Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 1,261 records · Page 70Linked to original sources

bioRxiv2024

Deep learning based genomic breeding of pest-resistant grapevine

Crop pests have profoundly deleterious effects on crop yield and food security. However, conventional pest control depends heavily on the utilization of insecticides, which develops strong pesticide resistance and concerns of food safety. Crop and their wild relatives display diverse levels of pest resistance, indicating the feasibility for breeding of pest-resistant crop varieties. In this study, we integrate deep learning (DL)/machine learning (ML) algorithms, plant phenomics and whole genome sequencing (WGS) data to conduct genomic selection (GS) of pest-resistance in grapevine. We employ deep convolutional neural networks (DCNN) to accurately calculate the severity of damage by pests on grape leaves, which achieves a classification accuracy of 95.3% (Visual Geometry Group 16, VGG16, for binary trait) and a correlation coefficient of 0.94 in regression analysis (DCNN with Pest Damage Score, DCNN-PDS, for continuous trait). We apply DL models to predict and integrate phenotype (both binary and continuous) along with WGS data from 231 grape accessions, conducting Genome-Wide Association Studies (GWAS). This analysis detects a total of 69 QTLs, encompassing 139 candidate genes involved in pathways associated with pest resistance, including jasmonic acid (JA), salicylic acid (SA), ethylene, and other related pathways. Furthermore, through the combination with transcriptome data, we identify specific pest-resistant genes, such as ACA12 and CRK3, which play distinct roles in resisting herbivore attacks. Machine learning-based GS demonstrates a high accuracy (95.7%) and a strong correlation (0.90) in predicting the leaf area damaged by pests as binary and continuous traits in grapevine, respectively. In general, our study highlights the power of DL/ML in plant phenomics and GS, facilitating genomic breeding of pest-resistant grapevine.

plant biology↗

bioRxiv2024

Transcriptomic and epigenomic consequences of heterozygous loss of function mutations in AKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons. In this study, we use genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygous AKAP11 LoF mutations on the gene expression landscape and profile the methylomic and acetylomic modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes functioning as DNA-binding transcription factors, actin and cytoskeleton regulators, and cytokine receptors, as well as genes involved in G-protein-coupled receptors (GPCRs) binding and signaling. A better understanding of the dysregulations resulting from haploinsufficiency in AKAP11 improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.

genomics↗

bioRxiv2024

A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimers Disease

SUMMARYWhile challenging, identifying individuals displaying resilience to Alzheimers disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline. Furthermore, DS individuals are at an increased risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Recent studies indicate that somatic mutations in hematopoietic cells may lead to resilience to neurodegeneration. Microglia, derived from hematopoietic lineages, play a central role in AD etiology. We therefore hypothesize that microglia carrying the somatic mutations associated with DS myeloid leukemia may impart resilience to AD. Using CRISPR-Cas9 gene editing, we introduce a trisomy 21-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses microglial type-1 interferon signaling, independent of trisomy 21 genetic background. This mutation reduces neuroinflammation and enhances phagocytic and autophagic functions, thereby ameliorating senescent and dystrophic phenotypes in human microglia. Moreover, the CSF2RB A455D mutation promotes the development of a unique microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity in chimeric mouse brains where human microglia largely repopulate the hippocampus. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize and replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest that hPSC-derived CSF2RB A455D microglia could be employed to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need to deplete endogenous diseased microglia prior to cell transplantation.

neuroscience↗

bioRxiv2024

Cervical collagen network porosity assessed by SHG endomicroscopy distinguishes preterm and normal pregnancy - a pilot study

