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Wu, Y.

Publications and source records attributed to Wu, Y..

At least 181 records · Page 10Linked to original sources

Flexible perception of face attributes under naturalistic visual constraints

How does human brain adapt face perception to naturalistic visual constraints? While faces are typically perceived under dynamic and uncertain conditions, most studies use static presentation and enough temporal exposure, leaving the neural mechanisms of adaptive face processing poorly understood. Here, we employed steady-state evoked potential electroencephalography (EEG) to track how perception of multiple face attributes (age, emotion, gender, and race) adjusts to two ecologically relevant scenarios: (1) faces gradually sharpening from blur to clear (mimicking approaching from a distance), and (2) faces presented with incrementally increasing exposure times (mimicking brief, flashed encounters). By progressively increasing sensory input (via spatial frequency content in Experiment 1 and exposure time in Experiment 2) in a stepwise manner, we show that emotion and race categorization emerge early, even under high blur (e.g., 4.89 cycles/image) or brief exposures (e.g., 41.7-50 ms), reflecting coarse visual processing. In contrast, age discrimination requires higher clarity (e.g., 7.31 cycles/image) but shorter exposure (e.g., 41.7 ms) if clear images are presented. In both scenarios, gender processing exhibits the strongest dependence on clarity (e.g., 10.94 cycles/image) and time (e.g., 66.7 ms). Representational similarity analyses further show that reliable response patterns for emotion and race emerge earlier in the posterior brain region relative to those for gender in both experiments. Together, these results identify a flexible temporal order for face perception that adapts to naturalistic visual constraints, bridging the gap between controlled laboratory paradigms and naturalistic social vision.

neuroscience↗

The curse of dimensionality in motor cortex

Understanding how motor cortex generates movement is a foundational challenge in neuroscience. Unsupervised dimensionality reduction techniques, such as principal component analysis (PCA), are widely used to transform high-dimensional neural recordings into a compact, low-dimensional space. The dimensionality of this space--that is, the number of principal components needed to explain a fixed fraction of variance--is broadly assumed to be an intrinsic property of the underlying neural dynamics, potentially modulated by task complexity. Here, by comparing con-strained reaching and unconstrained naturalistic behaviors recorded from the same animal on the same day, we show that this assumption breaks down in two distinct ways. First, across four non-human primates, the dominant axes of low-dimensional neural activity separate behavioral contexts rather than movement kinematics, with neural activity shifting rapidly between task-specific regions of state space at task transitions. Notably, traditional dimensionality metrics are insensitive to movement complexity across tasks. Instead, unsupervised dimensionality scales with the number of recorded neurons, exhibiting non-saturating growth up to 1000 simultaneously recorded electrodes, a pattern that holds across PCA, factor analysis, shared variance component analysis, and nonlinear autoencoders. This scaling has direct consequences for decoding: while decoders trained on unsupervised subspaces improve only modestly with electrode count, super-vised methods leverage additional electrodes to separate neural states from a vanishingly small fraction of total variance (<10% at 1000 electrodes). Together, these results challenge current views on cortical dimensionality, reveal a greater-than-appreciated role for behavioral context in shaping motor cortical activity, and motivate careful consideration of computational methods as experimental data volumes scale.

neuroscience↗

Ulacamten: A Novel, RLC-Targeting Cardiac Myosin Inhibitor for Potential Treatment of Cardiac Hypercontractility, Including HFpEF

