Biology subjects

Cook, J.

Publications and source records attributed to Cook, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Two-State Effective Connectivity Predicts the effect of Anterior Cingulate Cortex Excitatory / Inhibitory Balance on Posterior Cingulate Cortex

Aims Excitatory/inhibitory imbalance - the equilibrium between glutamatergic excitation and {gamma}-Aminobutyric acid (GABA)ergic inhibition - is implicated in psychosis and may precede psychosis onset. Methods To investigate whether excitatory/inhibitory balance relates to subclinical psychotic experiences, anxiety and depression, we developed a network-level measure integrating Magnetic Resonance Spectroscopy Glutamate/GABA ratios with effective connectivity during resting-state fMRI. In 20 healthy young adults (aged between 18-32; 50% female), we first measured excitatory/inhibitory balance, operationalised as Glutamate/GABA and Glutamate+Glutamine(Glx)/GABA ratio, in the dorsal anterior cingulate cortex. Second, we applied Two-state Dynamic Causal Modelling to assess effective connectivity of the default-mode network, using these ratios as empirical priors to determine how they translate into network connectivity. Third, we ran Bayesian Model Selection at the model and family levels to identify the optimal models. Results The two-state model with Glx/GABA ratio as direct input into the posterior cingulate cortex best explained the data. This best-fitting model incorporated the neurometabolite ratio with Glutamate and GABA and used two-state connectivity. Conclusions Excitatory/inhibitory balance underlies resting-state effective connectivity, with the Glx/GABA ratio shaping connectivity networks. This pathway highlights excitatory/inhibitory balance as a predictor of two-state brain networks, potentially aiding identification of high-risk individuals and informing new interventions.

neuroscience↗

bioRxiv2026

APOE is a presynaptic protein that accumulates with age and modulates neurotransmitter release

The synaptic vesicle (SV) cycle is the fastest membrane trafficking and protein sorting process in biology. It underlies neuronal communication and cognition, yet synaptic function declines during normal aging, increasing vulnerability to neurologic disease. How the SV cycle is maintained across the lifespan of a complex organism remains unclear. Here, we used wild-type mice (C57BL/6J) to define the age- and sex-stratified molecular landscape of SVs and identified apolipoprotein E (APOE) as an abundant presynaptic protein further enriched in aged female samples. Super-resolution imaging, cell-type selective expression, and protease protection assays demonstrate that APOE originates from astroglia and associates with the cytosolic face of SVs. Using iGluSnFR and pHluorin optophysiology, we find that both decreased and increased APOE levels impair neurotransmission during stimulus trains. Together, these findings place APOE at the synapse and establish it as a cell-nonautonomous regulator of the SV cycle.

neuroscience↗

bioRxiv2025

A century of breeding has preserved genetic variation, accumulated favorable alleles, and shaped the Rht gene portfolio in North American spring wheat

Hard red spring wheat (HRSW) is an important market class of wheat in North America with a rich history of breeding. We genotyped 1,013 HRSW lines representing a century of breeding material using a SNP array and targeted KASP genotyping to assess the changes in genetic diversity and Rht genes in HRSW from North America. Results show that early breeding efforts broadened an initially narrow gene pool derived from a few founders and subsequently maintained the genetic diversity. Analysis of Rht genes revealed that Rht-D1b was the predominant semi-dwarf allele from introduction of the Green Revolution genes (Rht-B1 and Rht-D1) in 1960s until the FHB epidemics of 1990s, when most breeding programs shifted to Rht-B1b. However, adoption of Rht-B1b and Rht-D1b remains low in some regions of the Great Plains. The dwarf alleles at GA-sensitive Rht24 and Rht25 have persisted in the region at low frequencies before the introduction of Green Revolution genes and have increased in frequency in recent decades. We also analyzed the effect of Rht genes on plant height (PH) in the HRSW growing region and found that Rht-B1b or Rht-D1b results in [~]12% reduction in PH, which decreases to [~]9% in dry environments. Notably, combining dwarfing alleles at Rht24 and Rht25 reduced height by [~]6% in dry environments, suggesting an alternative approach for reducing PH. Our analysis also revealed significant genetic interactions between Rht-B1 and Rht25, as well as between Rht-D1 and Rht24, which could help fine-tune PH for different environments by employing appropriate Rht combinations. Furthermore, our results demonstrate positive selection for photoperiod sensitivity in recent decades, particularly in high-latitude regions. This study provides a valuable genomic resource, and the findings enhance our understanding of past breeding efforts while offering insights to guide future plant breeding strategies.

