Biology subjects

Mitra, A.

Publications and source records attributed to Mitra, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Petal photosynthesis and dynamic alterations of carbon metabolism orchestrate floral maturation in Gardenia carinata

During maturation, flowers exhibit complex and finely-coordinated metabolic events facilitating various physiological changes that occur in a short time-span. The floral carbon metabolism underpins a metabolic frame, which provides energy and metabolites to drive the life-processes in flowers. However, studies on floral maturation in the past mostly focused on specialized metabolism or certain metabolite classes of central carbon metabolism. This study aims to provide a detailed insight into the dynamics of floral carbon metabolism and its role in flower maturation; it also addresses a long-standing question on the role of petal photosynthesis in floral maturation. In this report, time-course metabolomic studies were integrated with various physiological, enzymological, histochemical and ultrastructural findings to present a multi-layered investigation on the maturation physiology of Gardenia carinata flowers. This integrated approach revealed the characteristic metabolic features of different floral maturation stages, and also highlighted the metabolic rearrangements that allow each stage to establish their characteristic metabolic state. The photosynthetic bud stages showed metabolism inclined toward active growth and carbon reserve accumulation. A shift to energy-rich metabolism was observed as the flowers unfurled, probably to support energy-demanding events such as flower opening and changes in specialized metabolism. Our study further demonstrates the mechanisms underlining the transition from autotrophic to heterotrophic metabolism during maturation, which also reflects the plasticity in source-sink dynamics of flowers. We envisage that this study could provide a springboard for elucidating the roles of individual metabolites and enzymes in regulating floral maturation.

plant biology↗

bioRxiv2026

Calsyntenin-1 and calsyntenin-3 coordinate TGN exit of axonal cargoes

Neurons rely on precise biosynthetic protein transport from the soma to the axon and dendrites. Brain-enriched calsyntenins (CSTN1-3) are unique transmembrane adaptors that link cargo to kinesin-1 for transport. Yet, the neuronal distribution and interdependence of the three CSTN paralogs remain unclear. Here, we dissected their subcellular localization and contribution to biosynthetic protein transport. CSTN paralogs were predominantly localized to the TGN and axonal vesicles, with CSTN1 and CSTN3 showing higher expression levels than CSTN2. Depletion of either CSTN1 or CSTN3 affected axonal abundance of the other, suggesting that they function within the same pathway. Consistently, knockdown of CSTN1 or CSTN3, but not CSTN2, impaired the TGN exit and transport of multiple biosynthetic cargoes to the axon. Interestingly, most CSTN-positive vesicles exiting the TGN and in the axon were marked by the biosynthetic trafficking regulator RAB6A. Furthermore, we identified opposing, paralog-specific roles of CSTN1 and CSTN3 in regulating RAB6A levels at the TGN, thereby contributing to Golgi organization and axonal trafficking. Loss of CSTN1 reduced RAB6A and induced Golgi compaction, whereas loss of CSTN3 increased RAB6A and promoted Golgi dispersal. Together, we reveal that CSTN1 and CSTN3 have distinct, yet intersecting roles in the regulation of biosynthetic axonal transport.

Cell Biology↗

bioRxiv2026

High-throughput discovery of arginine-depleted peptides enables effective antisense delivery for Duchenne muscular dystrophy

Phosphorodiamidate morpholino oligomers (PMOs) are approved exon-skipping antisense therapeutics for Duchenne muscular dystrophy (DMD), but their clinical utility is limited by poor uptake in muscle tissue, necessitating frequent high-dose administration. Cell-penetrating peptides (CPPs) can enhance intracellular delivery of PMOs, yet conventional arginine-rich CPPs often cause dose-limiting toxicity, including renal damage, which hinders their clinical translation. To address this challenge, we developed a high-throughput, charge-based chromatographic enrichment platform capable of screening over 15,000 synthetic peptides, including sequences with noncanonical (abiotic) amino acids. This approach enabled de novo discovery of arginine-depleted CPPs with improved delivery profiles. Four lead candidates demonstrated efficient nuclear PMO delivery with ~10-fold lower in vitro toxicity compared to standard CPPs such as penetratin. The top-performing peptide, CXP1, showed robust splice-switching activity and favorable tolerability in both cellular and animal models. In dystrophic mdx mice, CXP1-PMO conjugates achieved greater exon skipping compared to PMOs conjugated to R6G at equivalent doses. Tissue levels of CXP1-PMO correlated with exon-skipping efficacy, establishing a clear pharmacokinetic-pharmacodynamic relationship. These findings highlight a mechanistically novel and translationally relevant discovery strategy, demonstrating the potential of high-throughput platforms to generate more effective CPP-based delivery vehicles for antisense therapeutics in DMD and related neuromuscular disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=44 SRC="FIGDIR/small/730741v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@84b7f2org.highwire.dtl.DTLVardef@1487850org.highwire.dtl.DTLVardef@d2e263org.highwire.dtl.DTLVardef@10ce371_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2026

