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Biology subjects

Wang, F.

Publications and source records attributed to Wang, F..

At least 127 records · Page 7Linked to original sources

In Vivo Non-Invasive Observation of Dynamic Changes in Hair Shaft, Melanin, and Collagen During the C57BL/6 Follicle Cycle

This study systematically monitored hair shaft, melanin, and collagen dynamics in vivo using non-invasive methods, enabling continuous observation over multiple hair follicle cycles. The hair shafts of C57BL/6 mice were observed in vivo using dermoscopy, photography, and electron microscopy. Second harmonic generation (SHG) and photography were employed for in vivo observation and quantification of melanin dynamics throughout the hair follicle cycle--specifically during the anagen phase, catagen phase, and telogen phase stages. Accuracy was validated via hematoxylin and eosin (H&E) staining. Additionally, SHG was used for in vivo observation and quantification of collagen changes across the same hair cycle phases, with validation performed using a liquid crystal polarizing imaging system and Sirius Red staining. This project provides non-invasive and in vivo methods for evaluating hair shafts, melanin, and collagen fibers across different growth cycles, thereby supporting non-invasive research in the development of active agents for hair loss treatment.

animal behavior and cognition↗

stk32a links sleep homeostasis to suppression of sensory and motor systems

Sleep is regulated by a homeostatic process and associated with an increased arousal threshold, but the genetic and neuronal mechanisms that implement these essential features of sleep remain poorly understood. To address these fundamental questions, we performed a zebrafish genetic screen informed by human genome-wide association studies. We found that mutation of serine/threonine kinase 32a (stk32a) results in increased sleep and impaired sleep homeostasis in both zebrafish and mice, and that stk32a acts downstream of neurotensin signaling and the serotonergic raphe in zebrafish. stk32a mutation reduces phosphorylation of neurofilament proteins, which are co-expressed with stk32a in neurons that regulate motor activity and in lateral line hair cells that detect environmental stimuli, and ablating these cells phenocopies stk32a mutation. Neurotensin signaling inhibits specific sensory and motor populations, and blocks stimulus-evoked responses of neurons that relay sensory information from hair cells to the brain. Our work thus shows that stk32a is an evolutionarily conserved sleep regulator that links neuropeptidergic and neuromodulatory systems to homeostatic sleep drive and changes in arousal threshold, which are implemented through suppression of specific sensory and motor systems.

neuroscience↗

Breaking Free from the Acquisition Dogma for Volume Electron Microscopy

Volume electron microscopy (VEM) enables nanometer-resolution three-dimensional (3D) visualization of biological specimens via serial sectioning and imaging. Owing to precautions against additional challenges in downstream analysis, VEM datasets are often acquired unnecessarily at slow speeds and high resolutions, thereby limiting achievable imaging throughput. By systematically searching for optimal VEM acquisition conditions, we find that sufficient spatial resolution effectively counteracts high image noise in preserving 3D structural information. To further verify that denoising is more effective in restoring volumetric datasets than axial interpolation, machine learning-based methods, including a newly developed 3D context-based denoising model, were compared through various tasks on VEM datasets acquired simultaneously. Our volumetric approach not only outperforms other baseline methods in faithful feature recovery but also facilitates robust serial block-face cutting down to 20 nm by allowing fast imaging. This work provides both an optimized acquisition strategy and volumetric denoising methods as actionable guidelines for maximizing VEM throughput.

bioinformatics↗

IRE1α-XBP1s axis is required for BCG-induced trained immunity against viral infection by inhibiting AHR signaling

Although Bacille Calmette-Guerin (BCG) has been proved to be suitable in inducing trained immunity, mechanism-related issues have not yet been fully resolved. In this study, we found that in vitro BCG training protects both BCG harboring and bystander macrophages against DNA virus and RNA virus infection and demonstrated that BCG harboring cells protect bystanders partly by type I interferon (IFN). We determined aryl hydrocarbon receptor (AHR) as a negative regulator in BCG-induced trained immunity on defense against viral infection in vitro and in vivo and blockade of type I IFN signaling partially impaired the enhanced antiviral effect of AHR deficiency in BCG training. Furthermore, we revealed IRE1-XBP1s signaling as a critical pathway in BCG-induced trained immunity against viral infection in vitro and in mice. Mechanistically, we demonstrated that IRE1-XBP1s pathway influenced BCG-induced trained immunity by limiting AHR mRNA expression and the translocation of AHR protein into the nucleus.

