Biology subjects

Jain, P.

Publications and source records attributed to Jain, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Weak form Scientific Machine Learning for Systems Biology: A Tutorial on WENDy

Mechanistic ordinary differential equation models are widely used in systems biology to represent biochemical networks, population dynamics, cell-state transitions, and other biological processes; however, their predictive value depends critically on accurate parameter estimation from noisy and often sparse experimental data. In this tutorial, we present the Weak-form Estimation of Nonlinear Dynamics (WENDy) method as a forward-solver-free approach that reformulates parameter estimation as a covariance-corrected weak-form regression problem by integrating the model equations against compactly supported test functions. We present the background on the methodology through the lens of the familiar logistic equation, and we demonstrate applications of the method on real experimental data through two systems biology examples: a glycolytic oscillator with relatively dense time-course data and a sparse epithelial-mesenchymal cellstate transition model with multiple experimental replicates. Ultimately, using WENDy, we estimate interpretable biological parameters with uncertainty for systems with noisy and sometimes sparse available experimental data.

systems biology↗

bioRxiv2026

Functional importance of a structurally encoded succinimide modification in a high-affinity solute-binding protein

Post-translational modifications usually occur under enzymatic control as a mechanism for regulation of protein activity or localization, but can also occur spontaneously during protein aging and degradation. In contrast, there are few examples of spontaneous post-translational modifications with a significant role in the stability or biochemical function of a bacterial protein. Here we show that a spontaneous post-translational modification is structurally encoded and functionally important in a bacterial solute-binding protein. We show that the solute-binding protein SAR11_0655 from the abundant SAR11 marine bacterium Pelagibacter ubiqueversans contains an unusually stable succinimide residue important for its function in high-affinity binding of the amino acid derivative 5-oxoproline. Spontaneous cyclization of Asn269 to form a succinimide residue was inferred from high-resolution X-ray crystallography and confirmed by liquid chromatography-tandem mass spectrometry. Loss of the succinimide modification via the substitution N269A resulted in a >20 {degrees}C decrease in thermostability and a 15 to 50-fold decrease in binding affinity for 5-oxoproline. Analysis of sequence conservation indicated that both Asn269 and Asp269 are common among SAR11_0655 homologs, and the N269D variant of SAR11_0655 also showed partial formation of succinimide. These results reveal a previously unrecognized mechanism by which proteins exploit spontaneous post-translational chemistry as a design feature to enhance stability and function, and provides a potential basis for identification and design of structurally encoded succinimide residues for engineering of protein thermostability.

biochemistry↗

bioRxiv2026

Time-dependent memory of hypoxia exposure influences tumor invasion dynamics

Cancer cells in hypoxic environments often proliferate less but exhibit enhanced migration relative to their normoxic counterparts. Recent in vitro and in silico studies have characterized the role of hypoxic memory - the ability of cancer cells to retain their hypoxic phenotype even when reoxygenated - in tumor invasion. However, the observations have been limited either to exposing cancer cells to hypoxia for a fixed duration or by assuming a fixed-time persistence of the hypoxic state upon reoxygenation independent of the duration of hypoxia exposure. Thus, time-dependent cell-state changes during hypoxia and their impact on hypoxic memory remains unclear. Here, we first analyze transcriptomic data from breast cancer samples to show that the genes upregulated at transcriptional level and hypomethylated at epigenetic level are enriched in cell invasion, indicating hypoxic memory-driven process of tumor invasion. Next, we used a computational model to investigate how the spatial-temporal dynamics of oxygen levels in a tumor drive time-dependent changes in hypoxic memory and influence tumor invasion dynamics. Our simulation results show that such dynamic hypoxic memory can drive enhanced tumor invasion over a fixed hypoxic memory by a) enriching hypoxic cell density at the tumor front, b) reducing sensitivity of hypoxic cell state to fluctuations in oxygen supply, and c) enhancing effective diffusion of hypoxic cells. Our results highlight the crucial role of dynamic hypoxic memory in shaping tumor invasion dynamics, underscoring the need to elucidate its underlying mechanisms in future studies.

