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Wang, F.

Publications and source records attributed to Wang, F..

At least 109 records · Page 6Linked to original sources

Next-generation enhancer AAVs for selective interspecies targeting of midbrain dopaminergic neurons

Using single-nucleus multiomic profiling of the marmoset midbrain, we develop and benchmark enhancer-AAVs to selectively access dopamine (DA) neurons in wild-type animals without combinatorial systems. In vivo candidate screenings identified one highly specific DA enhancer, cjDAE8, in both mice and marmosets. To overcome low-level off-target (leaky) expression, a common limitation for enhancer AAVs, we engineered next-generation AAV backbones that strengthen expression while minimizing leakiness. Quantitative histology comparing natural versus antibody-amplified fluorescence defined AAV doses to achieve high labeling efficiency with greater than 90-95% DA-neuron specificity across species and injection routes. We further demonstrate applications of DA-enhancer-AAVs for (i) retrograde targeting of projection-defined DA populations in marmoset, (ii) fiber-photometric recording of divergent DA-axonal dynamics in striatal subregions, and (iii) optogenetic VTA-DA self-stimulation in mice. Our results establish a resource for cross-species DA targeting and two practical guidelines: backbone context critically shapes enhancer performance, and antibody-amplified readouts rigorously assess specificity.

neuroscience↗

A multi-tissue atlas of genetic regulatory effects in sheep

Characterizing the impact of genomic variants on genome function and ultimately complex traits in livestock is essential for the development of sustainable precision agriculture and comparative genomics. Here, as part of the Farm animal Genotype-Tissue Expression (FarmGTEx) project, we present the pilot phase of the SheepGTEx resource through analyzing 6,761 RNA-sequencing samples of 51 primary tissues in a multi-breed population of sheep. We identify millions of regulatory variants associated with seven types of molecular phenotypes, and fine-map 322,468 primary and 114,017 non-primary effects, revealing a high degree of regulatory allelic heterogeneity. We systematically characterize the pleiotropic effects of these variants on molecular phenotypes, assess their context-specific regulatory patterns across tissues, breeds, sexes, and developmental stages, as well as explore their evolutionary constraints across mammals. Finally, we demonstrate the substantial potential of the SheepGTEx resource (https://sheepgtex.farmgtex.org), by providing examples of regulatory mechanisms underpinning 34 complex traits, population divergence between European and Asian breeds, and adaptive evolution in sheep over the past ten millennia.

genomics↗

Rapid generation of ventral A9-like dopaminergic neurons from patterned iPSCs

In vitro modelling of highly vulnerable nigral dopaminergic (DA) neuronal subtypes in Parkinsons disease (PD), is necessary for studying disease mechanisms. Here, we optimized a new approach by expressing the pioneer neurogenic transcription factor, Achaete-scute-like 1 (Ascl1), implicated in determining dopaminergic fate. Sequential small-molecule patterning of iPSCs into early floor plate mesencephalic progenitors, followed by inducible Ascl1 expression, rapidly differentiates midbrain DA neurons. Immunocytochemistry and transcriptomic analysis of these patterned Ascl1-driven DA neurons (PA-DANs) confirmed midbrain-lineage specificity. Importantly, we found an enrichment of DA subpopulations that corresponded to the adult human ventral SOX6-positive A9 DA subtypes vulnerable in PD. Furthermore, we combined these ventral A9-like PA-DANs with human iPSC-derived midbrain astrocytes and microglia in defined ratios to generate mature 3D A9-like assembled organoids that display characteristic spontaneous neuronal activity and electrical propagation along the axon. Our method efficiently generates a mature and functional A9-like DA neuronal platform to study PD. HighlightsO_LISequential midbrain patterning and Ascl1 expression accelerates DA differentiation C_LIO_LIPA-DANs resemble human adult ventral A9-like DA subtypes vulnerable in PD C_LIO_LI3D assembled organoids show mature identity of PA-DANs, iAstrocytes and iMicroglia C_LIO_LIPA-DANs matured in 3D organoids show neuronal network activity within weeks C_LI eTOC blurbIn this study, Ullian and colleagues have developed a rapid method to differentiate dopaminergic neurons, using small molecules to generate early floor plate mesencephalic progenitors from human iPSCs and sequentially expressing a pioneer transcription factor, Ascl1, that accelerates uniform dopaminergic neurogenesis. Patterned Ascl1-driven dopaminergic neurons (PA-DANs) in 2D and 3D assembled organoids serve as a platform to study Parkinsons disease O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/685897v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1d83eb3org.highwire.dtl.DTLVardef@1fc7fa5org.highwire.dtl.DTLVardef@2033e3org.highwire.dtl.DTLVardef@2e8fa3_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