immunology↗

Time-Resolved Mapping in Calves Reveals BoHV-1 Shift From Mucosal Replication to Trigeminal Neuroinvasion and IFN-α-bPML Antagonism

Bovine herpesvirus 1 (BoHV-1) causes huge cattle losses, yet the transition from mucosal replication to neuroinvasion is poorly resolved. Using a controlled calf model, we integrated quantitative virology and transcriptomics to map pathogenesis and define the role of promyelocytic leukemia protein (PML). Calves inoculated intranasally/ocularly (1.4x10^6 pfu/head) were sampled daily (1-14 dpi) for gB-qPCR; tissues at 4 and 14 dpi were analyzed for viral DNA and trigeminal ganglia (TG) mRNA-seq. Shedding peaked at 3-6 dpi (nasal > ocular >> rectal) and declined by 10-14 dpi. Tonsils bore the highest burden at 4 dpi; TG was low-positive at 4 dpi but remained positive at 14 dpi, indicating neuroinvasion. TG programs shifted from early proteostasis priming (4 dpi) to immune/ECM activation with synaptic repression (14 dpi). In MDBK/Vero cells, IFN- increased bovine PML (bPML) and enlarged PML nuclear bodies (PML-NBs), reducing very-early viral DNA, whereas BoHV-1 disrupted PML-NB integrity. bPML isoforms diverged (bPML1/6 pro-viral; bPML3/4/5 antiviral). Cross-species STRING mapped a conserved PML-SUMO1-UBE2I-DAXX-SP100 core. These data delineate the mucosal-to-neuronal trajectory, establish PML as both effector and viral target, and nominate SUMO/ubiquitin-linked proteostasis as a tractable antiviral leverage point.

microbiology↗

Constructing and Using Cell Type Populations of the Human Reference Atlas

The human body contains [~]27-36 trillion cells of up to 10,000 cell types (CTs) within a volume of [~]62-120 liters (males) and 52-89 liters (females). The Human Reference Atlas (HRA) v2.3 provides a quantitative 3D framework of CTs across 73 reference organs and 1,283 3D anatomical structures (ASs). The HRA Cell Type Population (HRApop) effort has quantified CTs per AS using high-quality single-cell datasets processed through scalable, reproducible workflows and cell type annotation (CTann) tools. HRApop v1.0 includes reference CT populations for 73 ASs (112 when sex-specific) using 662 datasets spatially registered to 230 locations across 17 organs (31 when sex-specific). For 558 single-cell (sc-)transcriptomics datasets (11,042,750 cells), CTs and biomarker expressions were computed using Azimuth, CellTypist, and popV. To test generalizability, 104 sc-proteomics datasets (16,576,863 cells) were integrated. In total, HRApop includes 27,619,613 cells and serves as a healthy reference for researchers aiming to elucidate mechanisms underlying cellular interactions, FTU operations, and cellular and tissue level disease progression, which may facilitate advancements in basic discovery and lead to new therapeutic strategies.

bioinformatics↗

Light-Activated Nucleic Acid Amplification Systems Using Photo-caged DNA Polymerase or Primers

Precise control over nucleic acid amplification is essential for achieving reliable, quantitative, high-throughput, and multiplexed molecular diagnostics, particularly in point-of-care and field settings. However, conventional isothermal amplification methods, especially rapid assays at ambient temperature such as recombinase-aided amplification (RAA), suffer from spontaneous initiation and lack of synchronization across parallel reactions. Here, we report light-activatable RAA systems employing two distinct photocaging strategies to achieve spatiotemporal control. In the first, a photocaged DNA polymerase was engineered via site-specific incorporation of p-azido-L-phenylalanine and conjugation with a 2-nitrobenzyl-modified ssDNA blocker through click chemistry. This approach offers high stability, making it advantageous for long-term storage and lyophilized formats. In the second, 5'-nitrobenzyl-modified primers were synthesized to block hybridization or extension until UV activation, offering operational simplicity and rapid integration into existing workflows. Both strategies independently suppressed background activity in the dark and restored full amplification efficiency upon 365 nm UV exposure. The systems exhibited high sensitivity, low background, and compatibility with portable diagnostics. A custom-built device integrating UV activation and real-time fluorescence detection enabled seamless, on-demand operation. This modular platform provides flexible light-gated amplification solutions, allowing the selection of polymerase- or primer-based caging according to storage stability or workflow requirements, thereby advancing precise and field-ready molecular diagnostics.