systems biology↗

bioRxiv2025

A phenotype-structured PDE framework for investigating the role of hypoxic memory on tumor invasion under cyclic hypoxia

Tumor growth and angiogenesis drive complex spatiotemporal variation in micro-environmental oxygen levels. Previous experimental studies have observed that cancer cells exposed to chronic hypoxia retained a phenotype characterized by enhanced migration and reduced proliferation, even after being shifted to normoxic conditions, a phenomenon which we refer to as hypoxic memory. However, because dynamic hypoxia and related hypoxic memory effects are challenging to measure experimentally, our understanding of their implications in tumor invasion is quite limited. Here, we propose a novel phenotype-structured partial differential equation modeling framework to elucidate the effects of hypoxic memory on tumor invasion along one spatial dimension in a cyclically varying hypoxic environment. We incorporated hypoxic memory by including time-dependent changes in hypoxic-to-normoxic phenotype transition rate upon continued exposure to hypoxic conditions. Our model simulations demonstrate that hypoxic memory significantly enhances tumor invasion without necessarily reducing tumor volume. This enhanced invasion was sensitive to the induction rate of hypoxic memory, but not the dilution rate. Further, shorter periods of cyclic hypoxia contributed to a more heterogeneous profile of hypoxic memory in the population, with the tumor front dominated by hypoxic cells that exhibited stronger memory. Overall, our model highlighted the complex interplay between hypoxic memory and cyclic hypoxia in shaping heterogeneous tumor invasion patterns.

systems biology↗

bioRxiv2025

Minimal Perturbation of Activation Loop Dynamics Rewires KinaseSignaling

Enzymes are central to life, with their catalytic activity often shaped by the dynamic conformations of regulatory loops. In hub enzymes such as tyrosine kinases, the activation loop critically controls substrate specificity, catalytic efficiency, and downstream signaling, shaping cellular fate. Yet, the molecular mechanisms by which loop dynamics encode these functions remain incompletely understood. Here, we used SRC kinase as a model to dissect how minimal perturbations of the activation loop reprogram kinase behavior. By generating and characterizing multiple variants, we identified a triple-deletion mutant with altered loop dynamics. Structural and biochemical analyses revealed that this variant explores distinct loop conformations and exhibits a subtle shift in substrate preference toward more acidic motifs. These fine-tuned conformational changes translated into specific cellular signaling outcomes, as demonstrated by phosphoproteomic profiling. Comparative analysis across species further showed that nature exploits similar loop remodeling strategies to modulate kinase function. Together, our findings provide a blueprint for rationally tuning kinase activity and offer a generalizable framework for rewiring signaling pathways in diverse cellular contexts.

biochemistry↗

bioRxiv2025

Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas

Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using luciferase-labeled JeKo-1 and Maver mantle cell lymphoma xenografts demonstrate that ACSS1 knockdown significantly suppresses tumor growth. NSG mice injected with ACSS1-silenced cells exhibit a marked reduction in tumor burden, as measured by bioluminescence imaging and total photon flux, with significant differences observed at days 14 and 21 post-injection. These findings establish that ACSS1 is required not only for metabolic adaptation in vitro but also for lymphoma progression in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability. Statement of SignificanceThis study identifies ACSS1 as a critical metabolic vulnerability in mantle cell lymphoma (MCL), linking mitochondrial acetate metabolism to de novo pyrimidine biosynthesis and tumor progression. We demonstrate that ACSS1 is frequently overexpressed in MCL and is essential for converting acetate into mitochondrial acetyl-CoA, thereby sustaining TCA cycle activity, nucleotide production, and cell survival under nutrient stress. Loss of ACSS1 disrupts this acetate-pyrimidine axis, impairing oxidative metabolism and reducing lymphoma cell viability in vitro. Importantly, ACSS1 silencing significantly suppresses tumor growth in vivo, establishing its requirement for lymphoma progression. The ability of acetate or uridine supplementation to rescue ACSS1-deficient cells further highlights the functional coupling between mitochondrial acetate utilization and nucleotide synthesis. Together, these findings reveal a previously unrecognized mechanism of metabolic adaptation in aggressive lymphomas and offer ACSS1-mediated acetate metabolism as a promising therapeutic target.

