Biology subjects

Barua, A.

Publications and source records attributed to Barua, A..

At least 19 recordsLinked to original sources

bioRxiv2026

An evolvable and functionally partitioned network underlies developmental remodelling in teleosts

Comparative embryology has revealed that early animal development is based on highly conserved genetic programs. Beyond embryogenesis however, animals undergo remarkably diverse post-embryonic developmental transitions such as metamorphosis. Whether these transitions are also organised into conserved genetic programs remains largely unexplored. To identify conserved genetic programs underlying post-embryonic development, we examine metamorphic remodelling in five teleost fishes, spanning 200 million years of evolution. By integrating comparative co-expression networks, evolutionary genomics, phylogenetic modelling, and functional data in zebrafish, we uncovered a conserved post-embryonic developmental network. This conserved network comprises components involved in core cellular processes, and involved in development and physiology, both of which are under the control of thyroid hormone during metamorphosis. Despite evolutionary conservation at the coding sequence level, this network exhibits significant turnover in gene family copy number following the teleost-specific whole-genome duplication as well as lineage-specific expansions and contractions. The variation in gene copy numbers is associated with macroevolutionary variation in a number of ecological and morphological traits, including swimming performance, and trophic level. Cross-species tissue expression, zebrafish single-cell transcriptomics, and zebrafish perturbation phenotypes placed the implicated genes in biological contexts relevant to these traits. Together, our results provide evidence of an ancient, functionally partitioned post-embryonic developmental network that has diversified throughout teleost evolution. The heterochronic variation in network function, changes in endocrine activity, and gene-family turnover provide potential routes through which a shared developmental architecture contributed to the evolution of phenotypic diversity in teleosts.

evolutionary biology↗

bioRxiv2026

Regulatory memory and growth-coupled inheritance shape nutrient-dependent flagella number variation in Salmonella

Bacteria must balance the advantage of movement against the cost of building flagella, yet how nutrient availability shapes variation in flagellar number across single cells remains unclear. Here, we combine time-resolved basal-body measurements in Salmonella enterica with a mechanistically constrained stochastic model of flagellar remodeling. The model separates two routes from nutrient availability to flagellar number: an RflP-dependent regulatory memory that sets a synthesis target via a latent sensing-memory variable, and a physical inheritance process in which synthesis, binomial partitioning, and division reshape the flagellar-number distribution. Coarse-graining this process yields leaky-integrator dynamics in which the mean flagellar number tracks a regulatory target, while the latent correlation follows acquisition-decay dynamics. In wild-type cells, nutrient-dependent acquisition raises the target and increases flagellar investment; in {Delta}rflP cells, loss of acquisition produces a transient overshoot that isolates the intrinsic decay (memory) timescale of the regulatory state. The fitted model predicts a held-out nutrient condition and reveals which parameter combinations are identifiable from the data. Analysis of the fitted dynamics suggests that precision is tuned primarily by sensing-dependent signal amplitude, rather than integration time, with an apparent [~]1.7-fold increase in effective wild-type noise amplitude after mean normalization, consistent with a precision cost of active regulation relative to the mutant. A model-free, information-geometric (Cramer-Rao) speed limit further shows that active remodeling approaches the statistical speed allowed by the observed distributional variability. Together, these results reveal how Salmonella cells couple regulatory memory with growth-dependent inheritance to record recent nutrient history in their flagellar number.

systems biology↗

bioRxiv2026

Tumor-induced species-specific dysbiosis drives renal innate immunity and nephrogenic ascites

Ascites is a life-threatening complication of advanced malignancies, yet how tumors disrupt systemic fluid homeostasis remains poorly understood. Here, using a Drosophila tumor allograft model that recapitulates key features of cancer-associated ascites, we identify a tumor-microbiome-renal axis that controls host fluid balance. Tumor-bearing hosts develop severe abdominal fluid accumulation accompanied by marked expansion and systemic dissemination of the gut commensal Acetobacter aceti. Tumor-induced bacterial dissemination activates innate immune signaling in the Malpighian tubules, the insect renal tubules, leading to uric acid accumulation, nephrolithiasis, and progressive ascites. Selective elimination of A. aceti, or renal-tubule-specific suppression of IMD/NF-{kappa}B signaling, abolishes these pathological changes. Conversely, mono-association of axenic hosts with A. aceti is sufficient to recapitulate the ascites phenotype through IMD pathway activation. Together, these findings demonstrate that tumors can remotely induce nephrogenic pathology through species-specific microbiome-dependent immune activation, establishing a mechanistic link between cancer progression and systemic fluid imbalance.