TMEM100 attenuates NF-κB activation via disrupting the PRDX1-GNAI2 complex to alleviate acute lung injury

Acute lung injury (ALI) is a severe and diffuse inflammatory disorder of interstitial lung. Emerging evidence suggests that TMEM100 is closely associated with lung development and function. However, its role in ALI remains unclear. In this study, we observed a significant downregulation of TMEM100 expression in both mouse lung tissues with ALI and lipopolysaccharide (LPS)-induced pulmonary vascular endothelial cells (PVECs). Overexpression of TMEM100 markedly attenuates LPS-induced lung injury and inflammation, while also restoring the imbalance between proliferation and apoptosis in PVECs. Mechanistically, TMEM100 interacts with both PRDX1 and GNAI2, disrupting the PRDX1-GNAI2 complex and thereby inhibiting LPS-induced NF-{kappa}B activation, which contributes to its anti-inflammatory effects. These findings highlight the protective role of TMEM100 in endotoxin-induced ALI and provide a theoretical basis for understanding its biological functions and potential applications in ALI gene therapy.

immunology↗

A Bundled Antiparallel Cytochrome Nanowire Structure Suggests Roles in Cell-Cell Electron Transfer and Biofilm Formation

Long-range extracellular electron transfer enables respiring microbes to use minerals, other organisms, or electrodes as electron acceptors by transporting electrons microns away from the cell surface. This process is primarily studied in Geobacter sulfurreducens, which produces at least three different micrometer-long, multi-heme cytochrome nanowires capable of electron transfer. However, the distribution and higher-order structure of these types of cytochrome nanowires remains largely unknown. Here, we employed cryo-electron microscopy to determine the atomic structure of a unique cytochrome nanowire from Desulfuromonas soudanensis WTL, a halophilic, iron- and electrode-reducing bacterium found in deep subsurface brine. These filaments are based on a homolog of the OmcE tetraheme cytochrome, which then assemble into highly ordered bundles of antiparallel filaments. This arrangement likely arises from the association of nanowires extending from adjacent cells. Furthermore, a similar cytochrome bundle structure was observed in Geobacter metallireducens, suggesting that this quaternary structure may be a common feature among nanowires secreted by electroactive microbes. Our findings demonstrate that cytochrome nanowires in diverse taxa can form specialized bundle interfaces, potentially facilitating conductive biofilm formation and representing a novel strategy for microbial electron exchange. More broadly, this work expands understanding of electron transfer mechanisms and demonstrates the production of multi-heme filaments across distinct lineages. These insights could guide future research into cytochrome nanowire secretion and conductive biofilm engineering, with potential applications in electrochemical technologies.

microbiology↗

Adjacent Rare-Earth Separation via a Protein Atomic Ruler

The separation of rare-earth elements (REEs) poses a formidable challenge due to their nearly identical ionic radii and chemical properties. Here, we present a transformative strategy for REE separation using a multimetal ion-stacking metalloprotein framework (MIF) that functions as an atomic ruler, effectively amplifying subtle differences in REE ionic radii. This approach achieves exceptional selectivity, enabling the separation of all 13 adjacent REE pairs with ultrahigh purity (up to 99.999%). Remarkably, the MIF retains its lanthanide-binding capacity over 410 consecutive absorption-desorption cycles, demonstrating outstanding stability. Structural insights reveal that the MIFs densely packed REE coordination environment magnifies minute radius variations--a key mechanism underlying its unparalleled separation efficiency. Our MIF-based strategy offers a sustainable, scalable solution to rare-earth separation in industrial applications.

biophysics↗

Multiple Allosteric Sites Allow for Synergistic Enhancement of GPCR Signaling

Allosteric modulation of G protein-coupled receptors (GPCRs) is an emerging therapeutic paradigm that has proven effective, yet the cooperative action of multiple modulators remains unexplored. Here, we reveal how positive allosteric modulators (PAMs) synergistically enable extraordinary signal amplification through the D1 dopamine receptor (D1R). We developed UNC9815 and UNC10062 as enhanced D1R PAMs from the parent compound MLS6585, and then employed cryo-electron microscopy to reveal concurrent occupancy of three distinct allosteric sites by PAMs of different scaffolds, including LY3154207, BMS-A1, and our UNC compounds. Remarkably, we discovered two adjacent allosteric pockets at the transmembrane helix (TM) 1-7 interface: BMS-A1 occupies an intracellular site promoting activation through TM7 conformational shifts, while the UNC compounds complementarily stabilize the extracellular side of the interface. When combined with LY3154207, this cooperative architecture enhances dopamine potency by more than 1,000-fold. These findings elucidate the first structural blueprint for multi-site GPCR cooperativity, unlocking transformative therapeutic strategies inaccessible to orthosteric and single- site allosteric drugs.