Structured AbstractO_ST_ABSBackgroundC_ST_ABSPreterm birth (PTB) is a global public health issue affecting millions of newborns every year. Orchestrated remodeling of the cervix is essential for normal pregnancy and birth, while PTB is closely related with premature cervical ripening and loss of cervical mechanical strength. The structure and organization of fibrillar collagen in the extracellular matrix are of vital importance to the biomechanical properties of the cervix. Second harmonic generation (SHG) microscopy has proved capable of revealing the progressive changes in cervical collagen morphology over the course of pregnancy. To translate this promising imaging technology to clinical practice, a flexible SHG endomicroscope has long been envisaged for label-free, non-invasive visualization of cervical collagen architecture and for assessment of PTB risk. ObjectiveTo evaluate the potential of our newly-developed SHG endomicroscope for imaging-based differentiation of cervical collagen architecture between normal pregnant mice and RU486/mifepristone-induced PTB mouse models. Study DesignWe undertook endomicroscopy SHG imaging of cervical collagen on two types of ex vivo samples: 1) frozen cervical tissue sections ([~]50 {micro}m thick) and 2) resected intact cervices, and performed SHG-image-based quantitative collagen morphology analysis to distinguish RU486 mouse models from normal pregnant mice. ResultsEndomicroscopic SHG images of cervical tissue sections from mifepristone-treated mouse models exhibit statistically larger collagen fiber diameter, increased pore size, and reduced pore numbers than those of normal pregnant mice. Similar changes are also observed on SHG images of subepithelial collagen fibers acquired from intact cervices by the endomicroscope. ConclusionThe experiment results demonstrated that SHG endomicroscopy along with quantitative image analysis holds promising potential for clinical assessment of cervical collagen remodeling and preterm birth risk.

bioengineering↗

bioRxiv2024

The Compensatory Mechanism of the Prefrontal Cortex in Preserving Speech-in-Noise Comprehension Among Older Adults

The capacity of comprehending others amidst noise is essential for human communication. However, it presents significant challenges for the elderly who often face progressive declines in the peripheral auditory system and the whole brain. While previous studies have suggested the existence of neural reserve and neural compensation as potential mechanisms for preserving cognitive abilities in aging, the specific mechanisms supporting speech-in-noise comprehension among the elderly remain unclear. To address this question, the present study employs an inter-brain neuroscience approach by analyzing the neural coupling between brain activities of older adults and those of speakers under noisy conditions. Results showed that the neural coupling encompassed more extensive brain regions of older listeners compared to young listeners, with a notable engagement of the prefrontal cortex. Moreover, the neural coupling from prefrontal cortex was coordinated with that from classical language-related regions. More importantly, as background noise increases, the older listeners speech comprehension performance was more closely associated with the neural coupling from prefrontal cortex. Taken together, this study reveals the compensatory recruitment of neurocognitive resources, particularly within the prefrontal cortex, to facilitate speech processing in the aging brain, and further highlights the critical role of prefrontal cortex in maintaining the elderlys ability to comprehend others in noisy environments. It supports the neural compensation hypothesis, extending the knowledge about the neural basis that underlies cognitive preservation in the aging population.

neuroscience↗

bioRxiv2024

Interpretable antibody-antigen interaction prediction by bridging structure to sequence

With the application of personalized and precision medicine, more precise and efficient antibody drug development technology is urgently needed. Identification of antibody-antigen interactions is crucial to antibody engineering. The time-consuming and expensive nature of wet-lab experiments calls for efficient computational methods. Taking into account the non-overlapping advantage of current structure-dependent and sequence-only computational methods, we propose an interpretable antibody-antigen interaction prediction method, S3AI. The introduction of structural knowledge, combined with explicit modeling of chemical rules, establishes a sequence-to-function route in S3AI, thereby facilitating its perception of intricate molecular interactions through providing route and priors guidance. S3AI significantly and comprehensively outperforms the state-of-the-art models and exhibits excellent generalization when predicting unknown antibody-antigen pairs, surpassing specialized prediction methods designed for out-of-distribution generalization in fair comparisons. More importantly, S3AI captures the universal pattern of antibody-antigen interactions, which not only identifies the CDRs responsible for specific binding to the antigen but also unearths the importance of CDR-H3 for the interaction. Structure-free design and superior performance make S3AI ideal for large-scale, parallelized antibody optimization and screening, enabling the rapid and precise identification of promising candidates within the extensive antibody space.

bioinformatics↗

bioRxiv2024

The Kv2.2 channel mediates the inhibition of Prostaglandin E2 on glucose-stimulated insulin secretion in pancreatic β/-cells