cancer biology↗

bioRxiv2025

Identification of novel exosomal miRNAs and their role in diagnosis and prognosis of Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype with poor prognosis and limited treatment options. Exosomal microRNAs (miRNAs), encapsulated within secretory vesicles, have emerged as promising biomarkers for cancer detection and monitoring. In this study, we identify five novel exosomal miRNAs--hsa-miR-6803, hsa-miR-1180, hsa-miR-4728, hsa-miR-1915, and hsa-miR-940--that are consistently overexpressed in TNBC cells, stem-like subpopulations, and patient tumor tissues. Integrated analysis of public datasets and in vitro validation revealed that elevated expression of these miRNAs correlates with poor overall survival. Functional assays demonstrated that miR-1180 and miR-4728 significantly promote TNBC cell migration and invasion. These miRNAs also target critical oncogenic pathways, including Wnt, Notch, and EGFR. Their enrichment in exosomes highlights their translational potential as liquid biopsy-based biomarkers and therapeutic targets. This work is the first to link this miRNA panel to both TNBC tumorigenesis and stem-like cell biology, offering new insights into disease progression and potential strategies for personalized care.

cancer biology↗

bioRxiv2025

How memory and adaptation cost shape cell phenotypic dynamics in response to fluctuating environments

Cells invariably encounter unpredictable changes in their microenvironment and adapt by orchestrating substantial alterations in their molecular states, often resulting in appreciable phenotypic changes. The timescale of molecular adaptation depends on how quickly a cell loses its molecular memory of past environmental encounters through the degradation rate of proteins unfavorable to the current environment. Concurrently, de novo synthesis of favorable biomolecules during adaptation imposes an energetic cost that impacts cellular fitness. Here, by developing a phenomenological model of intracellular processing of environmental signals and associated cell-state switching, we study the dynamical implications of cellular memory and adaptation cost on cellular responses to a changing environment. We find that while increasing cellular memory reduces cell fitness in periodic environments, counterintuitively, increasing adaptation cost can improve growth by minimizing mismatches between the environment and the cell state. Similarly, we observed a variable role of memory capacity and adaptation cost for stochastic correlated environments, with increasing memory and cost improving cellular fitness in negatively but not positively correlated environments. Lastly, we show that cellular memory and population heterogeneity in adaptation cost explained reported experimental observations in melanoma: increased population survival during drug treatment when the population was either enriched for rare cells expressing resistance marker genes or primed with low-dose drug treatment before exposure to high-dose treatment. Overall, this work establishes a foundational model for studying how cellular memory dynamics and adaptation cost drive cellular adaptation under different environmental conditions and explain complex cellular behaviors.

systems biology↗

bioRxiv2025

Frontal Vulnerability vs. Temporal Resilience: Neuro-compensatory mechanisms underline differential language aging trajectories

Age-related decline underlies cognitive functions such as sensorimotor control, executive functioning, memory, and language production (LP), whereas language comprehension (LC) tends to remain intact or improve across healthy adult lifespan. This preservation likely stems from structural and functional integrity within core language network (cLAN) regions. To investigate this hypothesis, we analyzed the relationships among brains resting-state functional connectivity (FC), structural connectivity (SC), and language behaviour (LC and LP) using a cross-sectional cohort of healthy adults (N = 652; M/F = 322/330; aged 18-88) from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset. Six cognitive tasks assessing LC and LP were employed, with neuroimaging measures focused on region-specific connections within the cLAN. Using generalized additive mixed models (GAMMs), complex brain-behaviour interactions were identified. Behavioral analyses revealed established age-related dichotomy, LC abilities in vocabulary and proverb comprehension improved and in syntactic and semantic comprehension remained stable, whereas LP tasks, e.g., verbal fluency, picture priming, and tip of tongue exhibited significant decline across the lifespan. SC exhibited decline in both intra-and inter-hemispheric fronto-temporal and frontal lobe connections, contrasted by preserved or enhanced temporal lobe connectivity, supporting a pattern of frontal vulnerability concomitant with temporal resilience. Age-related FC patterns demonstrated overall preservation, reflecting compensatory mechanisms to sustain functional integrity despite structural degradation. GAMM analyses revealed complex relationships between brain connectivity and language performance across age. Thus, integrating knowledge of brain structure, function, and language abilities, we identified the brain network mechanisms associated with dichotomous language behavior along lifespan. SignificanceUnderstanding age-related changes in language abilities is vital for early detection of cognitive decline and intervention development. This study reveals heterogeneous language aging trajectories: language production often declines, while comprehension remains stable or improves. Notably, comprehension tasks with high executive and working memory demands also show resilience, suggesting compensatory mechanisms beyond crystallized knowledge. Using multimodal neuroimaging in a large adult lifespan cohort, we link behavioral patterns to distinct network dynamics within the core language system. We uncover relative vulnerability in frontal brain regions, with pronounced structural decline in fronto-temporal pathways, contrasted by resilience in temporal connectivity, which is preserved or strengthened. These findings highlight regionally specific vulnerabilities and compensatory functional adaptations, refining current models and providing a framework to guide research promoting healthy cognitive aging.