molecular biology↗

Targeting the host factor HGS-viral membrane protein interaction in coronavirus infection

While current antivirals primarily target viral proteins, host-directed strategies remain underexplored. Here, we performed a genome-wide CRISPRi screening to identify the host protein, Hepatocyte Growth Factor-Regulated Tyrosine Kinase Substrate (HGS), as essential for the pan-coronaviruses infection both in vitro and in vivo. Mechanistically, HGS directly interacts with the viral membrane (M) protein, facilitating its trafficking to the ER-Golgi intermediate compartment (ERGIC) for virion assembly. Conversely, HGS deficiency caused M retention in the ER, blocking assembly. Leveraging this interaction, we designed M-derived peptides and screened over 5,000 FDA-approved drugs, identifying riboflavin tetrabutyrate (RTB). Both the peptides and RTB bind HGS and disrupt its interaction with the M protein, leading to M retention in the ER and subsequent blockade of virion assembly. These agents demonstrated broad anti-pan-coronavirus activity in vitro and in vivo. Collectively, our findings establish HGS as a druggable host target and identify RTB as a promising broad-spectrum antiviral candidate.

microbiology↗

Quantifying Uncertainty in Polygenic Risk Scores Using Conformalized Quantile Regression

Polygenic risk scores (PRS) are widely used in post-GWAS analyses to predict complex traits across humans, animals, and plants, yet the uncertainty of these predictions is rarely quantified at the individual level. Here, we introduce a framework for individualized uncertainty quantification based on quantile regression and conformal prediction, enabling the construction of prediction intervals with guaranteed coverage under minimal assumptions. Quantile regression enables adaptive, individual-specific prediction intervals that capture asymmetry and allow interval widths to vary substantially across individuals based on genetic information alone. Applying this framework to 62 traits in the UK Biobank and the ProgeNIA/SardiNIA studies, we show that these intervals maintain valid coverage and reduce uncertainty in risk stratification compared to existing methods, driven by their adaptive construction. Prediction interval width correlates positively with age and BMI, indicating reduced genetic predictability in subsets of the population where genetic effects interact with environmental factors. Our results demonstrate that incorporating uncertainty is essential for interpreting polygenic predictions and provide a principled approach to distinguish individuals whose phenotypes are well explained by genetic predictors from those in whom non-genetic influences dominate.

bioinformatics↗

A Critical Rectal Temperature Defines Sex-Specific Leukocyte and Neutrophil Activation During Prolonged Passive Heat Exposure in Young Adults

BackgroundProlonged heat exposure disrupts immune homeostasis and can precipitate acute systemic inflammation. However, the core temperature threshold that triggers sex-specific leukocyte and neutrophil activation during passive heat stress remains undefined. MethodsWe studied 52 males and 58 females exposed to wet-bulb temperatures of 32-35 {degrees}C. Rectal temperature (Trec) was continuously monitored, and blood samples were collected at 0.5 {degrees}C increments up to 38.6 {degrees}C. Leukocyte and neutrophil counts were modeled using quadratic and segmented regression to identify inflection points of immune activation. ResultsBoth leukocytes and neutrophils increased nonlinearly with rising Trec (p < 0.05). A critical Trec of 38.1 {degrees}C--closely aligns with the 38.0 {degrees}C occupational core temperature limits--marked an inflection in leukocyte responses: below this point, females showed steeper increases; whereas above it, males showed accelerated activation. Neutrophils demonstrated consistently greater mobilization in males across the entire temperature range (36.9-38.6 {degrees}C). ConclusionsA distinct core temperature threshold ([~]38.1 {degrees}C) governs immune cell activation and reveals sex-dependent response patterns. This finding provides an immunological rationale for current occupational het limits and highlights the importance of integrating sex-specific considerations into protective guidelines under extreme heat. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/681783v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@9620dorg.highwire.dtl.DTLVardef@47beborg.highwire.dtl.DTLVardef@6396daorg.highwire.dtl.DTLVardef@44c890_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Dynamic updating of cognitive maps via traces of experience in the subiculum

