Biology subjects

Kong, Y.

Publications and source records attributed to Kong, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Naturally occurring Alzheimer's disease in rhesus monkeys

Alzheimers disease (AD) is the most common neurodegenerative disease. To date, its cause is unclear and there are no effective treatments or preventive measures. Despite there are accumulating evidences for the existence of AD pathological hallmarks in the brain of aging rhesus monkeys, it remains a mainstream notion that monkeys do not develop AD naturally. This is an important issue because it will determine how we use monkeys in AD studies. To settle down this issue, a group (n=10) of aged rhesus monkeys 26 years old or above went through a systematic AD screening procedure in this study. Three of these monkeys showed severe memory impairments (SMI) after evaluated with a classic working memory test. Further behavioral testing revealed that the SMI monkeys also exhibited apathy-like behavior, which is another core AD clinical symptom. In addition to the cognitive deficits, two of the three SMI monkeys developed all of the three AD pathological hallmarks, including neurofibrillary tangles, senile plaques and neuronal loss. According to the diagnostic criteria of human AD, the two SMI monkeys were clearly naturally occurring AD monkeys. These results suggest that AD is not a uniquely human disease and monkeys have great potential for the development of much needed etiological AD models, which are vital for better understanding of developmental process of AD and the base of identification of early diagnostic biomarkers and effective therapeutic targets of AD.

neuroscience↗

bioRxiv2022

Inflammation Of The Retinal Pigment Epithelium Drives Early-Onset Photoreceptor Degeneration In Mertk-Associated Retinitis Pigmentosa

Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation is determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3. Here we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk-/- mice. Neither inflammation nor severe, early-onset PR degeneration were observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration-associated with Mertk loss of function.

immunology↗

bioRxiv2022

Age-associated sleep-wake patterns are altered with Prdm13 signaling in the dorsomedial hypothalamus and dietary restriction in mice

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here we demonstrated that dorsomedial hypothalamus-specific PR-domain containing protein 13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during sleep deprivation (SD). These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep alterations, whereas these effects of DR were abrogated in DMH-Prdm13-KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated sleep fragmentation and excessive sleepiness during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep-wake patterns during aging.

physiology↗

bioRxiv2022

Epigenetic Changes in Saccharomyces cerevisiae Alters the Aromatic Profile in Alcoholic Fermentation

Epigenetic changes in genomics provide phenotypic modification without DNA sequence alteration. This study shows that benzoic acid, a common food additive and known histone deacetylase inhibitor (HDACi), has an epigenetic effect on Saccharomyces cerevisiae. Benzoic acid stimulated formation of epigenetic histone marks H3K4Me2, H3K27Me2, H3K18ac and H3Ser10p in S. cerevisiae and altered their phenotypic behavior, resulting in increased production of phenylethyl alcohol and ester compounds during alcoholic fermentation. Our study demonstrates the HDACi activity of certain dietary compounds such as sodium butyrate, curcumin and anacardic acid, suggests the potential use of these dietary compounds in altering S. cerevisiae phenotypes without altering host-cell DNA. This study highlights the potential to use common dietary compounds to exploit epigenetic modifications for various fermentation and biotechnology applications as an alternative to genetic modification. These findings indicate that benzoic acid and other food additives may have potential epigenetic effects on human gut microbiota, in which several yeast species are involved. ImportanceThis manuscript investigates and reports for the first time utilizing microbial epigentics to alter the fermentation process of Pinot noir wines. We have experimentally demonstrated that certain dietary epigenetic compounds possess histone deacetylase (HDAC) inhibiting activity and can alter the wine characteristics by altering yeast gene expression. We have coined the term nutrifermentics to represent this newly proposed field of research, which provides insights on the effect of certain dietary compounds on microbial strains and their potential application in fermentation process. This technological approach is a novel way to manipulate microorganisms for innovative food and beverage production with quality attributes.