neuroscience↗

bioRxiv2025

Impacts of competition and phenotypic plasticity on the viability of adaptive therapy

Cancer is heterogeneous and variability in drug sensitivity is widely documented across cancer types. Adaptive therapy is an emerging modality of cancer treatment that leverages this drug resistance heterogeneity to improve therapeutic outcomes. Current standard treatments typically eliminate a large fraction of drug-sensitive cells, leading to drug-resistant relapse due to competitive release. Adaptive therapy aims to retain some drug-sensitive cells, thereby limiting resistant cell growth by ecological competition. While early clinical trials of such a strategy have shown promise, optimisation of adaptive therapy is a subject of active study. Current methods largely assume cell phenotypes to remain constant, even though cell-state transitions could permit drug-sensitive and -resistant phenotypes to interchange and thus escape therapy. We address this gap using a deterministic model of population growth, in which sensitive and resistant cells grow under competition and undergo cell-state transitions. Based on the models steady-state behaviour and temporal dynamics, we identify distinct balances of competition and phenotypic transitions that are suitable for effective adaptive versus constant dose therapy. Our data indicate that under adaptive therapy, models with cell-state transitions show a higher frequency of fluctuations than those without, suggesting that the balance between ecological competition and phenotypic transitions could determine population-level dynamical properties. Our analyses also identify key limitations of applying phenomenological models in clinical practice for therapy design and implementation, particularly when cell-state transitions are involved. These findings provide an overall perspective on the relevance of phenotypic plasticity for emerging cancer treatment strategies using population dynamics as an investigation framework. Significance StatementDrug-sensitive and -resistant cancer cells can compete with each other within the same tumour, and adaptive therapy exploits this competition to control overall tumour growth. The fact that sensitive and resistant cell types can switch phenotypes complicates the implementation of adaptive therapy. Our ODE-based theoretical ecology framework shows that asymmetric competition favouring sensitive cells generally benefits therapy outcomes, while phenotypic plasticity is usually detrimental. Our model also provides cell population-level indicators that can help predict the underlying balance between competition and plasticity. Phenomenological models are limited by whether their parameters can be reliably identified given scarce data, and our study illuminates the scope of such models in understanding cancer population dynamics and the need for mechanistic modelling.

systems biology↗

bioRxiv2025

Loss of plasma membrane conductance in outside-xylem zone explains non-stomatal control of transpiration

The conventional assumption is that stomatal conductance (gs) dominates the regulation of water and carbon dioxide fluxes between leaves and the atmosphere. Here, a nanoreporter of water status at the mesophyll cell surface and local xylem within intact maize leaves documents significant undersaturation of water vapor in the outside-xylem zone (OXZ) and a large loss of conductance of this zone (goxz) at moderate xylem water stress (no turgor loss). The ratio of the resistances (1/goxz)/(1/gs) serves as a predictive phenotype of undersaturation, non-stomatal regulation of transpiration, errors in standard gas exchange analysis, and an increase of intrinsic water use efficiency (iWUE). Cell-scale access to water status reveals symplasmic-apoplasmic disequilibrium and informs a biophysical model that can explain experimental observations quantitatively based on localization of variable conductance to the plasma membrane. This work opens new paths of inquiry into the molecular basis and functional consequences of non-stomatal regulation of transpiration.