cancer biology↗

bioRxiv2026

The Alternative Polyadenylation Factor CFIm25 Orchestrates Macrophage Antibacterial Immunity by Amplifying TAB2-Mediated MAPK and NF-κB Signaling During Salmonella Infection

Macrophage antimicrobial programs are regulated not only by transcriptional networks but also by RNA processing mechanisms affecting signal transduction and effector responses. One such mechanism, alternative polyadenylation (APA), determines mRNA fate by changing the length of the 3' UTR. However, our understanding of the impact of APA on antibacterial functions and how we can manipulate it to influence infection outcomes remains limited. In this study, we identify the APA regulator CFIm25 (NUDT21) as a promoter of macrophage defense against Salmonella enterica serovar Typhimurium (STM). STM infection is known to drive macrophages toward an M2-like immunosuppressive state conducive to bacterial survival. Concurrent with this transition, the CFIm25 level is reduced, and the 3 UTRs of CFIm25 targets encoding key immune proteins, such as TAB2 and TBL1XR1, are lengthened, suggesting a role for APA changes in the response to STM. Overexpression of CFIm25 in infected macrophages blocks these Salmonella-induced 3 UTR changes, leading to greater mRNA and protein expression. Significantly, the increase in CFIm25 suppresses infection, thereby creating a more antimicrobial intracellular environment, improving macrophage survival, and reducing M2 properties that support bacterial replication. Specifically, CFIm25 enhances production of the antibacterial peptide LL-37, increases reactive oxygen species and nitric oxide levels, suppresses arginase activity and lactate production, and stimulates release of pro-inflammatory cytokines while inhibiting anti-inflammatory cytokines. Depletion studies show TAB2 mediates CFIm25s antibacterial effects by activating both MAPK and NF-kB pathways. Our findings highlight APA regulation as a potential target for boosting immune defenses and developing treatments for chronic bacterial infections.

immunology↗

bioRxiv2025

PDK1 and YAP1/TEAD signaling drive acquired KRAS inhibitor resistance in KRAS-mutant non-small cell lung cancer.

Mutations in KRAS are responsible for driving approximately 30% of NSCLC. While historically considered undruggable, recent breakthroughs have seen the FDA approval of two potent KRASG12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). However, the efficacy of these inhibitors in the clinics has been limited by primary and acquired means of resistance. To elucidate mechanisms of acquired resistance, we generated a panel of resistant cell lines to the allele-specific KRAS inhibitors MRTX849 and MRTX1133 and observed an increased activation of the PDK1 and YAP1/TEAD signaling pathways. Pharmacological inhibition and genetic loss-of-function studies revealed a strong dependence on these pathways for the generation and maintenance of resistance to KRAS inhibition, which was then validated in vitro and in vivo. Furthermore, overexpression studies revealed that forced expression of either PDK1 or YAP1 led to increased resistance to KRAS inhibition in the sensitive lines. Taken together, our findings suggest that co-targeting PDK1 or YAP1/TEAD might be a potential approach to overcoming resistance to KRAS inhibition in NSCLC.

cancer biology↗

bioRxiv2025

Ecological and Stochastic Determinants of the Growth and Persistence of the Oral Pathogen Porphyromonas gingivalis

Population density plays a critical role in microbial fitness, yet its influence on pathogen colonization and persistence remains incompletely understood. Porphyromonas gingivalis (Pg) exhibits Allee-type growth, requiring a quorum threshold to replicate, yet is frequently detected at low abundance in vivo. We integrate quantitative growth experiments with mathematical modeling to identify ecological and stochastic determinants of Pg persistence. A cubic Allee-effect model quantifies a quorum threshold below which populations collapse, while conditioned medium from Veillonella parvula (Vp) lowers this threshold, indicating early-colonizer facilitation. Stochastic extensions and Fokker-Planck analysis show that microenvironmental noise enables escapes across the Allee barrier, consistent with long-term subthreshold experiments yielding a stationary, powerlaw-like distribution and under-threshold survival. Pg-Vp co-cultures further demonstrate replicate rescue outcomes for subcritical inocula. Critically, Vp reliably saturates to capacity, constraining terminal phases within the experimental horizon to coexistence (Pg persists with Vp at capacity) or Pg extinction. A two-species replicator model maps these outcomes onto a ({beta}, {gamma}) plane, restricting accessible regions once Vp is established and suggesting interventions that reduce facilitation or variability to restore eubiosis and limit Pg-associated inflammation.