plant biology↗

bioRxiv2025

A common cross-species atlas of cortical gray matter

Translational neuroscience requires consistent anatomical frameworks to compare brain organization across species despite differences in size and specialization. Existing atlases are species-specific, limiting cross-species analyses. Here we developed a hierarchical common atlas delineating homologous cortical and subcortical gray matter regions across mouse, rat, marmoset, rhesus macaque, and human, built upon population-averaged minimal deformation templates and uniform tissue segmentation. The atlas was validated through cross-atlas Dice similarity against established human parcellations, cross-scale containment against species-specific atlases, cross-species geometric consistency of regional positioning, and comparison of independent mouse and marmoset invasive tracer connectivity, with a per-region homology confidence index quantifying the strength of each regional assignment. Cross-species tracer comparison revealed a structured gradient of correspondence, with sensorimotor connections showing strong conservation and association connections showing progressive divergence. This freely available atlas provides a unified coordinate system for comparative neuroscience, enabling quantitative evaluation of where cross-species correspondence holds and where species-specific divergence emerges.

neuroscience↗

bioRxiv2025

Cooperativity between Ras pathway mutations in colonic tumorigenesis

The Kirsten rat sarcoma (KRAS) gene is the most frequently mutated oncogene in colorectal cancer (CRC). We previously characterized two activating alleles of KRAS, A59T and A59E, that show impaired BRAF dimerization. These alleles of KRAS are enriched in CRC tumors with genetic alterations in genes that regulate MAPK signaling (e.g. EGFR, NF1). Using a new conditional mouse model of K-Ras (LSL-K-Ras A59E) we show that, despite its inability to universally activate RAF kinases, K-Ras A59E disturbs colon epithelium and decreases mouse survival in a tumor model. By combining LSL-K-Ras A59E mice with a conditional knockout of Nf1, we demonstrate cooperation between these alleles at multiple levels. Consistent with cooperation and clinical observations, we show that K-Ras A59E neither promotes EGF independence of organoid growth, nor confers intrinsic resistance to EGFR inhibition. Thus, our data provide a deeper understanding of the role of RAF isoforms in mutant KRAS driven CRC and argue for the use of anti-EGFR therapies against some Ala59 mutant alleles of KRAS. Statement of significanceOur studies on oncogenic K-RAS mutants demonstrate that the biochemical properties of a mutant oncoprotein are reflected in the somatic genetics of cancer, in particular in the cooperating mutations that occur. These mutant-specific genetic interactions influence therapeutic responses. As such, KRAS mutation may not be a univariate predictor of response to EGFR inhibition.

cancer biology↗

bioRxiv2025

Adolescent morphine exposure does not alter low-dose lipopolysaccharide-induced sickness behavior in adult mice

Adolescent opioid use in the United States commands attention: millions of twelve- to nineteen-year-olds are exposed to opioids each year by prescription and misuse. Recent findings show that opioids bind not only to canonical opioid receptors but also interact with receptors on immune cells within both the central and peripheral nervous systems. The potential for early life opioid exposure to induce long-term changes in the neuroimmune system is not fully understood, particularly given the adolescent brains high susceptibility to neuroplastic changes. The goal of this study was to investigate the hypothesis that adolescent opioid use potentiates physiological and behavioral responses to pathogen-induced sickness later in life. To achieve this, we treated adolescent mice (PND 35-42) with bi-daily escalating doses of morphine to model dependence and then administered a low dose of lipopolysaccharide (LPS, 0.1 mg/kg) in adulthood (PND 60-76) to induce an immune response. In contrast to our hypotheses, we found that adolescent morphine exposure had no additive effect on low-dose LPS-induced sickness measures when assessed in adulthood. These data suggest that adolescent opioid exposure may have minimal effects on future immune challenges, although further research is needed to confirm this.