BackgroundCardiac myosin inhibitors (CMIs) demonstrate advantages over other guideline-directed therapy for patients with obstructive hypertrophic cardiomyopathy (oHCM). By reducing hypercontractility, CMIs abrogate excessive systolic function and improve diastolic function; diminish hypertrophy of the left ventricle (LV); and improve exercise capacity, functional class, and symptoms. Whether CMIs are therapeutic in heart failure with preserved ejection fraction (HFpEF) is of interest because a significant subset of these patients demonstrate supranormal ejection fractions and abnormal LV structure, characteristics in common with HCM, where CMIs have proved effective. ObjectivesOur goal was to characterize the mechanism of myosin inhibition for ulacamten and determine its efficacy in a rodent model of HFpEF. MethodsUlacamten was characterized using biophysical and biochemical approaches, cardiomyocytes from humans and the ZSF1 obese rat model of HFpEF, hypercontractile human-engineered heart tissues, and echocardiography in the ZSF1 rat model. ResultsUnlike the other CMIs, aficamten and mavacamten, ulacamten binds outside the S1 domain of myosin and requires the regulatory light chain domain to bind and inhibit the activity of 2-headed myosin. Ulacamten only partially inhibits the myosin ATPase activity in both myofibrillar and protein systems, but inhibition of contractility was nearly complete in cardiomyocytes. Improvement in relaxation was demonstrated in hypercontractile-engineered heart tissues, and chronic treatment of ZSF1 obese rats showed benefits in both cardiac structure and function. ConclusionsUlacamten inhibits myosin in a manner distinct from aficamten and mavacamten, potentially broadening the mechanistic properties of CMIs available for treatment of hypercontractile cardiac dysfunction. CONDENSED ABSTRACTCardiac myosin inhibitors (CMIs) abrogate excessive systolic function and improve diastolic function, diminish cardiac hypertrophy, and improve exercise capacity in humans with obstructive hypertrophic cardiomyopathy (oHCM). Supranormal ejection fraction underlies heart failure with preserved ejection fraction (HFpEF) in some patients. We describe a new CMI, ulacamten, with binding and inhibitory properties distinct from two other FDA-approved CMIs, aficamten and mavacamten. Specifically, ulacamten requires 2-headed myosin to inhibit activity, whereas aficamten and mavacamten inhibit single-headed myosin. Ulacamten inhibits contractility in primary myocytes isolated from control human and hypercontractile ZSF1 obese rat hearts, as well as engineered heart tissues created with induced pluripotent stem cell cardiomyocytes bearing an HCM mutation. Chronic treatment of ZSF1 obese rats as a preclinical model of HFpEF improves diastolic function and reduces hypertrophy and fibrosis, broadening the potential mechanistic landscape of CMIs. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/701387v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@11f9cecorg.highwire.dtl.DTLVardef@776847org.highwire.dtl.DTLVardef@15f19ddorg.highwire.dtl.DTLVardef@9b20c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

Bright calcium-modulated bioluminescent indicators for activity imaging and red photon-assisted synaptic transmission

Bioluminescent calcium sensors have unique uses in neuroscience and neuroengineering, enabling noninvasive imaging of neuronal activity and contactless activation of opsin-expressing neurons. However, the speed, range, and robustness of non-invasive imaging and rewiring or neuronal activity are limited by the radiance and dynamic range of existing bioluminescent calcium sensors. Here, we report the stepwise engineering of improved cyan-excitable red fluorescent proteins (mCyRFP4 and dCyRFP4), an improved red bioluminescent protein based on NanoLuc and CyRFP4 (Antares3), and an improved bioluminescent calcium sensor based on Antares3 (CaMBI3). Antares3 is 3-fold brighter than its predecessor, while CaMBI3 responds with an overall dynamic range of 24-fold, enabling high-sensitivity detection of calcium dynamics in muscle and neuronal tissues in vivo. Finally, a CaMBI3 variant and a red-shifted opsin ChRmine enabled red photon-assisted synaptic transmission in C. elegans. CaMBI3 thus facilitates genetically targeted non-invasive imaging and rewiring of neural activity in living animals.

neuroscience↗

Functional Stratification Reveals Speed-Independent Gait Impairments Beyond Chronological Age