microbiology↗

bioRxiv2022

Neural mechanisms underlying distractor suppression guided by spatial cues

A growing body of research demonstrates that distracting inputs can be proactively suppressed via spatial cues, nonspatial cues, or experience, which are governed by more than one top-down mechanism of attention. However, how the neural mechanisms underlying spatial distractor cues guide proactive suppression of distracting inputs remains unresolved. Here, we recorded electroencephalography signals from 110 subjects in three experiments to identify the role of alpha activity in proactive distractor suppression induced by spatial cues and its influence on subsequent distractor inhibition. Behaviorally, we found novel spatial changes in spatial distractor cues: cueing distractors far away from the target improves search performance for the target while cueing distractors close to the target hampers performance. Crucially, we found dynamic characteristics of spatial representation for distractor suppression during anticipation. This result was further verified by alpha power increased relatively contralateral to the cued distractor. At both the between- and within-subjects levels, we found that these activities further predicted the decrement of subsequent PD component, which was indicative of reduced distractor interference. Moreover, anticipatory alpha activity and its link with subsequent PD component were specific to the high predictive validity of distractor cue. Together, these results provide evidence for the existence of proactive suppression mechanisms of spatial distractors, support the role of alpha activity as gating by proactive suppression and reveal the underlying neural mechanisms by which cueing the spatial distractor may contribute to reduced distractor interference. (235). SignificanceIn space, the attention-capturing distractors are obstacles to successfully identifying targets. How to sidestep task-irrelevant distractors that stand between the target and our focus in advance is essential but still unclear. This research investigated how dynamic spatial cues can help us proactively eliminate attention-capturing distractors. Using three cue-distractor tasks that manipulate the predictive validity of distractor occurrence, we provide a series of evidence for the presence of alpha power activity related to distractor anticipation. Critically, this was the first study linking cue-elicited alpha power and distractor-elicited PD, indicating that spatial modulation of alpha power may reduce distractor interference. These findings delineate the neural mechanisms of proactive suppression for spatial distractors. (109)

neuroscience↗

bioRxiv2022

Tissue-specific modifier alleles determine Mertk loss-of-function traits

Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with Mertk KO. MERTK is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Similarly, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. Here we report that the loss of Mertk alone is not sufficient for retinal degeneration. This trait only manifests when the function of the paralog Tyro3 is concomitantly lost. Additionally, the dramatic resistance against two syngeneic mouse tumor models observed in Mertk KO cannot, at least entirely, be ascribed to the loss of Mertk. The widely used Mertk KO carries multiple coincidental changes in its genome that affect the expression of a number of genes, including Tyro3. Nonetheless, neither Tyro3, nor macrophage phagocytosis by alternate genetic redundancy, accounts for the absence of anti-tumor immunity in two independent Mertk KOs. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determine Mertk KO traits.

immunology↗

bioRxiv2022

The Structural and Biochemical Basis for FER Receptor Kinase Early Signaling Initiation in Arabidopsis

Accumulating evidence has indicated that receptor-like kinase (RLK) autophosphorylation and substrate phosphorylation triggered by RLK are early and essential events for RLK function. However, the structural and biochemical basis for these early events is largely unclear. Herein, we used RLK FERONIA (FER) as a model and crystallized its core kinase domain (FER-KD) in the dephosphorylated state. We found that FER-KD adopts an active conformation in its crystal structure. Moreover, FER-KD mutants with reduced or no catalytic activity also adopt an active conformation before phosphorylation. Collectively, these observations suggest that FER employs a phosphorylation-independent active state before ligand-induced phosphorylation and full activation. We further demonstrated that FER is a dual-specificity kinase and that autophosphorylation on Tyr residues lags somewhat behind Ser/Thr phosphorylation. More importantly, Tyr phosphorylation is essential for FER-KD to initiate substrate GRP7 phosphorylation. Our work provides a paradigm to study the mechanisms of the early steps of RLK signaling initiation and highlights its "active" form and Tyr phosphorylation-gated roles in response to signaling stimuli.

biochemistry↗

bioRxiv2022

Transcranial photobiomodulation enhances visual working memory capacity in humans

Transcranial photobiomodulation (tPBM) is a novel and noninvasive intervention, which has shown promise for improving cognitive performances. Whether tPBM can modulate brain activity and thereby enhance working memory (WM) capacity in humans remains unclear. In this study, we delivered double-blind and sham-control tPBM with different wavelengths to the prefrontal cortex (PFC) in 90 healthy participants and conducted four electroencephalography (EEG) experiments to investigate whether individual visual working memory capacity and related neural response could be modulated. We found that 1064 nm tPBM applied to the right PFC has both a substantial impact on visual working memory capacity and occipitoparietal contralateral delay activity (CDA), no matter orientation or color feature of the memorized objects. Importantly, the CDA set-size effect during the retention mediated the effect between 1064 nm tPBM and subsequent WM performance. However, these behavioral benefits and the corresponding changes of CDA set-size effect were absent with tPBM at 852 nm wavelength or with the stimulation on the left PFC. Our findings provide converging evidence that 1064 nm tPBM applied on the right PFC can improve visual working memory capacity, as well as explain the individuals electrophysiological changes about behavioral benefits.

neuroscience↗

bioRxiv2022

Multiplexed imaging mass cytometry reveals distincttumor-immune microenvironments linked to immunotherapyresponses in melanoma