systems biology↗

bioRxiv2025

CFIm25-Dependent Alternative Polyadenylation in AKT2 mRNA Programs Macrophage Polarization

Macrophage polarization is essential for immune responses, tissue homeostasis, and progression of many diseases. It is a tightly regulated process involving an intricate network of signaling pathways and control mechanisms at the level of transcription, alternative mRNA splicing, translation and mRNA stability. However, regulation through alternative mRNA polyadenylation (APA), remains poorly understood. This study explores the function of CFIm25, a key APA regulator, in macrophage polarization. Our findings show that CFIm25 overexpression drives M1 polarization, as evident from increased nitric oxide synthase activity, CD80 expression, and pro-inflammatory cytokine secretion, but dampens the M2 phenotype. Conversely, CFIm25 knockdown suppresses M1 traits and promotes M2 characteristics. Functionally, CFIm25 enhances phagocytosis, migration, and cancer cell inhibition. Mechanistically, CFIm25 favors proximal polyadenylation site usage of AKT2 mRNA, increasing Akt2 protein levels to support M1 polarization. Blocking this site with an antisense oligonucleotide reduces Akt2 expression and M1 traits. These findings establish CFIm25 as a crucial regulator of macrophage identity, offering insights into RNA-based immune regulation and potential therapeutic targets. In briefCFIm25 drives macrophage polarization toward the M1 phenotype through specific regulatory pathways. The presence of CFIm25 profoundly shifts surface marker expression, enhancing M1 markers while suppressing M2 signatures. This extends to biochemical properties, where CFIm25 boosts nitric oxide and pro-inflammatory cytokine production while reducing anti-inflammatory mediators. Functionally, CFIm25 enhances phagocytosis, inflammatory migration, and cancer cell killing. Mechanistically, this orchestration of the M1 polarization program involves CFIm25s regulation of AKT2 mRNA alternative polyadenylation which increases Akt2 protein expression and amplifies NF-{kappa}B pathway activation, a central driver of M1 polarization. HighlightsO_LICFIm25 overexpression enhances M1 surface markers and biochemical properties including nitric oxide production and pro-inflammatory cytokine secretion. C_LIO_LICFIm25 promotes M1 functional activities including phagocytosis, migration, and cancer-cytotoxic effects. C_LIO_LIBlocking the AKT2 proximal polyadenylation site usage causes a decrease in Akt2 protein, suppressing M1 polarization phenotypes including NOS activity and cytokine profiles. C_LIO_LIThe CFIm25-Akt2-NF-{kappa}B axis represents a novel target for macrophage polarization reprogramming. C_LI O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/660629v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@15e28f6org.highwire.dtl.DTLVardef@d35314org.highwire.dtl.DTLVardef@1f382feorg.highwire.dtl.DTLVardef@1d083d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Alternative Polyadenylation Releases PCBP1-Mediated Suppression of CFIm25 During Macrophage Differentiation

CFIm25, a key component of the CFIm complex needed for mRNA 3 end processing, shows increased protein expression during monocyte-to-macrophage differentiation despite stable mRNA levels. We demonstrate that PCBP1 suppresses CFIm25 translation in monocytes by binding to its long 3UTR. During differentiation, alternative polyadenylation generates a shorter CFIm25 3UTR lacking PCBP1 binding sites. RNA immunoprecipitation confirms PCBP1 binding to the long 3UTR, while ribosome association analysis shows enhanced translation without this interaction. PCBP1 knockdown increases CFIm25 protein specifically in undifferentiated cells and induces macrophage differentiation markers without stimulation. These findings reveal how alternative polyadenylation controls CFIm25 expression during immune cell differentiation by modulating RNA-binding protein interactions and provide insight into post-transcriptional regulation of RNA processing factors.