In the classical view of hippocampal function, the subiculum is assigned the role as the output layer. In spatial paradigms, some subiculum neurons manifest as so-called boundary vector cells (BVCs), firing in response to boundaries at specific allocentric directions and distances. More recently it has been shown that some subiculum BVCs can be classified as vector trace cells (VTCs), which exhibit traces of activity after a boundary/object has been removed. Here we propose a model of processing within subiculum that accounts for VTCs, taking into account proximodistal differences in subiculum (pSub vs dSub) and CA1. dSub neurons receive feedforward input, either in the form of perceptual information (from BVCs in pSub) or mnemonic information (from place cells in CA1). Mismatch between these two inputs updates associative memory encoded in the synapses between CA1 and dSub. With a range of learning rates, the model captures the majority of experimental findings, including the distribution of VTCs along the proximodistal axis, the percentage of VTCs across different cue types, and the hours-long persistence of the vector trace. Incorporating experimentally reported effects of inserted objects/rewards on place cells (place field shift), we also explain why VTCs have longer tuning distances after cue removal. This adds predictive character to subiculum traces and suggests the online use of mnemonic content during navigation. Our model suggests that mismatch detection for updating spatial memory content provides a mechanistic explanation for findings in the CA1-subiculum pathway. This work constitutes the first dedicated circuit-level model of computation within the subiculum, consistent with known effects in CA1, and provides a potential framework to extend the canonical model of hippocampal function with a subiculum component.

neuroscience↗

Distinct cell wall molecular architecture of dimorphic Talaromyces marneffei cells revealed by solid-state NMR spectroscopy

Talaromyces marneffei, causing systemic infections in immunocompromised patients ranging from HIV/AIDS individuals to cancer and transplant recipients, is an increasingly urgent global pathogen. However, the fungus remains underrecognized despite the systemic infection disease talaromycosis caused by this pathogen is associated with high mortality rates. Its pathogenicity depends on a temperature-triggered shift from saprophytic mold (25 {degrees}C) to pathogenic yeast (37 {degrees}C), and the two growth forms display distinct sensitivity to antifungal drugs, which processes involve extensive cell wall structure and components remodeling. To dissect these processes, we use solid-state nuclear magnetic resonance (ssNMR) and other techniques to show that T. marneffei yeast and hyphal cells have distinct cell wall thickness and hydrophobicity, and different assembly of mobile and rigid polymers within the T. marneffei cell wall. The yeast wall was 2.3 times thicker and more hydrated. ssNMR revealed a rigid core of {beta}-1,3-glucans, chitin and chitosan, with {beta}-1,3-glucan rising from 57% in mold to 72% in yeast. Both forms showed tight polysaccharide packing, but only mold exhibited lysine-containing protein interactions with chitin and chitosan. These insights not only map the structural basis of host temperature adaptation and also inform targeted antifungal design in future.

bioinformatics↗

The Sindbis virus nsP3 opal codon protects viral RNA and fitness by maintaining replication spherule integrity

Most alphaviruses maintain an in-frame opal stop codon that interrupts their non-structural polyprotein (nsP) ORF between nsP3 and nsP4 in both vertebrate and insect hosts. We show that the nsP3 opal stop codon confers a replicative advantage to Sindbis virus (SINV) in RNAi-competent mosquito cells and in Aedes aegypti mosquitoes, but not in cells or mosquitoes lacking RNAi. Mutation of the opal stop codon delays processing of the viral nsP polyprotein, disrupts viral replication spherule integrity, and renders viral RNA susceptible to Dicer 2 cleavage, resulting in higher antiviral siRNA responses against SINV. Similarly, these defects caused by opal codon mutations lead to increased viral RNA detection and enhanced immune signaling in vertebrate cells. Thus, a single stop codon in alphaviruses mediates a multipotent viral strategy to evade innate immune defenses across diverse hosts. TeaserA conserved ORF-interrupting stop codon helps alphaviruses avoid triggering innate antiviral immunity across diverse hosts.