Single-cell technologies have enabled extensive analysis of complex immune composition, phenotype and interactions within tumor, which is crucial in understanding the mechanisms behind cancer progression and treatment resistance. Unfortunately, the knowledge on cell phenotypes and their spatial interactions at present has only limited utilization in guiding pathological stratification on patients based on their immune microenvironments for better clinical decisions. Here we used imaging mass cytometry (IMC) to simultaneously quantify 35 proteins in a spatially resolved manner on tumor tissues from melanoma patients receiving anti-programmed cell death-1 (anti-PD-1) therapy. Unbiased single-cell analysis revealed highly dynamic tumor-immune microenvironments that are characterized with variable tumor and immune cell phenotypes and their organizations across and within melanomas, and identified distinct archetypes of melanoma microenvironments that are associated with benefit from anti-PD-1 therapy based on high-dimensional multicellular features. Our results demonstrate the utility of multiplex proteomic imaging technologies in studying complex molecular events in a spatially resolved manner for the development of new strategies for patient stratification and treatment outcome prediction.

immunology↗

bioRxiv2022

High-throughput analysis of ANRIL circRNA isoforms in human pancreatic islets

The antisense non-coding RNA in the INK locus (ANRIL) is a hotspot for genetic variants associated with cardiometabolic disease. We recently found increased ANRIL abundance in human pancreatic islets from donors with certain Type II Diabetes (T2D) risk-SNPs, including a T2D risk-SNP located within ANRIL exon 2 associated with beta cell proliferation. Recent studies have found that expression of circular species of ANRIL is linked to the regulation of cardiovascular phenotypes. Less is known about how the abundance of circular ANRIL may influence T2D phenotypes. Herein, we sequence circular RNA in pancreatic islets to characterize circular isoforms of ANRIL. We identify highly expressed circular ANRIL isoforms whose expression is correlated across dozens of individuals and characterize ANRIL splice sites that are commonly involved in back-splicing. We find that samples with the T2D risk allele in ANRIL exon 2 had higher ratios of circular to linear ANRIL compared to protective-allele carriers, and that higher circular:linear ANRIL was associated with decreased beta cell proliferation. Our study points to a combined involvement of both linear and circular ANRIL species in T2D phenotypes and opens the door for future studies of the molecular mechanisms by which ANRIL impacts cellular function in pancreatic islets.

genomics↗

bioRxiv2021

Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies has been limited by the continuous emergence of viral variants, and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on Omicron variant RBD recognized by broadly neutralizing antibodies. Based on this finding, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant RBD as revealed by Cryo-EM structures. This inhalable antibody exhibited exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. The structures also deciphered an uncommon cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

immunology↗

bioRxiv2021

LINE-1 activation in the cerebellum drives ataxia

Previous studies have revealed that dysregulation of long interspersed nuclear element 1 (LINE-1), a dominant class of transposable elements in the human genome, correlates with neurodegeneration1-3. Yet whether LINE-1 dysregulation is causal to disease pathogenesis has not been proven directly. Here, we demonstrate that expression of evolutionarily younger LINE-1 families is elevated in the cerebella of ataxia telangiectasia (AT) patients, which was correlated with extensive downregulation of epigenetic silencers. To examine whether LINE-1 activation causes neurologic disease, we established an approach to directly target and activate the promoter of a young family of LINE-1 in mice. LINE-1 activation in the cerebellum was sufficient to lead to robust progressive ataxia. Purkinje cells in the diseased mice exhibited marked electrophysiological dysfunctions and degeneration with a significant accumulation of cytoplasmic ribonucleoprotein LINE-1Orf1p aggregates, endoplasmic reticulum (ER) stress, and DNA damage. Treatment with lamivudine, a nucleoside reverse transcriptase inhibitor, blunted the disease progression by reducing DNA damage, attenuating gliosis and interferon gene signature, and recovering the loss of key functional molecules for calcium homeostasis in Purkinje cells. This study provides direct evidence that young LINE-1 activation drives ataxia phenotype, and points to its pleiotropic effects leading to DNA damage, inflammation, and dysfunction and degeneration of neurons.

neuroscience↗

bioRxiv2021

IMCellXMBD: A statistical approach for robust cell identification and quantification from imaging mass cytometry images