molecular biology↗

The antioxidant networks act as a firewall in maintenance of genomic integrity

Reactive oxygen species (ROS) threatens genomic integrity by both destruction of DNA metabolic enzymes and oxidative DNA damage. We find a negative correlation between oxidative DNA damage and activity of antioxidant enzymes. An antioxidant network formed by interactions between the antioxidant enzymes and the proteins involved in maintenance of genomic integrity was indentified in the nucleus by multi-proteomic investigations. The protein-protein interactions in the antioxidant network are up-regulated under oxidative stress, as proved by quantitative proximity ligation assays in situ within single cells. The antioxidant network catalyzes the ROS dismutation cascade before ROS attacks DNA-processing enzymes, thereby preventing DNA and DNA metabolic enzymes from oxidative damage and dysfunction. Therefore, the antioxidant network plays a firewall role in maintenance of genomic integrity.

biochemistry↗

An evolutionary leap in plant reproduction: From archegonia and motile sperm to embryo sacs and pollen tubes

The transition of plants from water to land marks a pivotal step in their evolutionary history, with the change in reproductive mode being the most fundamental. This change freed plant reproduction from aquatic dependence, fostering terrestrial lifes prosperity. Key to the shift from archegonial to embryo sac reproduction are pollen tube emergence and female gametophyte changes, though their evolutionary trajectories and mechanisms remain unclear. Ginkgo, a basal gymnosperm, occupies a pivotal position in this transition, retaining motile sperm, simplified archegonia, and primitive pollen tubes, making it an ideal model. To study how the transition between these two reproductive modes occurred, we collected transcriptome data from the reproductive organs of Ginkgo and evolutionarily representative species. Our findings reveal the MYB98-CRP-ECS module- critical for angiosperm pollen tube guidance--in Ginkgos mature archegonia, with pollen tubes containing guidance components. While egg cells are transcriptionally and functionally conserved across land plants, changes in the cell fate of other female gametophyte component cells drove the shift from archegonia to embryo sacs. Pollen tubes may originate from fern male gametophyte internalization and modification. These findings clarify the evolutionary path and molecular basis of this major reproductive transition.

plant biology↗

ZmCRY1s interact with GL2 in a blue light dependent manner to regulate epidermal wax composition in Zea mays

Cryptochromes (CRYs) are photolyase-like blue-light / ultraviolet-A (UV-A) receptors that regulate diverse aspects of plant growth. Maize (Zea mays), a major crop often grown under high UV-B radiation, possesses four copies of CRY. However, it remains unclear whether the multiple copies of CRY in maize have evolved to improve UV tolerance or to acquire new functions. In this study, CRISPR-Cas9-engineered Zmcry mutants were used to investigate the functions of four cryptochromes (ZmCRYs) in maize. The findings revealed that ZmCRYs play a redundant role in mediating blue light signaling and in inhibiting the elongation of the mesocotyl. The results also demonstrated that ZmCRYs mediated blue light-enhanced UV-B stress tolerance in Zea mays by upregulating the expression of genes involved in UV-B stress tolerance-related metabolites such as phenylpropanoid, flavonoid, and fatty acid biosynthesis. Furthermore, blue light was found to influence both the accumulation and composition of epidermal waxes, suggesting that blue light enhances epidermal wax accumulation for UV-B stress tolerance. Additionally, it was discovered that ZmCRY1 directly interacted with GLOSSY2 (GL2) in a blue light dependent manner to mediate blue light promoted C32 aldehyde accumulation, shedding new light on the enigma of aldehyde-forming. These results highlight the critical roles of ZmCRY1s in mediating blue light regulated epidermal wax biosynthesis and UV-B tolerance in Zea mays.

plant biology↗

Distinguishing cortical indexes of arousal and awareness in sleeping patients with unresponsive wakefulness syndrome

Consciousness is assumed to be defined by two components: awareness and arousal. However, compared with awareness, the cortical index for arousal remains lacking in clues. Since patients with unresponsive wakefulness syndrome (UWS) are supposed to have no awareness but arousal, sleep-wake cycle in patients with UWS may reflect pure arousal fluctuations, and then could highlight the cortical indexes for arousal. This study recorded nighttime polysomnography in patients with UWS, patients with minimally conscious state and healthy controls. The EEG signal showed that spectral slope could index arousal, fluctuating among sleep stages in all three groups. Both spectral entropy and Lempel-Ziv complexity indexed awareness, showing a significant difference between conscious and unconscious states. These findings provide fundamental evidence for the two-component hypothesis of consciousness.