Prostaglandin E2 (PGE2) is an endogenous inhibitor of glucose-stimulated insulin secretion (GSIS) and plays an important role in pancreatic {beta}-cell dysfunction in type 2 diabetes mellitus (T2DM). This study aimed to explore the underlying mechanism by which PGE2 inhibits GSIS. Our results showed that PGE2 inhibited Kv2.2 channels via increasing PKA activity in HEK293T cells overexpressed with Kv2.2 channels. Point mutation analysis demonstrated that S448 residue was responsible for the PKA-dependent modulation of Kv2.2. Furthermore, the inhibitory effect of PGE2 on Kv2.2 was blocked by EP2/4 receptor antagonists, while mimicked by EP2/4 receptor agonists. The immune fluorescence results showed that EP1-EP4 receptors are expressed in both mouse and human {beta}-cells. In INS-1(832/13) {beta}-cells, PGE2 inhibited voltage-gated potassium currents and electrical activity through EP2/4 receptors and Kv2.2 channels. Knockdown of Kv2.2 reduced the action potential firing frequency and alleviated the inhibition of PGE2 on GSIS in INS-1(832/13) {beta}-cells. PGE2 impaired glucose tolerance in wild-type mice but did not alter glucose tolerance in Kv2.2 knockout mice. Knockout of Kv2.2 reduced electrical activity, GSIS and abrogated the inhibition of PGE2 on GSIS in mouse islets. In conclusion, we have demonstrated that PGE2 inhibits GSIS in pancreatic {beta}-cells through the EP2/4-Kv2.2 signaling pathway. The findings highlight the significant role of Kv2.2 channels in the regulation of {beta}-cell repetitive firing and insulin secretion, and contribute to the understanding of the molecular basis of {beta}-cell dysfunction in diabetes.

physiology↗

bioRxiv2024

HemaCisDB: An Interactive Database for Analyzing Cis-Regulatory Elements Across Hematopoietic Malignancies

Noncoding cis-regulatory elements (CREs), such as transcriptional enhancers, are key regulators of gene expression programs. Accessible chromatin and H3K27ac are well-recognized markers for CREs associated with their biological function. Deregulation of CREs is commonly found in hematopoietic malignancies yet the extent to which CRE dysfunction contributes to pathophysiology remains incompletely understood. Here, we developed HemaCisDB, an interactive, comprehensive, and centralized online resource for CRE characterization across hematopoietic malignancies, serving as a useful resource for investigating the pathological roles of CREs in blood disorders. Currently, we collected 922 ATAC-seq, 190 DNase-seq, and 531 H3K27ac ChIP-seq datasets from patient samples and cell lines across different myeloid and lymphoid neoplasms. HemaCisDB provides comprehensive quality control metrics to assess ATAC-seq, DNase-seq, and H3K27ac ChIP-seq data quality. The analytic modules in HemaCisDB include transcription factor (TF) footprinting inference, super-enhancer identification, and core transcriptional regulatory circuitry analysis. Moreover, HemaCisDB also enables the study of TF binding dynamics by comparing TF footprints across different disease types or conditions via web-based interactive analysis. Together, HemaCisDB provides an interactive platform for CRE characterization to facilitate mechanistic studies of transcriptional regulation in hematopoietic malignancies. HemaCisDB is available at https://hemacisdb.chinablood.com.cn/.

bioinformatics↗

bioRxiv2024

Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation

Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division. PLK1 activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate PLK1 in mitosis remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.

cell biology↗

bioRxiv2024

Distinct Patterns of SARS-CoV-2 BA.2.87.1 and JN.1 Variants in Immune Evasion, Antigenicity and Cell-Cell Fusion

The rapid evolution of SARS-CoV-2 variants presents a constant challenge to the global vaccination effort. In this study, we conducted a comprehensive investigation into two newly emerged variants, BA.2.87.1 and JN.1, focusing on their neutralization resistance, infectivity, antigenicity, cell-cell fusion, and spike processing. Neutralizing antibody (nAb) titers were assessed in diverse cohorts, including individuals who received a bivalent mRNA vaccine booster, patients infected during the BA.2.86/JN.1-wave, and hamsters vaccinated with XBB.1.5-monovalent vaccine. We found that BA.2.87.1 shows much less nAb escape from WT-BA.4/5 bivalent mRNA vaccination and JN.1-wave breakthrough infection sera compared to JN.1 and XBB.1.5. Interestingly. BA.2.87.1 is more resistant to neutralization by XBB.15-monovalent-vaccinated hamster sera than BA.2.86/JN.1 and XBB.1.5, but efficiently neutralized by a class III monoclonal antibody S309, which largely fails to neutralize BA.2.86/JN.1. Importantly, BA.2.87.1 exhibits higher levels of infectivity, cell-cell fusion activity, and furin cleavage efficiency than BA.2.86/JN.1. Antigenically, we found that BA.2.87.1 is closer to the ancestral BA.2 compared to other recently emerged Omicron subvariants including BA.2.86/JN.1 and XBB.1.5. Altogether, these results highlight immune escape properties as well as biology of new variants and underscore the importance of continuous surveillance and informed decision-making in the development of effective vaccines.