Intrinsic space-time couplings governing multi-scale cortical dynamics

The neocortex covers a vast expanse of the mammalian brain and represents the principal target of clinical neuromodulation; however, the global principles of neocortical operation have been challenging to identify. In this regard, a limitation has been tracking activity with cortex-wide spatial coverage while maintaining access to the millisecond temporal resolution of neuronal firing-- a crucial combination not achievable with existing recording technologies. Here we introduce and apply conformal immersion microscopy, enabling activity tracking across the entire dorsal cortex with millisecond temporal resolution and 100 {micro}m spatial resolution (thus spanning five orders of magnitude in time and four in space), at sufficient sensitivity to resolve single-trial activity beyond 100 Hz. Drawing on physics-based frameworks, we apply multiscale analysis to identify a fundamental frequency-dependent coherence length that partitions the neocortex into discrete dynamical elements with well-defined propagation speeds, boundaries, and scale-invariant dynamics. These dynamical elements were found to be conserved from sub-threshold to suprathreshold (neuronal firing) regimes of neural activity, and were robust to diverse pharmacological, optogenetic, and genetic interventions. However, it was possible to identify and establish conditions allowing elemental boundaries to be selectively overridden, and to allow perturbation of specific elements even while conserving global dynamical architecture. Together, these findings enable measurement of intrinsic spatiotemporal parameters governing the dynamical organization of neocortex, which may provide a foundation for mechanistically-informed basic and translational understanding.

neuroscience↗

bioRxiv2026

Causal and directional elements of global brain dynamics

Mammalian cognition appears to involve coordinated neural activity within and across brain-spanning networks. However, the governing principles of large-scale integration remain largely unknown. Here we developed an approach to record spontaneous cortex-wide neural activity (including with novel genetically encoded activity sensors), over very long timescales, and applied unbiased computation to capture conserved spatiotemporal regularities in these data. Initial screening extracted a set of directional elements: consistent spatiotemporal patterns of cortical activity that generalized across excitatory and inhibitory neuronal cell types as revealed by genetic targeting of activity sensors. In particular, novel genetically encoded voltage-sensing strategies revealed that the directional elements were not only highly conserved, but also were represented across the full neural activity frequency spectrum including the fastest timescales (gamma rhythms) enabled by voltage-sensing. Exploiting the spatiotemporal structure revealed by these directional elements, we tested for causal rules governing cortical network activation, using patterned optogenetic stimulation combined with activity imaging. We found that the directional propagation structure of these elements encoded a causal control hierarchy, as source regions (but not sink regions) sufficed to drive full element recruitment--a principle that held across all tested directional elements. Employing a panel of psychotropic drugs, we showed that directional element structure and excitability were robust to manipulations of neural and behavioral state, even as spontaneous network dynamics were reshaped in compound-specific ways. Finally, we developed and applied an all-optical sensing/control approach targeting the directional elements in a behavioral visual detection paradigm, revealing contributions of these conserved large-scale dynamics to elevated sensorimotor behavioral performance.

neuroscience↗

bioRxiv2026

Accelerated amyloid neurodegeneration in HIV-1-infected APP-KI Alzheimer's disease mice