neuroscience↗

bioRxiv2025

Genetic Gains from Sixty Years of Spring Wheat Breeding in the Northern Plains of the US

Evaluating genetic gains over time is essential for assessing the success of breeding programs and refining strategies for ongoing improvement. Hard red spring (HRS) wheat is an important wheat class in the US and is primarily grown in the Northern Great Plains. Despite a long history of breeding efforts in this region, long-term quantification of genetic gains for key traits has remained limited. This study analyzes over sixty years of data from the USDA-coordinated Hard Red Spring Wheat Uniform Regional Nursery (HRSWURN) to evaluate genetic advancements in agronomic traits across multiple phases. A significant positive genetic gain of 0.61% per annum was observed for grain yield in HRS wheat released in the Northern US region, which is lower than the expected gains needed to meet future wheat demand. The change was 0.07% for test weight, -0.04% for days to heading, and -0.16% for plant height. Notably, sustained yield improvements have not affected grain protein levels since they were first measured in 1995, indicating that ongoing selection has effectively balanced grain yield and protein despite their negative correlation (r = -0.31). Assessment of genetic gains over 20-year phases suggested slowing rates of genetic gains for grain yield but did not indicate any plateaus. The realized genetic gains were generally higher for individual breeding programs when breeding for target environments, with the public breeding program in Minnesota observing gains of approximately 1% per annum. These findings highlight the significant impact of long-term breeding efforts and offer valuable insights for refining future breeding strategies.

plant biology↗

bioRxiv2025

Structure of YbbAP-TesA: a Type VII ABC transporter lipid-hydrolase complex

Type VII ABC transporters are ATP-powered membrane protein complexes that drive key biological processes in the bacterial cell envelope. In E. coli, three of the four Type VII ABC systems have been extensively characterised including: the FtsEX-EnvC cell division complex, the LolCDE-LolA lipoprotein trafficking machinery and the MacAB-TolC efflux pump. Here we describe a fourth E. coli Type VII ABC system, YbbAP-TesA, which combines a Type VII ABC transporter with a multifunctional hydrolytic enzyme. Structures of the complete YbbAP-TesA complex, and of YbbAP with and without bound ATP analogues, capture the long-range transmembrane conformational changes that are the hallmark of this ABC superfamilys mechanotransmission mechanism. We further show that YbbAP-TesA can hydrolyse a variety of ester and thioester substrates and experimentally confirm a constellation of active site residues in TesA. Our data suggests YbbAP has a role in extracting hydrophobic molecules from the inner membrane and presenting these to TesA for hydrolysis. The work extends collective knowledge of the remarkable diversity of the ABC superfamily and establishes a new function for Type VII ABC transporters in bacterial cells. Significance StatementType VII ABC transporters are unique to bacteria and play important roles in bacterial physiology including cell division, antibiotic resistance, siderophore secretion, antibiotic sensing, toxin secretion, biofilm regulation and lipoprotein trafficking. Here we identify a complex that combines an atypical Type VII ABC transporter (YbbAP) with a periplasmic lipid hydrolase (TesA). The YbbAP-TesA complex is structurally and functionally distinct from all known Type VII ABC transporter systems including FtsEX-EnvC, LolCDE-LolA, BceAB-BceS and MacAB-TolC. Structures suggest that YbbAP-TesA uses ATP-driven mechanotransmission to extract substrates from the inner membrane and hydrolyse them in the periplasmic space. The discovery and characterisation of YbbAP-TesA highlights the structural and functional diversity of Type VII ABC transporter complexes and suggests a new function for these proteins in the bacterial cell envelope.