neuroscience↗

Generation of effector CD4+ T cells from Human iPSC

Off the shelf CD4+ T cell therapies, particularly those with immunoregulatory or cell repair functions, could be transformative in CAR therapies for cancers and treatment of chronic inflammatory diseases. However, progress is stunted in this area due to challenges generating human CD4+ T cells from induced pluripotent stem cells. Here we describe a key role for the withdrawal of Notch ligand during the final step of stimulation through the T cell receptor to prompt T cell maturation allowing access to the CD4 lineage in iPSC T cells (iCD4+ T cells). Functional analyses of iCD4+ T cells using a novel high-parameter CyTOF intracellular cytokine staining panel revealed both canonical Th1 cytokine signatures and cells producing varying combinations of other cytokines including IL-4, IL-8, and IL-13. Single cell RNA sequencing of iCD4+ T cells demonstrated a transcriptional signature similar to human blood CD4+ T cells. We believe this robust yet simple platform represents a key step towards the generation of off the shelf iCD4+ T cell therapies with utility for the treatment of a panoply of diseases including cancer and inflammatory autoimmune disorders. HIGHLIGHTST cell receptor stimulation of iPSC CD4+/CD8+ T cell progenitors on coating without Notch ligand allows access to the CD4+ T cell lineage iPSC derived CD4+ T cells express varied cytokines in response to stimulation

immunology↗

Intracranial Insights into the Developing Neural Basis of Moral Punishment

Third-party punishment (TPP) is a critical component of social regulation and justice, in-tegrating moral reasoning and emotional salience. However, the neural developmental basis underpinning this complex process remains largely unknown. Using rare intracranial stereo-electroencephalography (SEEG) in 14 children and 17 adults, we investigated the developing neural circuits of TPP. We found that broad-band gamma activity in the amygdala and ventromedial prefrontal cortex (vmPFC) encodes inferred intentions, with different patterns across age groups. Furthermore, the vmPFC, insula, and inferior parietal lobule (IPL) integrate punishment efficacy, also showing significant developmental differences. Combining task and resting state functional connectivity analyses, we further found age-dependent interactions among the amygdala-insula and IPL-vmPFC neural couplings during decision-making. These findings provide valuable intracranial evidence that the maturation of moral decision-making stems from the developmental refinement of subcortical-cortical circuits that integrate emotional and cognitive evaluations, explaining the shift from intuitive decisions in children to context-sensitive judgments in adults.

neuroscience↗

BioTransformer4.0 a comprehensive computational tool for small molecule metabolism prediction

BioTransformer 4.0, the successor to BioTransformer 3.0, is a freely available in silico metabolism prediction tool. It integrates both knowledge-based and machine learning approaches to predict metabolites for small molecules using one of seven modules: abiotic, environmental, CYP450, phase II, enzyme commission-based, human gut microbial, and all human metabolism. It also provides a customizable sequence prediction module that allows users to simulate multi-step metabolic transformations by chaining among the first six different modules. BioTransformer 4.0 can make predictions more efficiently and accurately than the previous version, as it includes more than 130 new reaction rules, and also an optional validation module to improve the efficiency by restricting the number of predicted metabolites, due to their similarity among real human metabolites. We evaluated its performance by running the six-step all-human metabolism prediction on the DrugBank dataset of 2,457 known biotransformations, and the PhytoHub dataset of 633 known biotransformations - achieving recall values of 87.2% (resp., 91.6%) for the DrugBank (resp., PhytoHub) datasets.

bioinformatics↗

Rlim coordinates diurnal regulation of food intake and thermogenesis

Energy homeostasis in mice is maintained through coordinated activity among hypothalamic nuclei that regulate food intake and thermogenesis. These processes must adapt to the sleep-wake cycle, yet the underlying pathways, cell types, and molecular mechanisms governing their diurnal regulation remain poorly understood. We show that mice lacking the E3 ubiquitin ligase Rlim are lean and resistant to diet-induced obesity, owing to reduced food intake and enhanced brown adipose tissue (BAT) thermogenesis. We identify GABAergic neurons in the suprachiasmatic nucleus (SCN)--components of the central circadian clock--as mediators of these effects. Specifically, Rlim in RIP-Cre+ neurons governs daily thermogenic rhythms, while Rlim in vasoactive intestinal peptide (VIP)-expressing neurons modulates diurnal feeding behavior. Thus, Rlim is a key regulator of diurnal rhythms controlling energy balance.