microbiology↗

bioRxiv2024

Unicellular cyanobacteria rely on sodium energetics to fix N2

Diazotrophic cyanobacteria can thrive in combined nitrogen (N)-limited environments due to their ability to fix nitrogen gas (N2) from the atmosphere. Despite this, they occur in low abundance in N-limited coastal waters, which represents an ecological paradox1-3. One hypothesis is that this is partly due to elevated salinity (> 10 g/L NaCl), which inhibits cyanobacterial N2 fixation2,3. Here we show that N2 fixation in a unicellular coastal cyanobacterium is not inhibited but rather exclusively dependent on sodium (Na+) ions. In N-deficient environments, both N2 fixation and population growth were significantly inhibited at low NaCl concentrations (< 4 g/L). Additional experiments indicated that sodium energetics, rather than proton energetics, is necessary for N2 fixation, as Na+ deficiency resulted in insufficient ATP supply for N2 fixation. We show that this is due to the non-functioning Na+-coupled ATP synthase, which we found to be likely coupled to anaerobic rather than aerobic respiration. Sequence alignment analysis of the ion-coupling site of the ATP synthase revealed a high prevalence of Na+ energetics in cyanobacteria, with all unicellular N2 fixers capable of Na+ energetics. This suggests a critical role for sodium energetics in cyanobacteria. It also raises the possibility that sodium energetics is not as rare as thought, but that we may have underestimated the prevalence and importance of sodium energetics in other organisms. Finally, the low abundance of diazotrophic unicellular cyanobacteria in coastal waters may be due to insufficient NaCl levels to support N2-fixation during periods of growth-supporting high temperatures. This provides another perspective on the regulation of the oceanic N cycle that needs to be considered in times of global climate change. Changes in current patterns could lead to an overlap of periods optimal for N2 fixation and population growth, likely resulting in dense cyanobacterial blooms.

microbiology↗

bioRxiv2024

PFKP regulates AXL-MET oncogenic and metabolic pathways in lung cancer

ObjectivePFKP (Phosphofructokinase, Platelet Type isoform), as an essential metabolic enzyme, contributes to the high glycolysis rates seen in cancers, while its role in oncogenic pathways, especially from a non-metabolic aspect, is not fully understood. MethodsHere we performed a comprehensive analysis of published RNA-seq, microarray data, and immunohistochemistry of tissue microarray to evaluate the significance of PFKP expression in non-small cell lung cancer (NSCLC). Functionally, we tested the cell proliferation, colony formation, invasion, and migration upon PFKP knockdown in lung cancer cells. Mechanistically, we performed RNA-seq, DIA-mass spectrum, western blot, and qPCR to probe the change of cell signaling pathways upon PFKP silencing. Co-immunoprecipitation and mass spectrum were used to uncover potential PFKP interacting proteins. ResultsWe found that PFKP was highly expressed in NSCLC and was related to poor patient survival. Knockdown of PFKP significantly inhibited cell proliferation, colony formation, invasion, and migration of NSCLC cells. Mechanistically, we found that PFKP can directly bind with AXL and promote its phosphorylation at Y779, thus activating the AXL signaling pathway and promoting MET phosphorylation. In addition, several glycolysis, glutaminolysis, and TCA cycle proteins were downregulated following PFKP silencing. ConclusionsThese data demonstrate that PFKP, beyond its known role in glycolysis, also has a distinct non-metabolic function in affecting lung cancer progression by directly interacting with the AXL-MET axis, thus indicating a potential therapeutic target for lung cancer.