microbiology↗

A neural circuit for female-specific defensive homeostasis in risk assessment

HighlightsSC CB1R+ neurons encode visual survival threats and initiate risk assessment in both sexes CB1R+ SC-LHb GABAergic circuit maintains defensive homeostasis in risk assessment in females eCBs gate this circuit by disinhibiting presynaptic GABA release exclusively in females Disruption of this mechanism female-specifically impairs risk assessment and stress coping In BriefLiu et al. identify a female-specific subcortical circuit in which eCB signaling, via CB1R on GABAergic terminals in the SC, suppresses transmission to the LHb to maintain precise defensive homeostasis in risk assessment. These findings uncover the circuit and neuronal mechanisms that contribute to the sexually dimorphic maintenance of defensive homeostasis. Risk assessment in defensive behavior is an adaptive mechanism shaped by natural selection, enabling individuals to evaluate potential threats and thereby maintain defensive homeostasis. However, it remains unknown whether specific neural circuits maintain their behavioral homeostasis in a sex-specific manner. To address this, we investigated its neural basis by hierarchical behavior analysis framework with neural circuit dissection. In mice of both sexes, visual survival threats activated cannabinoid 1 receptor (CB1R)-expressing neurons in the superior colliculus (SC) to initiate consistent risk assessment. Deletion of CB1R in SC GABAergic neurons female-specifically impairs risk assessment by disinhibiting GABA release in SC-lateral habenula (LHb) projections, resulting in shortened risk assessment. This disruption furthermore increases the occurrence of abnormal spontaneous behavior following chronic stress exclusively in females. We identified a female-specific SC-LHb GABAergic circuit gated by CB1R maintains defensive homeostasis in risk assessment. Our findings reveal how a conserved neuromodulatory system sex-specifically gates a subcortical circuit to orchestrate distinct survival strategies.

neuroscience↗

Cortex-Wide Substrates for Body Schema and Action Awareness

The concept of the body schema originated from studies of patients with cortical lesions who were unable to localize their body parts in space or perceive passive movements (Head & Holmes, 1911). Current consensus defines the body schema as the brains internal representation of the body configuration in space used for both embodied perception and voluntary action (de Vignemont, 2010; Berlucchi & Aglioti, 2010; Vallar et al., 2025). Despite extensive research, how the cortex efficiently encodes the vast repertoire of body postures to support natural behavior remains poorly understood. Here, we reveal the representational format underlying the body schema by combining large-scale electrophysiological recordings with full-body 3D tracking and joint angle computation in freely behaving mice. Across cortical regions, neurons encoded diverse postural features in distinct reference frames: posterior parietal cortex (PPC) populations preferentially encoded body midline-referenced features, while sensorimotor cortices utilized a gravity-referenced frame. Strikingly, during performance of different stereotyped actions, distinct cortical ensembles were selectively activated. These action ensembles fired in phase-locked sequences that tiled the full action cycle, providing a neural substrate for action awareness. A network model recapitulated these dynamics and identified low-dimensional action subspaces within population activity. Together, these findings reveal that the cortex organizes the body schema around actions, compressing high-dimensional kinematics into an efficient, body-midline-and gravity-anchored, action-aware neural code.

neuroscience↗

Mapping Human Survivability at Extreme Wet-Bulb Temperatures 32-35°C

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/677706v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@70b72dorg.highwire.dtl.DTLVardef@9fbfeorg.highwire.dtl.DTLVardef@17f05a5org.highwire.dtl.DTLVardef@4b977b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG HighlightsWe report the first empirical human survival map across wet-bulb temperatures of 32-35{degrees}C. HydraAon and behavior cooling extend survival beyond the 6-hour theoreAcal limit. Females consistently tolerate extreme humid heat longer than males in controlled trials. Our findings refine heat-health models and inform equitable climate adaptaAon strategies. In briefExtreme humid heat, measured by wet-bulb temperature (Tw), is nearing the threshold of human survivability under climate change. In controlled trials with 36 adults, we provide the first empirical survival map across Tw=32-35{degrees}C, showing that hydration and behavioral adaptations extend endurance beyond the theoretical 6-hour limit, with women tolerating heat longer than men. These findings refine human heat tolerance thresholds and inform equitable climate adaptation and heat-health strategies. SCIENCE FOR SOCIETYAs climate change accelerates, extreme humid heat events--measured by wet-bulb temperature (Tw)--pose a growing threat to human survival. This study provides the first empirical benchmarks of human survivability across Tw=32-35{degrees}C, clarifying how long healthy adults can endure these conditions under full hydration and minimal activity. We find that while the theoretical 6-hour survival limit at Tw=35{degrees}C is partly supported, both men and women can withstand these conditions for 7-8 hours when hydrated, with women demonstrating greater tolerance. At Tw=34{degrees}C, projected heatstroke onset extends beyond 12-16 hours, while conditions at Tw=32-33{degrees}C remain largely compensable for more than 30 hours. These results challenge prevailing heat tolerance models, underscore the role of behavioral and physiological adaptations, and provide critical data for designing equitable heat-health policies and early warning systems that account for sex differences and vulnerable populations. Climate change-driven extreme heat events increasingly threaten human health. Here, we provide the first empirical map of human survivability across four extreme wet-bulb temperatures (Tw=32- 35{degrees}C) in controlled trials. Thirty-six healthy young adults (20 males, 16 females) were exposed to twelve dry-bulb temperature and relative humidity combinations in shaded indoor settings under full hydration. Participants remained seated and performed light office tasks until core temperature (Tcore) reached 39{degrees}C or exposures lasted 8 hours. Clinical heatstroke threshold (Tcore=40.5{degrees}C) were projected by extrapolating from our direct Tcore measurements during controlled exposure trials. At Tw=35{degrees}C, males and females reached heatstroke in approximately 7.1-7.7 and 8.3-8.6 hours, respectively--partly supporting the 6-hour theoretical limit while revealing enhanced short-duration resilience when hydrated. At Tw=34{degrees}C, projected times are 12.5-12.9 hours (males) and 15.5-16.2 hours (females). Conditions at Tw=32{degrees}C and 33{degrees}C remained (quasi-)compensable, with projected heatstroke onset after 33-35 hours. Females consistently tolerated heat stress longer than males. These physiological benchmarks are critical for improving heat-health models and embedding sex-specific vulnerability in equitable adaptation strategies amid accelerating global warming.