plant biology↗

bioRxiv2025

Mapping the dimerization specificity of bZIP transcription factors in bread wheat

Dimerization plays a pivotal role in target-binding interactions among various transcription factors (TFs), including bZIPs, bHLHs, MYBs, and zinc finger TFs. The bZIP family is defined by an -helix class of TFs containing a basic region that binds to the major groove of double-stranded DNA (dsDNA), followed by a leucine zipper motif that mediates dimerization through coiled-coil structures, forming homo- or heterodimers. In polyploid bread wheat (Triticum aestivum cv.), bZIPs and their homeologs interact through the dimerization motifs to form specific bZIP pairs with distinct regulatory functions. The dimerization pattern of bZIPs is critical for gene regulation, however, the mechanisms underlying their specificity remain poorly understood. Here, we focus on the dimerization specificity of coiled-coil - helical bZIP proteins in bread wheat, highlighting the leucine zipper region as a key dimerization motif. We identified 265 bZIPs containing the bZIP motif, following dimerization criteria established in humans, Drosophila, and Arabidopsis based on the presence of specific amino acids at the a, d, e, and g positions in heptads. Eight key bZIP TFs were cloned, expressed, and purified for the structural analysis. This study not only provides the dimerization trend exhibited by bZIPs during thermal stability analysis but also provides the reversibility pattern followed by the thermal denaturation exposure at 85{degrees}C. Our study also points towards that how amino acid substitutions and the length of the leucine zipper influence the formation of coiled-coil structures among bZIP homeologs of polyploid wheat. Overall, the study advances our understanding of the role of leucine zippers, in determining the specificity and stability of bZIP dimers, which in turn governs DNA binding and gene regulation in plants.

biochemistry↗

bioRxiv2024

Mitochondrial ACSS1 regulates the oncometabolite 2-hydroxyglutarate and De Novo Pyrimidine biosynthesis under nutrient-deprived conditions in lymphoma

The mitochondrial Acetyl-CoA synthetase short-chain family member 1 (ACSS1) converts acetate, an energy source in nutrient-deprived conditions, to mitochondrial acetyl-CoA. However, the specific mechanism behind this process remains unknown. Here, we show that ACSS1 is overexpressed in patients with mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and Ibrutinib (IBR)-resistant cell lines. The mitochondrial stress test showed reduced oxygen consumption in ACSS1 knockdown (KD) cell lines. 13C-acetate stable isotope tracing revealed that ACSS1 knockdown (KD) in MCL cell lines attenuates the flux of mitochondrial acetate to acetyl-CoA, acetylcarnitine, and TCA cycle intermediates, including glutamine and aspartate, which are precursors for de novo pyrimidine synthesis. Consistently, there was a decrease in the labeling of glutamate, aspartate, dihydroorotate, and orotate pools in KD cell lines. Pathway analysis revealed the enrichment of de novo pyrimidine synthesis metabolites and depleting ACSS1 impaired cell growth and potential vulnerability of IBR-resistant MCL cells. Further, we discovered that acetate is used to synthesize 2-hydroxyglutarate in an ACSS1-dependent manner, and it is involved in histone methylation. These results highlight a metabolic phenotype in MCL cells, showing their ability to metabolize acetate in nutrient-deprived conditions and provide new insights into the role of ACSS1 in cancer metabolism. SignificanceThe enzyme ACSS1 catalyzes the conversion of acetate, an energy source in nutrient-deprived conditions, to mitochondrial acetyl-CoA. Our results show that ACSS1 may affect cancer metabolism, particularly in MCL. Studies using MCL cell lines showed that reducing ACSS1 activity affects acetate utilization for various metabolic pathways and influences the production of oncometabolite D-2-hydroxyglutarate. Additionally, reducing ACSS1 activity affects the expression of cyclin D1 and inhibits cell growth, highlighting the potential significance of ACSS1 in cancer metabolism.