microbiology↗

bioRxiv2025

Extrachromosomal DNA Gives Cancer a New Evolutionary Pathway

During tumor progression, it has been assumed that individual cells that have acquired advantageous mutations overtake the population. Cancers driven by extrachromosomal DNA (ecDNA) do not follow this paradigm. Instead, these tumors have a spectrum of oncogene copy numbers across cells, and graded ecDNA variation may function as a form of bet-hedging that equips tumors with a broad range of phenotypes. Using imaging, single-cell multiomics, and multiplexed proteomics, we systematically characterized ecDNA levels across thousands of single cells. Higher ecDNA dosage produces proportional changes in transcript abundance, chromatin accessibility, protein levels, cell-cycle progression, and proliferation. Genes amplified on ecDNA exhibit distinct transcriptional scaling regimes that shift when the same genes are reintegrated into chromosomal homogeneous staining regions. When we experimentally disrupted the continuum of ecDNA dosage by sorting cells into low- and high-copy number states, the population rapidly recovered its original, continuous distribution. Our time-course data, live-cell imaging, and stochastic models collectively show that restoring this spectrum is an active, deterministic process rather than the passive outcome of random segregation. Together, these findings position ecDNA-mediated expression as a distinct evolutionary mechanism that endows tumors with rapid, population-level adaptability. These findings offer insight into why ecDNA-driven cancers are among the most aggressive and treatment-resistant.

genomics↗

bioRxiv2025

Modelling the effects of adult emergence on the surveillance and age distribution of medically important mosquitoes

Entomological surveillance is an important component of mosquito-borne disease control. Mosquito abundance, infection prevalence and the entomological inoculation rate are the most widely reported entomological metrics, although these data are notoriously noisy and difficult to interpret. For many infections, only older mosquitoes are infectious, which is why, in part, vector control tools that reduce mosquito life expectancy have been so successful. The age structure of wild mosquitoes has been proposed as a metric to assess the effectiveness of interventions that kill adult mosquitoes, and age grading tools are becoming increasingly advanced. Mosquito populations show seasonal dynamics with temporal fluctuations. How seasonal changes in adult mosquito emergence and vector control could affect the mosquito age distribution or other important metrics is unclear. We develop stochastic mathematical models of mosquito population dynamics to show how variability in mosquito emergence causes substantial heterogeneity in the mosquito age distribution, with low frequency, positively autocorrelated changes in emergence being the most important driver of this variability. Fitting a population model to mosquito abundance data collected in experimental hut trials indicates these dynamics are likely to exist in natural Anopheles gambiae populations. Incorporating age structuring into an established compartmental model of mosquito dynamics and vector control, indicates that the use of mosquito age as a metric to assess the efficacy of vector-control tools will require an understanding of underlying variability in mosquito ages, with estimates affected by short-term and seasonal fluctuations in mosquito emergence.

ecology↗

bioRxiv2025

Probing the mechanism of peptidoglycan amidase activation by FtsEX-EnvC

The FtsEX-EnvC-AmiA/B system is a key component of the E. coli cell division machinery that directs breakage of the peptidoglycan layer during separation of daughter cells. Structural and mechanistic studies have shown that ATP binding by FtsEX in the cytoplasm drives periplasmic conformational changes in EnvC that lead to the binding and activation of peptidoglycan amidases such as AmiA and AmiB. The FtsEX-EnvC amidase system is highly regulated to prevent cell lysis with at least two separate layers of autoinhibition that must be relieved to initiate peptidoglycan hydrolysis during division. Here we test the FtsEX-EnvC amidase activation mechanism through site-directed mutagenesis. We identify mutations that disrupt the autoinhibition mechanism of FtsEX-EnvC and an N-terminal deletion variant that prevents activation. Finally, we develop a cysteine locking residue pair that stabilises the complex in its amidase activating conformation. The reported EnvC variants greatly enhance our understanding of the FtsEX-EnvC autoinhibition mechanism and the conformational changes underpinning amidase activation. Our observations are consistent with the proposed mechanism of amidase activation by large-scale conformational changes in FtsEX-EnvC allowing recruitment and activation of peptidoglycan amidases. ImportanceIn E. coli, the FtsEX-EnvC system regulates two of the three division-associated amidases that break the peptidoglycan layer during bacterial division. Structural and mechanistic studies have revealed a detailed molecular mechanism for amidase activation in which an ABC transporter and its periplasmic partner reversibly activate periplasmic amidases under direction of the cytoplasmic cell division machinery. This paper explores structural features of EnvC that underpin autoinhibition and the activation mechanism. The FtsEX-EnvC system serves as a powerful example of a Type VII ABC transporter that uses transmembrane conformational change to drive work in the periplasmic space.

biochemistry↗

bioRxiv2024

StayRose: a photostable StayGold derivative red-shifted by genetic code expansion