physiology↗

Synaptic density and relative connectivity conservation maintain circuit stability across development

As bodies grow during postembryonic and postnatal development, nervous systems must expand to preserve circuit integrity. To investigate how circuits retain stable wiring and function throughout development, we combined synaptic-level resolution electron microscopy (EM) with computational modeling in the Drosophila larval nociceptive system. Based on EM data, we generated the "contactome"--the set of synaptic membrane contacts--of this circuit across development to evaluate how different mechanisms contribute to wiring stability. Specifically, we investigated three mechanisms: correlation-based plasticity and synaptic scaling, which modify synaptic strength, and structural plasticity, which preserves synaptic density. We found that synaptic sizes remain largely stable across development, and synapses between the same pre- and postsynaptic neurons do not correlate in size, suggesting that synaptic scaling and correlation-based plasticity play a limited role in shaping connectivity. In contrast, dendritic synaptic density remains invariant despite a previously reported fivefold increase in neuron size and synapse number. This conservation requires increased axonal presynaptic density to compensate for unequal axonal and dendritic growth. As neurons grow, this adjustment is necessary to maintain the relative synaptic input associated with each presynaptic partner across development. Our EM analysis and modeling show that conserving relative connectivity and synaptic density is sufficient to maintain consistent postsynaptic responses across development, highlighting these conserved structural features as key contributors to circuit stability during growth.

neuroscience↗

Remodeling of the immune-metabolic landscape triggered by long-term high-altitude exposure

Growing evidence indicates that immunological and metabolic outcomes are key mediators of long-term high-altitude exposure (LTHAE) adaption, but the underlying mechanisms remain poorly understood. This study employs plasma metabolomics and peripheral blood single-cell transcriptomic sequencing to analyze the metabolic and immune dynamic regulation in 46 young male lowlanders following a 90-day adaptation period at high altitude. Single-cell analysis shows a pattern of "innate immune activation and adaptive immune suppression" under LTHAE, characterized by facilitated maturation of neutrophils, enhanced cytotoxicity of CD56dim NK cells, and increased immune responsiveness of cDC2 and pDC, while inhibited maturation of plasmablasts and suppressed immune responsiveness of CD8{square}TEM and CD4+ T cells. Plasma metabolic analysis reveals significant alterations, involving enhanced steroid hormone synthesis, unsaturated fatty acid and amino acid metabolism under LTHAE, which in turn are associated with immune remodeling. Moreover, transcriptomic-metabolic integration analysis indicates the molecular mechanisms of enhanced aerobic oxidation efficiency under LTHAE. Collectively, these findings provide integrated insights into immune-metabolic landscape remodeling and suggest potential mutual regulatory relationship between immune and metabolic state following LTHAE, offering a molecular foundation for high-altitude adaptation research.

genomics↗

Deep-learning triage of 3D pathology datasets for comprehensive and efficient pathologist assessments

Standard-of-care slide-based 2D histopathology severely undersamples spatially heterogeneous tissue specimens, with each thin 2D section representing <1% of the entire tissue volume (in the case of a biopsy). Recent advances in non-destructive 3D pathology, such as open-top light-sheet microscopy (OTLS), enable comprehensive high-resolution imaging of large clinical specimens. While fully automated computational analyses of such 3D pathology datasets are being explored, a potential low-risk route for accelerated clinical adoption would be to continue to rely upon pathologists to provide final diagnoses. Since manual review of these massive and complex 3D datasets is infeasible for routine clinical practice, we present CARP3D, a deep learning triage framework that identifies high-risk 2D cross sections within large 3D pathology datasets to enable time-efficient pathologist evaluation. CARP3D assigns risk scores to all 2D levels within a tissue volume by leveraging context from a subset of neighboring depth levels, outperforming models in which predictions are based on isolated 2D levels. In two use cases - risk stratification based on prostate cancer biopsies and screening for dysplasia/cancer in endoscopic biopsies of Barretts esophagus - AI-triaged 3D pathology, enabled by CARP3D, demonstrates the potential to improve the detection of high-risk diseases in comparison to slide-based 2D histopathology while optimizing pathologist workloads.

pathology↗