physiology↗

3D-printing-assisted, microfabricated devices reveal hierarchical and temporal mechanosensing in high-density fibroblast culture

Understanding how cells integrate mechanical forces across multiple directions, length scales, and timescales remains a fundamental challenge in mechanobiology. Deciphering how cells integrate this information is particularly important in the context of wound healing, where the timing and duration of the fibroblast-to-myofibroblast transition can determine healing outcomes. Here, we discovered that fibroblasts in engineered tissues respond to directional anisotropy in stress through a hierarchical temporal cascade, with individual cell elongation (24 hr) preceding collective alignment (40 hr), which then drives -smooth muscle actin expression and myofibroblast transition (96h). To enable this discovery, we developed a modified hydrogel-assisted stereolithographic elastomer (HASTE) prototyping platform to incorporate a detergent that improves wettability of template agar hydrogels by poly(dimethylsiloxane) elastomer. HASTE allowed rapid prototyping of intricate 3D micropost arrays that provides isotropic (8-post) versus anisotropic (4-post) boundary conditions. Fibroblasts sensed and responded to stress directionality before bulk tissue reorganization occurs. Computational modeling predicted steady-state activation patterns based on initial stress anisotropy rather than magnitude, and our experiments reveal that reaching this state requires sequential mechanosensitive processes operating across distinct timescales. This temporal hierarchy persists even when extensive cell-cell contacts might be expected to mask matrix-mediated mechanical signals. Our findings demonstrate that fibroblast mechanosensing involves adaptive responses encoded through progressive cell and tissue reorganization. Results provide insight into how nanoscale mechanosensing scales up to direct tissue-level organization, with implications for understanding wound healing, understanding fibrosis, and engineering functional tissue replacements.

bioengineering↗

Characterization of adult hippocampal neurogenesis in the novel AppSAA Knock-in Alzheimer's disease mouse model

Adult hippocampal neurogenesis (AHN) declines with age and is thought to be severely exacerbated in neurodegenerative disorders like Alzheimers disease (AD). Despite numerous efforts to understand how AHN is altered in AD mouse models, results have been inconsistent, largely due to limitations of first-generation transgenic AD mouse models. The newly developed App Knock-in models address many of these limitations. Here, we provide the first in-depth characterization of hippocampal cell populations and AHN across different ages in the novel AppSAAKnock-in (AppKI) mouse model. Our findings reveal that AppKI mice show no early deficits in excitatory dentate granule cells or inhibitory interneurons at 2 and 4 months, but significant loss of both populations emerges by 6 months of age. We also identified a progressive decline in AHN with the survival of newborn neurons being impaired first at 4 months, followed by a deficit in proliferation at 6 months. Furthermore, we demonstrate that exposure to enriched environment, a form of hippocampus-engaged exploration, robustly enhances AHN in AppKI mice, primarily by promoting survival. In conclusion, our study provides a foundational characterization of the AppKI model, establishing a timeline for cellular and AHN deficits.

neuroscience↗