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSA higher incidence of dementia, including Alzheimer s-like pathology, is observed in aged people living with HIV-1. However, mechanisms linking HIV-1 to Alzheimers disease (AD) pathology remain unclear, due to the lack of animal models that allow for concurrent study. METHODSWe created a novel APP knock-in (KI) AD mouse, NOG/APPKM670,671NL/IL-34 (hNAIL) that permits study of progressive brain HIV-1 replication. The mice harbor human microglia-like cells. Four-month-old CD34+ human cell reconstituted mice infected with the HIV-1ADA strain facilitated studies of HIV-1 replication on AD pathologies. RESULTSHIV-1 replication increased A{beta} levels and reduced synaptic and neuronal integrity. Spatial transcriptomics demonstrated distinct A{beta} and HIV-1 transcriptional patterns, whereas dual diseased combinations amplified AD pathology. Neurons showed highest transcriptional change, with genes linked to neuroinflammation, protein trafficking, and synaptic dysfunction. DISCUSSIONThe hNAIL mice enable interrogation of HIV-AD comorbidities, with a future potential for the development of novel therapeutic interventions.

neuroscience↗

bioRxiv2026

Intraflagellar transport of tubulin maintains steady-state axoneme integrity in C. elegans cilia

The integrity of the axoneme - the microtubule (MT)-based core of the cilium - and intraflagellar transport (IFT) are interdependent. The mechanisms determining axoneme structure and dynamics have remained largely unknown, especially in primary cilia with a more variable architecture and longer MT singlet parts. Using fluorescence imaging in the phasmid neurons of C. elegans, we here demonstrate that {beta}-tubulin isotype TBB-4 diffuses through the dendrite and employs a combination of anterograde IFT and diffusion to reach the sites of incorporation in the steady-state axoneme. Disrupting tubulins ability to bind to the IFT significantly reduces its share in the axoneme. We suggest that, in phasmid cilia, a constant supply of tubulin by IFT is required for steady-state length maintenance, in order to elevate soluble tubulin concentration near the axonemal tips and to promote MT stability.

cell biology↗

bioRxiv2025

Macrophage-derived WNT regulates tumor immune microenvironment to reduce colitis-associated colon cancer

Prolonged colonic inflammation and ulcerative colitis lead to colon cancer. The rapid growth and treatment-resistant nature of these tumors are primarily influenced by an immunosuppressive tumor microenvironment, which is led by tumor-associated macrophages (TAMs). However, factors influencing or regulating the immunosuppressive nature of TAMs have not been sufficiently studied. In this manuscript, we use a mouse model of colitis-associated colorectal cancer (CRC) to demonstrate that WNT expression in TAMs regulates their immunosuppressive function by inhibiting Glycogen synthase kinase-3 beta (GSK-3{beta}) within the macrophages, possibly through an autofeedback loop. GSK3{beta} is a positive regulator of PD-1 and PDL1 expression in macrophages and promotes an immunosuppressive microenvironment. Therefore, GSK-3{beta} inhibition alters the immunosuppressive nature of the immune microenvironment and effectively controls tumor growth. In Csf1r-iCre; Porcnfl/fl mice, the absence of macrophage-derived WNT promotes tumor growth in the model of colitis-associated colon cancer. Absence of macrophage-derived WNT stabilizes GSK-3{beta} in macrophages and promotes an immunosuppressive tumor microenvironment. We also show that pharmacological inhibition of GSK-3{beta} in a macrophage-specific manner, achieved by systemic delivery of a lipo-GSK3{beta} inhibitor, effectively inhibits tumor growth. Therefore, this manuscript demonstrates for the first time that the macrophage-specific modulation of GSK3{beta} can be a potential target to treat colitis-associated colon cancer.

cancer biology↗

bioRxiv2025

Could malaria mosquitoes be controlled by periodic releases of transgenic mosquitocidal Metarhizium pingshaense fungus? A mathematical modeling approach