cancer biology↗

bioRxiv2024

Oxidative Phosphorylation Inhibition in Different Prostate Cancer Models and the Interplay with Androgen Receptor Signaling

IntroductionIn prostate cancer (PCa), androgen receptor signaling stimulates both glycolysis and oxidative phosphorylation (OxPhos). Early-stage prostate cancer is particularly reliant on OxPhos for its bioenergetic needs. OxPhos inhibitors have entered clinical trials. Here we investigated their interplay with androgens in different PCa cell lines. MethodsWe investigated the effects on PCa cell viability of an ATPase inhibitor (oligomycin) and a complex 1 inhibitor (IACS-010759) in the presence or absence of low testosterone concentrations in vitro. Both androgen-sensitive and insensitive PCa cell lines were used. The effects were assessed using MTT assay, flow cytometry and cell morphology. ResultsTreatment with oligomycin resulted in massive apoptotic death of VCAP cells in castrate conditions within 48 hours, but the simultaneous addition of low testosterone levels restored VCAP cell viability. However, complex 1 inhibition with IACS-010759 increased cell viability, which was further promoted in the presence of testosterone. Both oligomycin and IACS-010759 dramatically decreased viability in LNCaP cells, while testosterone had a small but statistically non-significant effect. The antitumor effect of OxPhos inhibitors was smaller in LNCaP-C4-2B compared to LNCaP cells. OxPhos inhibitors slightly decreased proliferation rates in androgen-independent PC3 cells and HEK293 cells. Oligomycin on LNCaP-C4-2B and PC3 cells resulted in an increased number of cells in G0-G1 phase and decreased in S-phase and G2M phase, rather than massive apoptosis. ConclusionThere is an interplay between androgen signaling and OxPhos in androgen-dependent PCa cells. Complex 1 inhibitors should be used with caution, given potential pro-tumorigenic effects in subsets of PCa cells.

cancer biology↗

bioRxiv2024

Effects of Tasks on Functional Brain Connectivity Derived from Inter-Individual Correlations: Insights from Regional Homogeneity of Functional MRI Data

Research on brain functional connectivity often relies on intra-individual moment-to-moment correlations of functional activity, typically using functional MRI (fMRI). Inter-individual correlations are also employed on data from fMRI and positron emission tomography (PET). Many studies have not specified tasks during scanning, keeping participants in an implicit "resting" condition. This lack of task specificity raises questions about how different tasks impact inter-individual correlation estimates. In our analysis of fMRI data from 100 unrelated participants, scanned during seven tasks and in a resting state, we calculated Regional Homogeneity (ReHo) for each task as a regional measure of brain functions. We found that changes in ReHo due to tasks were relatively small compared with its variations across brain regions. Cross-region variations of ReHo were highly correlated among tasks. Similarly, whole-brain inter-individual correlation patterns were remarkably consistent across the tasks, showing correlations greater than 0.78. Changes in inter-individual correlations between tasks were primarily driven by connectivity in the visual, somatomotor, default mode network, and the interactions between them. This subtle yet statistically significant differences in functional connectivity may be linked to specific brain regions associated with the studied tasks. Future studies should consider task design when exploring inter-individual connectivity in specific brain systems. Impact StatementInter-individual correlation is increasingly used to estimate brain connectivity, complementing intra-individual correlations in fMRI, particularly for measures like cerebral blood flow obtained via fMRI and PET. However, how task performance affects inter-individual correlations is largely unknown. This study used regional homogeneity as a summary measure of brain functions from task-based fMRI data across eight tasks. The inter-individual correlations were highly similar across tasks, indicating the underlying brain network structure can be inferred under various conditions. Subtle but statistically significant differences in connectivity estimates suggest the functional significance of this approach.