molecular biology↗

bioRxiv2024

Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

cancer biology↗

bioRxiv2024

Evolution of venom production in marine predatory snails

Venom-secreting glands are highly specialised organs evolved throughout the entire animal kingdom to synthetise and secrete toxins for predation and defence. Venom is extensively studied for its toxin components and application potential; yet, how animals become venomous remains poorly understood. Venom systems therefore offer a unique opportunity to understand the molecular mechanisms underlying functional innovation. Here, we conducted a multi-species multi-tissue comparative transcriptomics analysis of 12 marine predatory gastropods, including species with venom glands and species with homologous non-venom producing glands, to examine how specialised functions evolve through gene expression changes. We found that while the venom gland specialised for the mass production of toxins, its homologous glands retained the ancestral digestive functions. The functional divergence and specialisation of the venom gland was achieved through a redistribution of its ancestral digestive functions to other organs, specifically the oesophagus. This entailed concerted expression changes and accelerated transcriptome evolution across the entire digestive system. The increase in venom gland secretory capacity was achieved through the modulation of an ancient secretory machinery, particularly genes involved in endoplasmic reticulum stress and unfolded protein response. This study shifts the focus from the well-explored evolution of toxins to the lesser-known evolution of the organ and mechanisms responsible for venom production. As such, it contributes to elucidating the molecular mechanisms underlying organ evolution at a fine evolutionary scale, highlighting the specific events that lead to functional divergence.

evolutionary biology↗

bioRxiv2024

The alternative polyadenylation regulator CFIm25 promotes macrophage differentiation and activates the NF-κβ pathway

Macrophages are required for our bodys development and tissue repair and protect against microbial attacks. We previously reported a crucial role for regulation of mRNA 3-end cleavage and polyadenylation (C/P) in monocyte to macrophage differentiation. The CFIm25 subunit of the C/P complex showed a striking increase upon differentiation of monocytes with Phorbol Myristate Acetate, suggesting that it promotes this process. To test this hypothesis, CFIm25 was overexpressed in two different monocytic cell lines, followed by differentiation. Both cell lines showed a significant increase in macrophage characteristics and an earlier slowing of the cell cycle. In contrast, depletion of CFIm25 hindered differentiation. Cell cycle slowing upon CFIm25 overexpression was consistent with a greater decrease in the proliferation markers PCNA and cyclin D1, coupled with increased 3UTR lengthening of cyclin D1 mRNA. Since choice of other poly(A) sites could be affected by manipulating CFIm25, we identified additional genes with altered use of poly(A) sites during differentiation and examined how this changed upon CFIm25 overexpression. The mRNAs of positive regulators of NF-{kappa}B signaling, TAB2 and TBL1XR1, and NFKB1, which encodes the NF-{kappa}B p50 precursor, underwent 3UTR shortening that was associated with increased protein expression compared to the control. Cells overexpressing CFIm25 also showed elevated levels of phosphorylated NF-{kappa}B-p65 and the NF-{kappa}B targets p21, Bcl-XL, ICAM1 and TNF- at an earlier time and greater resistance to NF-{kappa}B chemical inhibition. In conclusion, our study supports a model in which CFIm25 accelerates the monocyte to macrophage transition by promoting alternative polyadenylation events which lead to activation of the NF-{kappa}B pathway.

molecular biology↗

bioRxiv2024

Estimates of molecular convergence reveal pleiotropic genes underlying adaptive variation across teleost fish

Molecular convergence, where specific non-synonymous changes in protein-coding genes lead to identical amino acid substitutions across multiple lineages, provides strong evidence of adaptive evolution. Detecting this signal across diverse taxa can reveal broad evolutionary mechanisms that may not be apparent when studying individual lineages. In this study, we search for convergent substitutions in the most speciose group of vertebrates, teleost fishes. Using an unsupervised approach, we detected convergence in 89 protein-coding genes across 143 chromosomal-level genomes. To assess their functional implications, we integrate data on protein properties, gene expression across species and tissues, single-cell RNA sequencing of zebrafish embryonic development, and gene perturbation experiments in zebrafish. The convergent genes were associated with diverse processes including embryonic development, tissue morphogenesis, metabolism, and responses to hormones and heat stress. The convergent substitutions altered amino acid properties, with some occurring at functionally critical sites. Notably, only one-third of these genes were tissue-specific, while the majority were expressed across multiple tissues and cell types. Genetic perturbation data further showed that the convergent genes can affect multiple structures across diverse tissues. These results highlight the pleiotropic nature of the convergent genes. Using an evolutionary modeling approach, we show that adaptive variation tends to accumulate in genes with intermediate pleiotropy, enabling organisms to overcome selective pressures during ecological shifts. Although traditionally considered a source of constraint, we argue that adaptation via genes with intermediate pleiotropy might be particularly advantageous following periods of ecological shifts, and can potentially lead to the evolution of convergent phenotypes.