Photobleaching of fluorescent proteins often limits the acquisition of high-quality images in microscopy. StayGold, a novel dimeric green fluorescent protein recently monomerised through sequence engineering, addresses this challenge with its high photostability. There is now focus on producing different colour StayGold derivatives to facilitate concurrent tagging of multiple targets. The unnatural amino acid 3-aminotyrosine has previously been shown to red-shift super folder GFP upon incorporation into its chromophore via genetic code expansion. Here we apply the same strategy to red-shift StayGold through substitution of Tyrosine-58 with 3-aminotyrosine. The resultant red fluorescent protein, StayRose, shows 530 nm excitation and 588 nm emission peaks, shifting from the 497 nm and 504 nm excitation and emission peaks of StayGold. StayRose also retains the favourable photostability of StayGold and can be similarly monomerised using mutations at the dimer interface. A high-resolution crystal structure of StayRose confirms the modified structure of the amino-chromophore within an unperturbed 3D fold. Although reliant on genetic code expansion, StayRose provides an important step towards developing red-shifted StayGold derivatives.

bioengineering↗

bioRxiv2024

Sequential design of single-cell experiments to identify discrete stochastic models for gene expression.

Control of gene regulation requires quantitatively accurate predictions of heterogeneous cellular responses. When inferred from single-cell experiments, discrete stochastic models can enable such predictions, but such experiments are highly adjustable, allowing for almost infinitely many potential designs (e.g., at different induction levels, for different measurement times, or considering different observed biological species). Not all experiments are equally informative, experiments are time-consuming or expensive to perform, and research begins with limited prior information with which to construct models. To address these concerns, we developed a sequential experiment design strategy that starts with simple preliminary experiments and then integrates chemical master equations to compute the likelihood of single-cell data, a Bayesian inference procedure to sample posterior parameter distributions, and a finite state projection based Fisher information matrix to estimate the expected information for different designs for subsequent experiments. Using simulated then real single-cell data, we determined practical working principles to reduce the overall number of experiments needed to achieve predictive, quantitative understanding of single-cell responses.

systems biology↗

bioRxiv2024

Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model

BackgroundDysregulated Tau phosphorylation (p-Tau) is a hallmark of neurodegenerative disorders such as Alzheimers disease (AD) or frontotemporal dementia (FTD), resulting in neurofibrillary tangle accumulation, neuronal atrophy and cognitive impairment. Impaired somatostatin (SST) expression and reduced SST-expressing GABAergic neurons significantly contributes to AD-related pathophysiology and correlates with cognitive impairment. SST+ interneurons inhibit the dendrites of excitatory neurons in cortical layers and hippocampus, primarily through 5-GABA-A receptors, regulating cognitive function. Leveraging a newly developed small molecule that targets the 5-GABA-A receptors via positive allosteric modulation (5-PAM), we assessed its effects on p-Tau-related neuronal morphology, cognitive deficits and protein expression. MethodsIn the PS19 transgenic mouse model, we administered the 5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months, corresponding to early and advanced stage of p-Tau accumulation. Golgi staining analyzed dendritic morphology and spine density in mice chronically exposed to 5-PAM. Western blotting was used to quantify p-tau and Tau expression. Spatial working memory was assessed using the Y-maze. ResultsChronic treatment at 3 and 6 months mitigated p-Tau-induced loss of spine density and reduced dendritic length. 5-PAM treatment did not affect p-tau levels. 5-PAM effectively reversed spatial working memory deficits induced by p-tau accumulation both acutely and chronically. Conclusions5-GABA-A receptor positive allosteric modulation displayed neurotrophic (spine and dendritic pathology) and procognitive (working memory) effects in the PS19 model, independently of p-Tau burden. This suggests a novel therapeutic strategy for p-Tau-related pathologies with both symptomatic and disease-modifying potential.