BackgroundGait is a clinically relevant indicator of functional decline in aging populations. However, most studies classify older adults by chronological rather than functional age, which may obscure early impairments detectable through kinematic profiling. This study examined whether stratifying older adults by functional status using the Short Physical Performance Battery (SPPB) enhances sensitivity in detecting gait abnormalities and instability-related compensatory patterns. MethodsA total of 190 adults completed gait trials on a pressure-sensitive walkway. Twenty-eight spatial, temporal, and variability-based gait parameters were derived. Participants were categorized as young adults or older adults, who were further stratified into high- and low-functioning groups based on SPPB scores. Analysis of covariance (ANCOVA) was performed, adjusting for habitual walking speed to isolate functional effects. FindingsAfter adjusting for speed, the low-functioning group demonstrated longer stance and double-support durations, wider step width, and greater step-to-step variability in both spatial and temporal domains compared with both the high-functioning and young reference groups. These findings indicate a compensatory, instability-driven control strategy that challenges the assumption of a "slower but steady" gait in aging. High-functioning older adults exhibited gait patterns more closely resembling those of younger adults. InterpretationFunctional classification using the SPPB provided greater sensitivity than chronological age in detecting early mobility decline. Gait variability emerged as a salient biomarker of impaired neuromuscular control. Integrating quantitative gait profiling with validated functional assessments may improve early screening, targeted intervention, and fall prevention strategies.

physiology↗

Direct evidence from kinetic D2O-MRI modeling that the choroid plexus is not the major source of cerebrospinal fluid

The role of the choroid plexus (CP) as the primary source of cerebrospinal fluid (CSF) remains controversial. Here, we used dynamic indirect D2O magnetic resonance imaging (MRI) at 9.4T to investigate whole-brain CSF dynamics in rats. Spin-echo echo-planar imaging (SE-EPI) was performed during intravenous D2O infusion with a temporal resolution of 10.69 s and an in-plane resolution of 150 x 150 {micro}m. An echo time of 150.0 ms was employed to effectively suppress signals from brain parenchyma, blood, and interstitial fluid, resulting in preferential visualization of CSF. The ambient and supracerebellar cisterns (AC+SC) exhibited the greatest signal attenuation, reaching 47.32 {+/-} 15.70% of baseline, whereas the lateral ventricles (LV1, LV2) showed smaller reductions (68.73 {+/-} 18.72%-72.64 {+/-} 15.07% of baseline). CSF production rates were quantified using a one-compartment perfusion model. Estimated secretion rates were 0.11 and 0.13 {micro}L/min in the lateral ventricles and 1.30 {micro}L/min in the AC+SC region, indicating a 5.42-fold higher CSF production outside the ventricles. These findings provide direct in vivo evidence that the lateral ventricles are not the primary site of CSF production. The proposed D2O-based dynamic SE-EPI approach is safe, non-invasive, cost-effective, and suitable for widespread application.

neuroscience↗

A methylome-derived m6-dAMP trigger assembles a PUA-Cal-HAD immune filament that depletes dNTPs to abort phage infection

Bacteria must distinguish phage attack from normal homeostatic processes, yet the danger signals that trigger many defence systems remain unknown. Here, we show that a PUA-Calcineurin-CE-HAD module from Escherichia coli ECOR28 confers broad anti-phage protection by binding Dam-methylated deoxyadenosine monophosphate (m6-dAMP) generated during phage-induced chromosome degradation. Ligand binding converts a preassembled PUA-Calcineurin-CE hexamer loaded with six HAD phosphatases into a polymerising filament. The filament acts as a high-flux dNTP sink through a two-enzyme cascade: HAD first dephosphorylates dATP to dADP, and Calcineurin-CE then converts dADP to dAMP. dNTP collapse halts phage replication and enforces abortive infection. Multiple mobile-element DNA mimic proteins block filament assembly, revealing a direct phage counter-defence. More broadly, our findings extend a conserved, cross-kingdom paradigm of immune filament assembly to nucleotide-depletion antiviral defence and suggest modified-nucleotide sensing by related PUA-Calcineurin-CE modules as a widespread, underappreciated bacterial strategy.

microbiology↗

Aging, dauer, and stature phenotypes are conferred by structure-directed missense mutations in the endogenous AGE-1/phosphatidylinositol 3-kinase catalytic subunit.