Insect pathogenic fungi offer a promising alternative to chemical insecticides for controlling insecticide resistant mosquitoes. One proposed method involves releasing male Anopheles mosquitoes contaminated with transgenic Metarhizium pingshaense (Met-Hybrid), to lethally infecting females during mating. This study presents a novel deterministic mathematical model to evaluate the impact of this control approach in malaria-endemic areas. The model incorporates two fungus transmission pathways: mating-based transmission and indirect transmission through contact with fungus-colonized mosquito cadavers. We found the fungus cannot establish in the mosquito population without transmission from infected cadavers (in this scenario, the reproduction number of the model is zero). However, if transmission from colonized cadavers is possible, the fungus can persist in the local mosquito population when the reproduction number exceeds one. Simulations of periodic releases of infected male mosquitoes, parameterized using Met-Hybrid-exposed mosquito data from Burkina Faso, show that an 86% reduction in the local female mosquito population can be achieved by releasing 10 Met-Hybrid-exposed male mosquitoes per wild mosquito every three days over six months. This matches the efficiency of some genetic mosquito control approaches. However, a 90% reduction in the wild mosquito population requires, for instance, daily releases of the fungal-treated mosquitoes in a 6:1 ratio for about 5 months, proving less efficient than some genetic approaches. This study concludes that fungal programs with periodic releases of infected males may complement other methods or serve as an alternative to genetic-based mosquito control methods, where regulatory, ethical, or public acceptance concerns restrict genetically-modified mosquito releases.

ecology↗

bioRxiv2025

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

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

cell biology↗

bioRxiv2025

CES1 DEFICIENCY IS ASSOCIATED WITH METABOLIC REPROGRAMING AND ENDOTHELIAL DYSFUNCTION IN PULMONARY ARTERIAL HYPERTENSION

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary microvascular loss and obliterative remodeling, driven by metabolic reprogramming, oxidative stress, and endothelial dysfunction. While BMPR2 mutations contribute to metabolic shifts in pulmonary microvascular endothelial cells (PMVECs), their low penetrance suggests additional genetic modifiers play a role. A genetic screen of PAH PMVECs identified carboxylesterase 1 (CES1)--an endoplasmic reticulum (ER) enzyme involved in lipid metabolism and detoxification--as a candidate regulator of endothelial metabolism and angiogenesis. We hypothesize that CES1 loss promotes endothelial dysfunction via metabolic reprogramming, lipotoxicity, and oxidative stress. MethodsPAH and healthy PMVECs and lung tissues were obtained from transplant donors and commercial sources. CES1 expression was modulated in PMVECs using siRNA knockdown and plasmid overexpression. Mitochondrial and ER function were assessed via confocal microscopy and proteomics. CES1 heterozygous knockout (HET KO) and endothelial-specific knockout (ECKO) mice were exposed to normoxia or hypoxia, with lung tissues analyzed by single-cell RNA sequencing (scRNA-seq) and histopathology. ResultsCES1 expression was significantly reduced in PAH PMVECs and vascular lesions. CES1-deficient PMVECs exhibited increased apoptosis, reactive oxygen species (ROS) production, mitochondrial fragmentation, ER stress, and impaired angiogenesis. Confocal imaging and metabolic studies revealed lipid droplet accumulation, reduced fatty acid oxidation, and a glycolytic shift-- phenotypes reversed by CES1 restoration. Mechanistically, CES1 transcription was induced by BMPR2 via NRF2 activation, a key regulator of redox and metabolic homeostasis. In vivo, CES1-deficient mice developed severe pulmonary hypertension (PH) under hypoxia, with extensive vascular remodeling, right ventricular dysfunction, and dysregulated angiogenesis and lipid metabolism pathways, as confirmed by lung scRNA-seq. ConclusionsCES1 is essential for pulmonary endothelial homeostasis and serves as a critical modifier of BMPR2 signaling. Given the limited efficacy of current PAH therapies in reversing endothelial dysfunction and small-vessel loss, restoring CES1 expression represents a promising therapeutic strategy.

biochemistry↗

bioRxiv2025

Acute chromatin decompaction stiffens the nucleus as revealed by nanopillar-induced nuclear deformation in cells