neuroscience↗

bioRxiv2024

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease models

Human genetics implicate defective myeloid responses in the development of late onset, age-associated Alzheimers disease (AD). Aging is characterized by a decline in myeloid metabolism that triggers maladaptive, neurotoxic immune responses. TREM1 is an amplifier of pro-inflammatory myeloid responses, and here we find that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation, and hippocampal memory function. Trem1 deficiency rescues age-associated declines in ribose-5P, a glycolytic intermediate and the precursor for purine, pyrimidine, and NAD+ biosynthesis. In vitro, Trem1 deficient microglia are resistant to bioenergetic changes induced by amyloid-{beta}42 oligomers (A{beta}42), suggesting that A{beta}42 stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD model of amyloid accumulation, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy independent of amyloid accumulation or changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency restores synaptic mitochondrial function and cerebral glucose uptake and prevents hippocampal memory decline. In post-mortem human brain, microglial TREM1 expression increases with clinical and neuropathological severity. Thus, TREM1-mediated disruption of myeloid metabolism, both in the periphery and brain, promotes cognitive decline in aging and amyloid accumulation, two major risk factors for AD development.

neuroscience↗

bioRxiv2023

Cell-state transitions and frequency-dependent interactions among subpopulations together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity in breast cancer

Individual cells in a tumour can be distributed among Epithelial (E) and Mesenchymal (M) cell-states, as characterised by the levels of canonical E and M markers. Even after E and M (E-M) subpopulations are isolated and then cultured independently, E-M heterogeneity can re-equilibrate in each population over time, sometimes regaining the initial distribution of the parental cell population. However, it remains unclear which population-level processes give rise to the dynamical changes in E-M heterogeneity observed experimentally, including 1) differential growth, 2) cell-state switching, and 3) frequency-dependent growth or state-transition rates. Here, we analyse the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that growth differences among E and M subpopulations, with and without any frequency-dependent interactions (cooperation or suppression) among E-M sub-populations, are insufficient to explain the observed population dynamics. This insufficiency is ameliorated by including cell-state transitions, albeit at slow rates, in explaining both PMC42-LA and HCC38 cells data. Further, our models predict that treatment of HCC38 cells with TGF{beta} signalling and JAK2/3 inhibitors could significantly enhance the transition rates from M state to E state, but does not prevent transitions from E to M. Finally, we devise a selection criterion to identify the next most informative time points for which future experimental data can optimally improve the identifiability of our estimated best fit model parameters. Overall, our study identifies the necessary population-level processes shaping the dynamics of E-M heterogeneity in breast cancer cells.

systems biology↗

bioRxiv2023

CDK12/CDK13 inhibition disrupts a transcriptional program critical for glioblastoma survival

Glioblastoma is the most prevalent and aggressive malignant tumor of the central nervous system. With a median overall survival of only one year, glioblastoma patients have a particularly poor prognosis, highlighting a clear need for novel therapeutic strategies to target this disease. Transcriptional cyclin-dependent kinases (tCDK), which phosphorylate key residues of RNA polymerase II (RNAPII) c-terminal domain (CTD), play a major role in sustaining aberrant transcriptional programs that are key to development and maintenance of cancer cells. Here, we show that either pharmacological inhibition or genetic ablation of the tCDKs, CDK12 and CDK13, markedly reduces both the proliferation and migratory capacity of glioma cells and patient-derived organoids. Using a xenograft mouse model, we demonstrate that CDK12/13 inhibition not only reduces glioma growth in vivo. Mechanistically, inhibition of CDK12/CDK13 leads to a genome-wide abrogation of RNAPII CTD phosphorylation, which in turn disrupts transcription and cell cycle progression in glioma cells. In summary, the results provide proof-of-concept for the potential of CDK12 and CDK13 as therapeutic targets for glioblastoma. Significance statementGlioblastoma is a common, aggressive, and invasive type of brain tumor that is usually fatal. The standard treatment for glioblastoma patients is surgical resection, radiotherapy, and chemotherapy with DNA-alkylating agents, and unfortunately current treatments only extend overall survival by a few months. It is therefore critical to identify and target additional biological processes in this disease. Here, we reveal that targeting a specific transcriptional addiction for glioma cells by inhibition of CDK12/CDK13 disrupts glioma-specific transcription and cell cycle progression and has potential to provide a new therapeutic strategy for glioblastoma.

cancer biology↗