cells to benzene metabolites. Of metabolites tested, trans,trans-mucondialdehyde (10 M, 18h) was most toxic. It induced caspases-3, -7 and -9 (intrinsic pathway) activation, and enhanced microparticle formation by 2.4-fold. Levels of plateletleukocyte aggregates, platelet macroparticles, and proportion of CD4+ and CD8+ T-cells were also significantly elevated in the blood of the benzene-exposed mice. We also found that benzene exposure increased the transcription of genes associated with endothelial cell and platelet activation in the liver; and induced inflammatory genes and suppressed cytochrome P450s in the lungs and the liver. Together, these data suggest that benzene exposure induces endothelial injury, enhances platelet activation and inflammatory processes; and circulatory levels of endothelial cell and platelet-derived microparticles and platelet-leukocyte aggregates are excellent biomarkers of cardiovascular toxicity of benzene. HighlightsO_LIInhaled benzene exposure increases the levels of blood endothelial microparticles. C_LIO_LIIn vitro, benzene metabolite trans, trans-mucondialdehyde induces endothelial cell apoptosis and microparticles formation. C_LIO_LIInhaled benzene exposure decreases the levels of hematopoietic progenitor cells in the bone marrow. C_LIO_LIInhaled benzene exposure augments the circulating levels of platelet-leukocyte adducts. C_LI

pharmacology and toxicology↗