Chromatin architecture is critical in determining nuclear mechanics. Most studies focus on the mechanical rigidity conferred by chromatin compaction from densely packed heterochromatin, but less is known on how transient changes in chromatin decompaction state impinge on nucleus stiffness. Here, we used an array of vertically aligned nanopillars to study nuclear deformability in situ after chromatin decompaction in cells. The nucleus significantly stiffened within 4 hours of chromatin decompaction but softened at longer timescales. This acute nucleus stiffening was predominantly underlied by an increase in nucleus volume, nuclear import and partially enhanced by lamin protein recruitment to the nuclear periphery. The coupling between nucleus stiffening and acute chromatin decompaction was observed in cancer cell lines with lower malignancy (e.g. MCF7, PEO1, A549) but weakened in those with higher metastatic potential (e.g. MDA-MB-231, HEYA8, HT1080), which was found to be associated with the capacity to efficiently compact heterochromatin into foci that sustains nucleus deformability required for confined migration. Our work signals how a rapid chromatin remodeling is a physiologically relevant pathway to modulate nucleus mechanics and cell migration behavior. STATEMENT OF SIGNIFICANCEMany cell processes such as wound healing, immune activation and DNA damage repair require a decompact and accessible chromatin structure. Whether such short-term remodeling of the chromatin impacts nucleus mechanics and function is poorly defined. Using nanopillars that allow interrogation of nucleus rigidity within intact cells, we showed that contrary to conventional knowledge the nucleus becomes less deformable and more rigid when chromatin is acutely decompacted due to enhanced nuclear import and swelling of the nucleus. In cancer cells, the coupling of transient chromatin decompaction to nucleus rigidity is weakened and appears to be countered by heterochromatin formation and compaction. We demonstrate here how short-term chromatin remodeling can impact nucleus and cellular properties in a time-dependent and non-genetic manner.

bioengineering↗

bioRxiv2025

Young KRAB-zinc finger gene clusters are highly dynamic incubators of ERV-driven genetic heterogeneity in mice

KRAB-zinc finger proteins (KZFPs) comprise the largest family of mammalian transcription factors, rapidly evolving within and between species. Most KZFPs repress endogenous retroviruses (ERVs) and other retrotransposons, with KZFP gene numbers correlating with the ERV load across species, suggesting coevolution. How new KZFPs emerge in response to ERV invasions is currently unknown. Using a combination of long-read sequencing technologies and genome assembly, we present a first detailed comparative analysis of young KZFP gene clusters in the mouse lineage, which has undergone recent KZFP gene expansion and ERV infiltration. Detailed annotation of KZFP genes in a cluster on Mus musculus Chromosome 4 revealed parallel expansion and diversification of this locus in different mouse strains (C57BL/6J, 129S1/SvImJ and CAST/EiJ) and species (Mus spretus and Mus pahari). Our data supports a model by which new ERV integrations within young KZFP gene clusters likely promoted recombination events leading to the emergence of new KZFPs that repress them. At the same time, ERVs also increased their numbers by duplication instead of retrotransposition alone, unraveling a new mechanism for ERV enrichment at these loci.

genetics↗

bioRxiv2025

The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux

Epigenetic regulation and metabolism are connected. Epigenetic regulators, like the SIN3 complex, affect the expression of a wide range of genes, including those encoding metabolic enzymes essential for central carbon metabolism. The idea that epigenetic modifiers can sense and respond to metabolic flux by regulating gene expression has long been proposed. In support of this cross-talk, we provide data linking SIN3 regulatory action on a subset of metabolic genes with the cellular response to changes in metabolic flux. Furthermore, we show that loss of SIN3 is linked to decreases in mitochondrial respiration and the cellular response to mitochondrial and glycolytic stress. Data presented here provide evidence that SIN3 is important for the cellular response to metabolic flux change.

molecular biology↗

bioRxiv2024

The farnesyl transferase inhibitor KO-2806 re-sensitizes relapsing tumors to RAS inhibition

Resistance remains a key issue limiting the clinical benefit from RAS-targeting therapeutic agents and necessitates combination approaches. We identify persistent mTORC1 activity in preclinical KRAS-mutant NSCLC and CRC models as a frequent, nongenetic driver of inherent and adaptive resistance to RAS inhibition. This vulnerability is targetable with the farnesyl transferase inhibitor KO-2806, which blocks mTORC1 activation via RHEB while sparing mTORC2 and its associated toxicities. The addition of KO-2806 to NSCLC or CRC tumors progressing on mutant-selective RAS inhibitors led to rapid and durable tumor regression. In contrast, switching from mutant-selective to pan-RAS inhibitor monotherapy resulted in only stasis of NSCLC tumors and had no effect on CRC tumor progression. Further, the addition of KO-2806 rescued sensitivity of progressing tumors to the pan-RAS inhibitor RMC-6236. Our results establish mTORC1 as an important mediator of escape from RAS inhibition and highlight KO-2806 as a promising RAS companion inhibitor in patients with prior RAS inhibitor exposure. SignificanceUtilizing in vivo models of tumor relapse, we define a subset of RAS inhibitor-resistant tumors in which vertical inhibition of MAPK is insufficient to restore sensitivity. By controlling parallel mTORC1 activity, KO-2806 may expand utility of RAS inhibitors in patients that have progressed on RAS-targeted therapy, regardless of inhibitor class.