Phosphatidylinositol 3-kinase (PI3K) integrates insulin/IGF signaling (IIS) and Ras inputs to control lifespan, metabolism and growth, yet the organismal consequences of selective structural perturbations remain poorly understood. Using structure-guided CRISPR/Cas9-dependent genome editing, we dissected functions of AGE-1, the sole Class IA PI3K catalytic subunit in Caenorhabditis elegans. An endogenously tagged AGE-1, containing a long flexible linker, epitope and fluorescent tag, retained full activity, enabling visualization of native protein dynamics in vivo. A constitutively active E630K substitution, modeled on oncogenic p110 alleles, markedly shortened lifespan and enhanced Ras-dependent induction of primary vulval precursor cell (VPC) fate, confirming evolutionary conservation of PI3K activation mechanisms that directly modulate longevity and development. Structural modeling further guided mutation of AGE-1 residues predicted to mediate Ras binding. Unexpectedly, a putative AGE-1 variant defective in Ras association, together with a complementary Ras effector-binding mutation, produced enlarged animals with reduced dauer formation. These phenotypes reveal a previously unrecognized Ras>PI3K signaling axis that restrains somatic growth and promotes entry into diapause, counter to canonical IIS models. Together, these structure-informed alleles show that discrete PI3K structural perturbations can differentially uncouple lifespan, growth, and developmental outcomes in vivo. By combining structural modeling with genome editing in a tractable aging model, this work establishes a framework for dissecting conserved signaling enzymes at single-residue resolution and uncovers unexpected organismal roles for PI3K structure in coordinating growth and longevity.

developmental biology↗

Serotonergic neurons in the dorsal raphe nucleus scale O2 utilization in response to traumatic stress

Trauma is a main cause of psychiatric disorders. Approximately 24% of trauma-exposed individuals suffer from posttraumatic stress disorder throughout their lifetime, however, the vast majority of people are resilient. Why some people are resilient while others develop mental disorders in face of trauma in a short timescale? Here, we show that O2 actively initiates a cell-signaling pathway that regulates behavioral outcomes in response to traumatic stress. We found that serotonergic neurons in the dorsal raphe nucleus (DRN5-HT neurons) projecting to the ventral caudate putamen and the ventral tegmental area exhibit distinct physiological patterns of O2 utilization. In response to traumatic stress, O2 utilization in these neurons changed individually, following either a susceptible or resilient pattern, thereby modulating corresponding behaviors. This O2 scaling was regulated by ferroptosis within the DRN5-HT neurons. Thus, we identify a previously unrecognized function of O2, opening an avenue for the treatment and prevention of stress-related disorders.

neuroscience↗

An Asynchronous Production Line of Meiotic Prophase I in the Mouse Fetal Ovary

The initiation of meiosis in the mammalian female germline has long been described as a synchronous event, occurring within a narrow developmental window. Here, we challenge this paradigm through a systematic, quantitative analysis of meiotic entry and progression in the mouse fetal ovary. Using dynamic expression profiling of key regulators Stra8, Sycp1, and Sycp3 alongside proliferation markers, we demonstrate that germ cells enter meiosis asynchronously and continuously between embryonic days E12.5 and E16.5. During this extended period, mitotic proliferation persists, indicating that germ cells are progressively recruited into the meiotic pathway rather than halting division simultaneously. Homologous chromosome synapsis, marked by Sycp1/Sycp3 co-localization, initiates at E14.5 and is completed prenatally by E18.5. Integrating these data into a continuous-time Markov chain model, we derive a "meiotic clock" that predicts fixed temporal intervals from meiotic entry to synapsis completion ([~]72 hours) and to meiotic arrest ([~]91 hours), regardless of entry time. This model provides a predictive framework for germ cell development and establishes that female meiotic initiation is a prolonged, asynchronous production line rather than a synchronized transition, reshaping our understanding of oogenesis and its regulatory logic. TEASERThe initiation of female meiosis in mice is redefined as an asynchronous, continuous production line from E12.5 to E16.5, supported by a predictive "meiotic clock" model with fixed temporal intervals for synapsis and arrest.