neuroscience↗

bioRxiv2024

USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination

The CMG helicase (CDC45-MCM2-7-GINS) unwinds DNA as a component of eukaryotic replisomes. Replisome (dis)assembly is tightly coordinated with cell cycle progression to ensure genome stability. However, factors that prevent premature CMG unloading and replisome disassembly are poorly described. Since disassembly is catalyzed by ubiquitination, deubiquitinases (DUBs) represent attractive candidates for safeguarding against untimely and deleterious CMG unloading. We combined a targeted loss-of-function screen with quantitative, single-cell analysis to identify human USP37 as a key DUB preventing replisome disassembly. We demonstrate that USP37 maintains active replisomes on S-phase chromatin and promotes normal cell cycle progression. Proteomics and enzyme assays revealed USP37 interacts with the CMG complex to deubiquitinate MCM7, thus antagonizing replisome disassembly. Significantly, USP37 protects normal epithelial cells from oncoprotein-induced replication stress. Our findings reveal USP37 to be critical to the maintenance of replisomes in S-phase and suggest USP37-targeting as a potential strategy for treating malignancies with defective DNA replication control.

cell biology↗

bioRxiv2023

An alpha 5-GABAa receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in an animal model for autism

Autism Spectrum Disorders (ASD) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of 5-containing GABAA receptors (5-GABAARs) SH-053-2F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in a rat model for autism based on in utero VPA exposure. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2F-R-CH3 could attenuate these changes. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Male and female adult VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2F-R-CH3. Despite sex differences, our findings indicate 5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.

neuroscience↗

bioRxiv2023

Extrasynaptic localization is essential for α5GABAA receptor modulation of dopamine system function

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting Gamma-Aminobutyric Acid type A receptors (GABAAR) containing the 5, but not 1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that 1GABAARs are primarily located in the synapse, whereas 5GABAARs are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected a small interfering ribonucleic acid (siRNA) into the vHipp to knock down radixin, a scaffolding protein that holds 5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of 5GABAARs (5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting 5GABAARs from the extrasynaptic space to the synapse would prevent the effects of 5-PAM on dopamine system function. As expected, knockdown of radixin significantly decreased radixin-associated 5GABAARs and increased the proportion of synaptic 5GABAARs, without changing the overall expression of 5GABAARs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of 5GABAARs is critical for hippocampal modulation of the dopamine system. These results may have important implications for clinical use of GL-II-73, as periods of high hippocampal activity appear to favor synaptic 5GABAARs, thus efficacy may be diminished in conditions where aberrant hippocampal activity is present. Significance StatementDopamine activity is known to be altered in both psychosis patients and in animal models, with promising new antipsychotics restoring normal dopamine system function. One such drug is GL-II-73, a positive allosteric modulator of 5GABAARs (5-PAM). Interestingly, previous research has shown that a positive allosteric modulator of 1GABAARs (1-PAM) does not share this ability, even when directly given to the ventral hippocampus, a region known to modulate dopamine activity. One potential explanation for this difference we examined in this study is that 1GABAARs are primarily located in the synapse, whereas 5GABAARs are mostly extrasynaptic. Determining the mechanism of this differential efficacy could lead to the refinement of antipsychotic treatment and improve patient outcomes overall.

neuroscience↗

bioRxiv2023

Piezo inhibition prevents and rescues scarring by targeting the adipocyte to fibroblast transition

While past studies have suggested that plasticity exists between dermal fibroblasts and adipocytes, it remains unknown whether fat actively contributes to fibrosis in scarring. We show that adipocytes convert to scar-forming fibroblasts in response to Piezo-mediated mechanosensing to drive wound fibrosis. We establish that mechanics alone are sufficient to drive adipocyte-to- fibroblast conversion. By leveraging clonal-lineage-tracing in combination with scRNA-seq, Visium, and CODEX, we define a "mechanically naive" fibroblast-subpopulation that represents a transcriptionally intermediate state between adipocytes and scar-fibroblasts. Finally, we show that Piezo1 or Piezo2-inhibition yields regenerative healing by preventing adipocytes activation to fibroblasts, in both mouse-wounds and a novel human-xenograft-wound model. Importantly, Piezo1-inhibition induced wound regeneration even in pre-existing established scars, a finding that suggests a role for adipocyte-to-fibroblast transition in wound remodeling, the least-understood phase of wound healing. Adipocyte-to-fibroblast transition may thus represent a therapeutic target for minimizing fibrosis via Piezo-inhibition in organs where fat contributes to fibrosis.

cell biology↗