cancer biology↗

bioRxiv2024

Spatial Transcriptomics of Spinal Ependymoma in NF2-related Schwannomatosis

Spinal ependymoma (SP-EPN) is a central nervous system (CNS) tumor that is associated with high morbidity. The only effective treatment for end-stage SP-EPN is surgery, but this is associated with high risk of injury to the sensorimotor spinal tracts and paralysis. There is a critical need to understand the cellular origins of this tumor so that disease models of tumor progression can be generated for drug development. Recent genomic studies with bulkRNA sequencing suggest the molecular signature of SP-EPN matches that of ependymal cells (EPCs). However, large-scale genomic studies can often misrepresent rare cancer stem cell populations within the tumor. In this study, we performed spatial transcriptomics (ST) on a SP-EPN resected from a patient with NF2-related neurofibromatosis to examine the spatial heterogeneity within the tumor. The SP-EPN sample exhibited cellular heterogeneity with diffuse expression of astrocytic and EPC markers, and smaller pockets with RGC or stem cell markers, as well as overlap between progenitor cell and mature cell markers. These findings suggest that there may be a developmental hierarchy within the EPC lineage in SP-EPN tumors, which may stem from aberrant radial glia cells.

cancer biology↗

bioRxiv2024

RGS10 deficiency facilitates distant metastasis by inducing epithelial-mesenchymal transition in breast cancer

AbstractDistant metastasis is the major cause of death in patients with breast cancer. Epithelial-mesenchymal transition (EMT) contributes to breast cancer metastasis. Regulator of G protein-signaling (RGS) proteins modulate metastasis in various cancers. This study identified a novel role for RGS10 in EMT and metastasis in breast cancer. RGS10 protein levels were significantly lower in breast cancer tissues compared to normal breast tissues, and deficiency in RGS10 protein predicted a worse prognosis in patients with breast cancer. RGS10 protein levels were lower in the highly aggressive cell line MDA-MB-231 than in the poorly aggressive, less invasive cell lines MCF7 and SKBR3. Silencing RGS10 in SKBR3 cells enhanced EMT and caused SKBR3 cell migration and invasion. The ability of RGS10 to suppress EMT and metastasis in breast cancer was dependent on lipocalin-2 and miR-539-5p. These findings identify RGS10 as a tumor suppressor, prognostic biomarker, and potential therapeutic target for breast cancer.

cancer biology↗

bioRxiv2024

A novel sulfatase for acesulfame degradation in wastewater treatment plants as evidenced from Shinella strains

The artificial sweetener acesulfame is a persistent pollutant in wastewater worldwide. So far, only a few bacterial isolates were recently found to degrade acesulfame efficiently. In Bosea and Chelatococcus strains, a Mn2+-dependent metallo-{beta}-lactamase-type sulfatase and an amidase signature family enzyme catalyze acesulfame hydrolysis via acetoacetamide-N-sulfonate (ANSA) to acetoacetate. Here, we describe a new acesulfame sulfatase in Shinella strains isolated from German wastewater treatment plants. Their genomes do not encode the Mn2+-dependent sulfatase. Instead, a formylglycine-dependent sulfatase gene was found, together with the ANSA amidase gene on a plasmid shared by all known acesulfame-degrading Shinella strains. Heterologous expression, shotgun proteomics and size exclusion chromatography corroborated the physiological function of the Shinella enzyme as a Mn2+-independent acesulfame sulfatase. Since both the Bosea/Chelatococcus sulfatase and the novel Shinella sulfatase are absent in other bacterial genomes or metagenome assembled genomes, we surveyed 60 tera base pairs of wastewater-associated metagenome raw datasets. The Bosea/Chelatococcus sulfatase gene was regularly found from 2014 on, particularly in North America, Europe and East Asia, whereas the Shinella sulfatase gene was first detected in 2020. The complete Shinella pathway is only present in five datasets from China, Finland and Mexico, suggesting that it emerged quite recently in wastewater treatment facilities. SynopsisA novel sulfatase was identified that hydrolyzes the once recalcitrant xenobiotic acesulfame. Surveying metagenome datasets revealed the recent emergence of gene homologs encoding this sulfatase in wastewater treatment systems worldwide.