developmental biology↗

A micropeptide component of the OGDH complex modulates ATP production in the TCA cycle

Since its elucidation, the tricarboxylic acid (TCA) cycle has been regarded as a fully defined enzymatic pathway. Here, we report the discovery of a previously unrecognized micropeptide component of this central metabolic system. Through analyzing ribosome profiling data from the mouse sORFs.org database, we discovered APPM (ATP production-promoting micropeptide), a 29-amino acid peptide encoded by a non-canonical small open reading frame within the mouse Ctsb gene. APPM localizes to the mitochondrial matrix and inner membrane, where it directly binds to the E1 subunit (OGDH) of the -ketoglutarate dehydrogenase complex (OGDHc). This interaction modulates OGDHc enzymatic activity, thereby regulating NADH and ATP production. We identified tyrosine-13 as the critical residue mediating the APPM-OGDH interaction and functional activation. Exogenous APPM administration increased ATP levels in vivo and, in a mouse model of heart failure, restored cardiac function, outperforming the reference drug trimetazidine. Collectively, our findings identify APPM as the first micropeptide regulator of the OGDH complex, expanding the known repertoire of the TCA cycle and presenting a potential therapeutic strategy for bioenergetic disorders.

molecular biology↗

Integrated Multi-omics Analysis Identifies Molecular Signatures of Regular Physical Activity in Human Peripheral Blood

Regular physical activity is well established to protect against metabolic disorders and bolster immunity; yet, the underlying molecular and cellular mechanisms remain incompletely understood. We integrated plasma metabolomics and lipidomics with single-cell transcriptomic and chromatin accessibility profiles to decode the systemic impact of physical activity on human immunity and metabolism. Our data reveal that regular physical activity is linked to a coordinated metabolic signature marked by enhanced fatty acid oxidation and antioxidant defense. In circulating immune cells, regularly active individuals exhibited synchronous enhancement at both the chromatin accessibility and transcriptional levels for antigen presentation-related genes in antigen-presenting cells (APCs), particularly in classical monocytes, naive B cells, and switched memory B cells. Meanwhile, cytotoxic programs in CD8+ cytotoxic T and mature NK cells showed epigenetic pre-activation of effector function regulators. Intercellular communication analysis further revealed that regular exercise enhanced MHC-I/II signaling between APCs and T cells and suppressed inflammatory signaling networks. Together, these findings elucidate molecular mechanisms underlying the health benefits of regular exercise and offer a theoretical basis for enhancing public health and preventing chronic diseases.

bioinformatics↗

CRANBERRY: An RNA Dynamics Model with Sugar Puckering and Noncanonical Base Pairing

We introduce a new coarse-grained model ''CRANBERRY'' that incorporates sugar puckering and non-canonical base pairing, two factors central to RNA structure and dynamics, yet rarely included in most coarse-grained models. Our model is parameterized through a contrastive divergence approach, combined with fine-tuning strategies to improve accuracy in generating disordered states, a feature that is critical for the accurate description of thermodynamics. This two-stage training procedure greatly enhances cooperative folding behavior. Due to these advances, the model's predictive performance is comparable to that of all-atom force fields for native-state structural fluctuations. Furthermore, CRANBERRY exhibits better agreement with experimental data on stacking free energies and disordered structures measured by Small Angle X-ray Scattering. In addition, CRANBERRY can reversibly fold tetraloops with a minimum RMSD of 1.4 Angstrom de novo, which continues to be challenging for all-atom models. It predicts melting temperatures in agreement with experimental values, and with a greater cooperativity than all-atom predictions.