evolutionary biology↗

bioRxiv2022

The genetic basis for adaptation in giant sea anemones to their symbiosis with anemonefish and Symbiodiniaceae

Sea anemones in the order Anthozoa play an integral part in marine ecosystems by providing refuge and habitat for various organisms. Despite this, much of their molecular ecology remains elusive. Sea anemones can nurture numerous symbiotic relationships; the most iconic being the one between giant sea anemones and anemonefish. However, the genes and biological processes associated with this symbiosis in the sea anemones in unknown. Additionally, it is unclear how genes can mediate interactions between sea anemones, anemonefish, and symbionts from the algal family Symbiodiniaceae. Here we compared the gene expression profiles of tentacles from several cnidarians to uncover the genetic basis for adaptations in giant sea anemones to their symbiosis with anemonefish and Symbiodiniaceae. We found that tentacle transcriptomes of cnidarians are highly diverse, with closely related species having more similar expression patterns. However, despite an overall high correlation between gene expression and phylogeny, the giant sea anemones showed distinct expression patterns. The giant sea anemones had gene co-expression clusters enriched for processes involved in nutrient exchange and metabolism. These genes were not only differentially expressed, but also experienced evolutionary shifts in expression in giant sea anemones. Using a phylogenetic multilevel model, we found that Symbiodiniaceae and anemonefish significantly affect gene expression in giant sea anemone tentacles. By characterizing gene expression patterns, we identify genes and biological processes that provide evidence for the cross-talk between Symbiodiniaceae, anemonefish, and giant sea anemones. Our study demonstrates how integrated biological processes can lead to the evolution of a successful multi-organism interaction.

evolutionary biology↗

bioRxiv2022

The multi-level regulation of clownfish metamorphosis by thyroid hormones

Most marine organisms have a biphasic life cycle during which a pelagic larva is transformed into a radically different juvenile. In vertebrates the role of thyroid hormones (TH) in triggering this transition is well known, but how the morphological and physiological changes are integrated in a coherent way with the ecological transition remains poorly explored. To gain insight into this question, we performed an integrative analysis of metamorphosis of a marine teleost, the clownfish Amphiprion ocellaris. We reveal how TH coordinate a change in color vision as well as a major metabolic shift in energy production, hence highlighting its central integrative role in regulating this transformation. By manipulating the activity of LXR, a major regulator of metabolism, we also reveal a tight link between metabolic changes and metamorphosis progression. Strikingly, we observed that these regulations are at play in the wild revealing how hormones coordinate energy needs with available resources during life cycle.

developmental biology↗

bioRxiv2021

Lattice-based microenvironmental uncertainty driven phenotypic decision-making: a comparison with Notch-Delta-Jagged signaling

Phenotypic decision-making is a process of determining important phenotypes in accordance with the available microenvironmental information. Although phenotypic decision at the level of a single cell has been precisely studied, but the knowledge is still imperceptible at the multicellular level. How cells sense their environment and adapt? How single cells change their phenotype in a multicellular complex environment (without knowing the interactions among the cells), is still a rheotorical question. To unravel the fragmental story of multicellular decision-making, Least microEnvironmental Uncertainty Principle (LEUP) was refined and applied in this context. To address this set of questions, we use variational principle to grasp the role of sensitivity, build a LEUP driven agent-based model on a lattice which solely hinges on microenvironmental information and investigate the parallels in a well-known biological system, viz., Notch-Delta-Jagged signaling pathway. The analyses of this model led us to interesting spatiotemporal patterns in a population of cells, responsive to the sensitivity parameter and the radius of interaction. This resembles the tissue-level pattern of a population of cells interacting via Notch-Delta-Jagged signaling pathway in some parameter regimes.