genomics↗

bioRxiv2024

Secondary microglia formation center in the human fetal brain

Yolk sac-derived microglia migrate and populate the brain during development, constituting 10-15% of the total brain cells. The human brain is the largest and most complex brain with the highest cognitive capacity among all species. Therefore, the limitations of rodent brain studies in interpreting the human brain are evident. By co-immunostaining microglia in 50 {micro}m fetal brain sections from 7.5 to 16 gestational weeks (gw) and combining high-resolution scanning, we identified a highly proliferative microglia aggregate (0.108-2.129 mm2) that expanded in Downs Syndrome fetal brain (4.168 mm2) and was located near the ganglion eminence, in which Ki67+ microglia accounted for 23.4% of total microglia compared to 6.3% in other brain regions. The microglia in the aggregates lack phagocytic bulbs, membrane ruffles, and long/branching processes compared to microglia in other brain regions. Introducing human microglia into cortical organoids, but not macrophages, replicated proliferative microglial aggregates on the brain organoid surface and sufficiently penetrated deeper regions of the cortical organoids. Penetrating microglia display phagocytic capacity, enhance immunity, and accelerate the maturation of brain organoids. The large proliferative microglial aggregate may be a unique secondary microglial formation center in the human fetal brain to compensate for the enormous microglial demands during brain expansion.

neuroscience↗

bioRxiv2024

Heterogeneous hybrid immunity against Omicron variant JN.1 at 11 months following breakthrough infection

A highly transmissible SARS-CoV-2 variant JN.1 is rapidly spreading throughout the nation, becoming the predominant strain in China and worldwide. However, the current immunity against the circulating JN.1 at population level has yet to be fully evaluated. We recruited representative cohorts with stratified age groups and diverse combinations of vaccination and/or infection in recent months, and promptly assessed humoral immunity for these subjects predominantly exhibiting hybrid immunity. We report that at 11 months following BA.5-wave breakthrough infection (BTI), these vaccinated individuals generally showed above-the-threshold yet low level of neutralizing activity against JN.1, with slightly greater potency observed in children and adolescents compared to adults and seniors. Meanwhile, XBB/EG.5-wave reinfection post-BTI significantly boosted the neutralizing antibodies against Omicron variants, including JN.1 in both adults (13.4-fold increase) and seniors (24.9-fold increase). To better understand respiratory mucosal protection against JN.1 over an extended period of months post-BTI, we profiled the humoral immunity in bronchoalveolar lavage samples obtained from vaccinated subjects with or without BTI, and revealed increased potency of neutralizing activity against the BA.5 and JN.1 variants in the respiratory mucosa through natural infection. Notably, at 11 months post-BTI, memory B cell responses against prototype and JN.1 were detectable in both blood and respiratory mucosa, displaying distinct memory features in the circulation and airway compartments. XBB/EG.5-wave reinfection drove the expansion of JN.1-specific B cells, along with the back-boosting of B cells responding to the ancestral viral strain, suggesting the involvement of immune imprinting. Together, this study indicates heterogeneous hybrid immunity over 11 months post-BTI, and underscores the vulnerability of individuals, particularly high-risk seniors, to JN.1 breakthrough infection. An additional booster with XBB-containing vaccine may greatly alleviate the onward transmission of immune-evasive SARS-CoV-2 variants.

immunology↗

bioRxiv2024

Two-photon imaging of excitatory and inhibitory neural response to infrared neural stimulation

SignificancePulsed infrared neural stimulation (INS, 1875 nm) is an emerging neurostimulation technology that delivers focal pulsed heat to activate functionally specific mesoscale networks and holds promise for clinical application. However, little is known about its effect on excitatory and inhibitory cell types in cerebral cortex. AimEstimates of summed population neuronal response timecourses provide a potential basis for neural and hemodynamic signals described in other studies. ApproachUsing two-photon calcium imaging in mouse somatosensory cortex, we have examined the effect of INS pulse train application on hSyn neurons and mDlx neurons tagged with GCaMP6s. ResultsWe find that, in anesthetized mice, each INS pulse train reliably induces robust response in hSyn neurons exhibiting positive going responses. Surprisingly, mDlx neurons exhibit negative going responses. Quantification using the index of correlation illustrates responses are reproducible, intensity-dependent, and distance-dependent. Also, a contralateral activation is observed when INS application. ConclusionsIn sum, the population of neurons stimulated by INS includes both hSyn and mDlx neurons; within a range of stimulation intensities, this leads to overall excitation in the stimulated population, leading to the previously observed activations at distant post-synaptic sites.

neuroscience↗