biophysics↗

Healthcare Infrastructure Shapes Evolutionary Trade-offs and Geographic Dissemination of Multidrug-Resistant Acinetobacter baumannii

Antimicrobial-resistant pathogens pose an existential threat to modern medicine, yet the evolutionary forces driving their adaptation in healthcare systems remain largely unexplored. We revealed that hospital network architecture functions as a primary selective pressure, driving pathogen evolution through infrastructure-dependent virulence-transmission trade-offs. Phylogenomic analysis of 5,023 Acinetobacter baumannii isolates across Chinas centralized healthcare system identifies two co-existing evolutionary strategies: a virulence-optimized clade (ESL2.4) that spread slowly (20.4 km per year) in low-connectivity hospitals, and a transmission-optimized clade (ESL2.5) that disseminate rapidly (65.2 km per year) through mega-city healthcare hubs, likely attributed to its capsule conversion and increased upper respiratory colonization. Comparative analysis with European A. baumannii populations demonstrates that healthcare connectivity, not geography, governs pathogen distribution through convergent genomic adaptations. Our simulation suggests competitive asymmetries of the two clades, following the ecotype principle and enabling stable coexistence. The COVID-19 pandemic provided a natural experiment validating these mechanisms: outpatient restrictions reduced transmission-optimized lineage spread by 89%, while virulence-optimized lineage persisted through inpatient networks. These findings establish healthcare infrastructure as a critical evolutionary driver with immediate implications for predicting and controlling antimicrobial resistance emergence across diverse healthcare systems.

microbiology↗

Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death

FOF1-ATP synthase is one of the most abundant proteins of the mitochondrial inner membrane and the primary enzyme responsible for ATP production in eukaryotic cells. Nevertheless, it was recently reported to play a prominent role in cell death by forming a large-conductance leak channel in the mitochondrial permeability transition pore (mPTP), making it a promising therapeutic target. Bedaquiline (BDQ), a member of the diarylquinoline class of drugs, was shown to selectively inhibit the catalytic activity of Mycobacterium tuberculosis ATP synthase with no effect on the mammalian enzyme. Here, we report a new role for BDQ as a potent inhibitor of the ATP synthase c-subunit leak channel in mammals. BDQ inhibited the single-channel activity of porcine heart ATP synthase in planar lipid bilayer recordings and prevented glutamate-induced cell death in primary hippocampal neurons. These findings reveal the potential new application of BDQ for treating mPTP-related diseases by targeting the ATP synthase c-subunit leak channel. Why it mattersBedaquiline (BDQ) is the only FDA-approved drug to treat pulmonary multidrug-resistant tuberculosis (TB), caused by the Mycobacterium tuberculosis. BDQ cures TB by specifically targeting mycobacterial ATP synthase and inhibiting ATP production. Recently, BDQ was also reported to bind to mammalian ATP synthase at the interface between the a and c-subunits and to inhibit its catalytic activity. However, the effect of BDQ on ATP synthase leak channel activity has not been explored. Here, we report that BDQ inhibits the ATP synthase c-subunit leak channel (ACLC) activity with an IC50 of [~]24 nM and prevents glutamate-induced neuronal death, suggesting a new therapeutic repurposing of BDQ for treating ACLC-related diseases.

biophysics↗

Functional Evaluation of TRPC6 Missense Variants in Cancer Patients via Molecular Docking Analysis Compared with Patch Clamp Electrophysiology