biophysics↗

bioRxiv2021

The parallel origins of vertebrate venoms

Evolution can occur with surprising predictability when organisms face similar ecological challenges. How and why traits arise repeatedly remains a central question in evolutionary biology, but the complexity of most traits makes it challenging to answer. Reptiles and mammals independently evolved oral venoms consisting of proteinaceous cocktails that allow mapping between genotype and phenotype. Although biochemically similar toxins can occur as major venom components across many taxa, whether these toxins evolved via convergent or parallel processes remains unknown. Most notable among them are kallikrein-like serine proteases that form the core of most vertebrate oral venoms. We used a combination of comparative genomics and phylogenetics to investigate whether serine protease recruitment into the venom occurred independently or in parallel in mammalian and reptilian lineages. Using syntenic relationships between genes flanking known toxins, we traced the origin of kallikreins to a single locus containing one or more nearby paralogous kallikrein-like clusters. Independently, phylogenetic analysis of vertebrate serine proteases revealed that kallikrein-like toxins in mammals and reptiles are homologous. Given the shared regulatory and genetic machinery, these findings suggest a unified model underlying vertebrate venom evolution. Namely, the common tetrapod ancestor possessed salivary genes that were biochemically suitable for envenomation. We term such genes toxipotent - in the case of salivary kallikreins they already had potent vasodilatory activity that was weaponized by venomous lineages. Furthermore, the ubiquitous distribution of kallikreins across vertebrates suggests that the evolution of envenomation may be more common than previously recognized, blurring the line between venomous and non-venomous animals.

evolutionary biology↗

bioRxiv2021

Close to optimal cell sensing ensures the robustness of tissue differentiation process: the avian photoreceptor mosaic case

The way that progenitor cell fate decisions and the associated environmental sensing are regulated to ensure the robustness of the spatial and temporal order in which cells are generated towards a fully differentiating tissue still remains elusive. Here, we investigate how cells regulate their sensing intensity and radius to guarantee the required thermodynamic robustness of a differentiated tissue. In particular, we are interested in finding the conditions where dedifferentiation at cell level is possible (microscopic reversibility) but tissue maintains its spatial order and differentiation integrity (macroscopic irreversibility). In order to tackle this, we exploit the recently postulated Least microEnvironmental Uncertainty Principle (LEUP) to develop a theory of stochastic thermodynamics for cell differentiation. To assess the predictive and explanatory power of our theory, we challenge it against the avian photoreceptor mosaic data. By calibrating a single parameter, the LEUP can predict the cone color spatial distribution in the avian retina and, at the same time, suggest that such a spatial pattern is associated with quasi-optimal cell sensing. By means of the stochastic thermodynamics formalism, we find out that thermodynamic robustness of differentiated tissues depends on cell metabolism and cell sensing properties. In turn, we calculate the limits of the cell sensing radius that ensure the robustness of differentiated tissue spatial order. Finally, we further constrain our model predictions to the avian photoreceptor mosaic.

biophysics↗

bioRxiv2020

Predicting the tension in actin cytoskeleton from the nucleus shape

Tension in actin cytoskeleton regulates many cellular processes and nuclear morphology. Here, we demonstrate a simple computational method for estimating actin cytoskeletal tension from nucleus shape. We first note that mechanics-based modeling defines a relationship among the volume, surface area, and projected area of the nucleus and hence a specific surface in the three-parameter space of the aforementioned geometric quantities. Data of nuclei from multiple cell types lie on such a surface. Furthermore, nuclei from a given cell population lie on a straight line on the surface. The location and orientation of the line varies with cell type. By using a mechanical model, we present two non-dimensional parameters, namely, the flatness and stretch indicators, which serve as curvilinear coordinates on the surface. Flatness indicator defines the extent of nuclear flattening due to actin cytoskeletal tension and the stretch indicator captures the effect of the elastic modulus of the nuclear envelope. We validate our assertions by modulating the actin cytoskeletal tension using three independent mechanisms: (i) direct downregulation by Cytochalasin D, (ii) indirect upregulation using Nocodazole, and (iii) mechanical stimulation by varying substrate stiffness. We also infer that the flatness indicator is equivalent to the ratio of the height to diameter of the nucleus and is related to the Vogel number. By using this geometric insight, we validate the predictions of our model with data from many previous studies. Finally, we present an analytical formula and a correlation for estimating actin cytoskeletal tension from nuclear projected area and volume.

biophysics↗