cancer biology↗

bioRxiv2024

The Alzheimers Disease Risk Genes MS4A4A And MS4A6A Cooperate to Negatively Regulate Trem2 and Microglia states

Genetic variations in MS4A4A and MS4A6A are linked to the regulation of cerebrospinal fluid soluble TREM2 (sTREM2) levels and are associated with Alzheimers disease (AD) risk and progression. Using CRISPR knockout and MS4A4A-degrading antibodies in primary human microglia, non-human primates (NHP), and a xenotransplantation model of amyloid pathology, we provide evidence that MS4A4A and MS4A6A are negative regulators of both the transmembrane and soluble TREM2 proteins. They also negatively regulate microglia proliferation, survival, metabolism, lysosomal function, energetics, phagocytosis, and disease-fighting states. Mechanistically, we find that MS4A4A exerts negative regulation by interacting with MS4A6A and protecting it from degradation. MS4A6A in turn forms a complex with and blocks the co-receptor DAP12, which is required for the stability, cell surface localization, and signaling of TREM2 and other receptors. Taken together, the data indicate that MS4A4A and MS4A6A are cooperating, post-transcriptional negative regulators of TREM2 and microglial function, and potential drug targets for AD.

neuroscience↗

bioRxiv2024

Cellular moonlighting function of Hsp20 directs morphological and pathogenic development in Ustilago maydis

Ustilago maydis Hsp20 is involved in the pathogenicity of the fungus. In this study we have investigated the molecular basis of contribution of Hsp20 to U. maydis pathogenicity. Through biochemical studies we have demonstrated environment-dependent oligomeric plasticity associated with Hsp20. Hsp20 was also found to form higher order oligomers that undergo phase separation in vitro. Within cells Hsp20 was found to form distinct punctate structures that we believe play a pivotal role in its function. These punctate structures were demonstrated to sequester proteins such as actin and septin within it. Absence of Hsp20 was found to significantly affect key cellular processes like endocytosis, budding, cell polarity determination and mating in U. maydis cells. The deletion mutant failed to sporulate and complete pathogenic life cycle. This study presents a comprehensive understanding of the pathogenic development of U. maydis in reference to the moonlighting function of Hsp20 within the cell.

microbiology↗

bioRxiv2024

Human Neural Organoid Microphysiological Systems Show the Building Blocks Necessary for Basic Learning and Memory

Brain Microphysiological Systems including neural organoids derived from human induced pluripotent stem cells offer a unique lens to study the intricate workings of the human brain. This paper investigates the foundational elements of learning and memory in neural organoids, also known as Organoid Intelligence by quantifying immediate early gene expression, synaptic plasticity, neuronal network dynamics, and criticality to demonstrate the utility of these organoids in basic science research. Neural organoids showed synapse formation, glutamatergic and GABAergic receptor expression, immediate early gene expression basally and evoked, functional connectivity, criticality, and synaptic plasticity in response to theta-burst stimulation. In addition, pharmacological interventions on GABAergic and glutamatergic receptors, and input specific theta-burst stimulation further shed light on the capacity of neural organoids to mirror synaptic modulation and short-term potentiation, demonstrating their potential as tools for studying neurophysiological and neurological processes and informing therapeutic strategies for diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/613333v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@50a256org.highwire.dtl.DTLVardef@1d1f8c9org.highwire.dtl.DTLVardef@24688borg.highwire.dtl.DTLVardef@4ba3b4_HPS_FORMAT_FIGEXP M_FIG C_FIG Overview of the main components of the experiments conducted. Figure created using BioRender.com.

neuroscience↗