Gain-of-function mutations in the transient receptor potential 6 (TRPC6) channel have recently been recognized as risk factors for both doxorubicin (DOX)-induced cardiomyopathy. Functional evaluation of TRPC6 missense variants is therefore important for cancer patients undergoing anthracycline treatment. However, traditional electrophysiological methods are labor-intensive and time-consuming. In this study, we compared the functional responses of TRPC6 missense variants to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, using molecular docking and patch clamp recording techniques. For the wild-type (WT) TRPC6 structure (PDB ID: 6UZ8), OAG exhibited a binding energy of -4.49 kcal/mol and a dissociation constant (Kd) of 0.511 mM. Twenty TRPC6 missense variants were identified from cancer patients in the Mayo Clinic database. Of these, fifteen variants had resolvable structures, nine of which displayed increased Kd values and six decreased Kd values compared to WT in molecular docking analysis. Patch clamp recordings revealed that TRPC6 WT and mutant channels were inactive at baseline but were activated upon 50 M OAG stimulation, except two loss-of-function variants. Moreover, a 24-h treatment with 0.5 M DOX significantly enhanced OAG-induced channel activation. All three variants identified in patients with heart failure demonstrated gain-of-function properties in both electrophysiological measurements and in-silico predictions. Importantly, the results obtained from molecular docking and patch clamp recordings were strongly correlated, showing an 82% concordance, higher than the predictions from AlphaMissense. These findings indicate that our computational analysis provides a rapid and reliable method for predicting the functional impact of TRPC6 missense variants, which may aid clinical decision-making in cancer patients receiving chemotherapy.

physiology↗

Spatial patterns of APOBEC mutagenesis in the tumour microenvironment of Asian breast cancer

A germline deletion of the coding region at the APOBEC3B (A3B) gene that is common in Asian and Oceanic populations has been found to be correlated with increased APOBEC mutagenesis, immune activation, and tumour heterogeneity in breast cancer. The mechanism by which A3B deletion and APOBEC mutagenesis induces immune activation in Asian breast cancers is still unclear, but has been thought to involve increased neoantigen burden. In this study, we investigated the mechanisms by which A3B deletion and APOBEC mutagenesis may lead to immune activation using Stereo-seq spatial transcriptomics of Malaysian triple-negative breast cancer (TNBC) tumours with and without the A3B deletion to examine the spatial expression patterns of APOBEC3A/B as well the spatial patterns of APOBEC-associated mutations and neoantigens. Unexpectedly, we found only limited associations between A3B deletion, APOBEC-associated neoantigens, and immune activation. Instead, we found strong spatial associations between mitochondrial APOBEC-associations mutations, the cGAS-STING pathway, and the NF-{kappa}B pathway. Our study thus supports a new model whereby APOBEC-mediated activation of the immune system does not occur via neoantigen presentation, but instead occurs via mitochondrial hypermutation that drives cGAS-STING activation of the NF-{kappa}B pathway. Our study may provide new insights into the spatial landscape of Asian breast tumours and the effect of germline A3B deletion and APOBEC mutagenesis on the tumour immune microenvironment.

cancer biology↗

Chronic stress abnormalize microglial-vascular interaction via AT1R signaling and microglia activation to drive depression-like behaviors

Depression entails a range of pathological processes in the brain, typically characterized by microglia activation, neural dysfunction, and vascular dysregulation. While it is well established that activated microglia inflict damage to neurons through direct and indirect microglia-neuron interactions, their interaction with vasculature and the associated regulation of vascular structure and function in depression remain poorly understood. Here, using a mouse model of depression induced by chronic unpredictable stress (CUS), we find that in stressed mice, activated microglia present reduced motility and decreased contact area with vasculature, which is accompanied by pathological vascular structure and function, marked by reduced vessel density, narrowed vascular diameters, and sluggish blood flow velocity. We observe that vascular structure in the stressed mice is rapidly modified by the vascular-contacted microglia. These vascular-contacted microglia show upregulated angiotensin II type 1 receptor (AT1R) expression, which is not present in the vascular-uncontacted microglia. Furthermore, we demonstrate that AT1R signaling together with microglia activation under chronic stress are critical mediators for the altered microglial-vascular contact situation, vascular dysregulation, as well as the depression-like behaviors. Together, our findings reveal that under CUS, the aberrant microglial-vascular interaction, including the dysregulated microglial vasoregulation arising from AT1R signaling and microglia activation, leads to depression, forging a new link between chronic stress and depression.

neuroscience↗