Imaging Mass Cytometry (IMC) has become a useful tool in biomedical research due to its capability to measure over 100 markers simultaneously. Unfortunately, some protein channels in IMC images can be very noisy, which may significantly affect the phenotyping results without proper data processing. We developed IMCellXMBD1, a highly effective and generalizable cell identification and quantification method for IMC images. IMCell performs denoising by subtracting an estimated background noise value from pixel values for each individual protein channel, identifies positive cells from negative cells by comparing the distribution between segmented cells and decoy cells, and normalize the protein expression levels of the identified positive cells for downstream data analysis. Experimental results demonstrate that our method significantly improves the reliability of cell phenotyping which is essential for using IMC in biomedical studies.

bioinformatics↗

bioRxiv2021

Synaptic and mitochondrial plasticity associated with fear memory revealed by deep learning-based 3D reconstruction

Serial section electron microscopy (ssEM) can provide comprehensive 3D ultrastructural information of the brain with exceptional computational cost. Targeted reconstruction of subcellular structures from ssEM datasets is less computationally demanding but still highly informative. We thus developed a Region-CNN-based deep learning method to identify, segment, and reconstruct synapses and mitochondria to explore the structural plasticity of synapses and mitochondria in the auditory cortex of mice subjected to fear conditioning. Upon reconstructing over 135,000 mitochondria and 160,000 synapses, we found that fear conditioning significantly increases the number of mitochondria but decreases their size, and promotes the formation of multi-contact synapses comprising a single axonal bouton and multiple postsynaptic sites from different dendrites. Modeling indicates that such multi-contact configuration increases the information storage capacity of new synapses by over 50%. With high accuracy and speed in reconstruction, our method yields structural and functional insight into cellular plasticity associated with fear learning.

neuroscience↗

bioRxiv2021

Size-scaling promotes senescence-like changes in proteome and organelle content

Senescent cells typically have an enlarged cell size but the reason for this has not been fully elucidated. As abnormal cell size may alter protein concentrations and cellular functionality, we used proteomic data from 59 unperturbed human cell lines to systematically characterize cell-size dependent changes in intracellular protein concentrations and organelle content. Increase in cell size leads to ubiquitous transcriptionally and post-transcriptionally regulated reorganization and dilution of the proteome. Many known senescence proteins display disproportionate size-scaling consistent with their altered expression in senescent cells, while lysosomes and the endoplasmic reticulum expand in larger cells contributing to the senescence phenotype. Analysis of organelle proteome expression identifies p53 and retinoblastoma pathways as mediators of size-scaling, consistent with their role in senescence. Taken together, cell size can alter cellular fitness and function through cumulative reorganization of the proteome and organelle content. An extreme consequence of this pervasive size-scaling appears to be senescence.

cell biology↗

bioRxiv2021

Characterization of glucosyltransferase and glucuronosyltransferase family members reveals how major flavone glycoside accumulate in the root of Scutellaria baicalensis

Flavonoid glycosides extracted from roots of Scutellaria baicalensis exhibit strong pharmaceutical effect in antitumor, antioxidative, anti-inflammatory, and antiviral activity. UDP glycosyltransferase family members are responsible for the transfer of a glycosyl moiety from UDP sugars to a wide range of acceptor flavonoids. Here, we report the phylogenetic analysis, tissue-specific expression and biochemical characterization of 10 glucosyltrasferases (SbUGTs) and 6 glucuronosyltransferases (SbUGATs) based on the recently released genome of S. baicalensis. These results reveal that the high expression level and affinity to substrate of SbUGAT4 make baicalin become the richest flavonoid glycoside in the root of S. baicalensis.

plant biology↗

bioRxiv2021

Detection of pigeon circoviruses in ticks of sheep and camels in Inner Mongolia, China

Circovirus is one of the smallest known DNA viruses infecting animals. In this report, circovirus was detected in two tick species- Hyalomma asiaticum and Dermacentor nuttalli collected from sheep and camels in Inner Mongolia, China by high-throughput sequencing. The reverse semi-nested PCR assay revealed a complete genomic sequence of 2042 base pairs of cyclic single-stranded DNA (ssDNA). Evolutionary analysis further revealed that it belonged to circovirus with two major open read frames (ORFs) that putatively encode replicase and capsid proteins, respectively. Sequence and phylogenetic analysis suggested that the circovirus belonged to pigeon circovirus. The results demonstrated the presence of pigeon circovirus in ticks in Inner Mongolia, which provide the basis for future exploration of the prevalence of pigeon circovirus in Inner Mongolia and the pathogens carried by ticks in Inner Mongolia.

microbiology↗

bioRxiv2021

Phylogenetic Analysis of Crimean-Congo Hemorrhagic Fever Virus in Inner Mongolia, China

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne arbovirus that can cause bleeding and death in humans. The mortality rate in humans is between 5 to 30%. The pathogen is prevalent in more than 30 countries in the world. In China, reports of strains of CCHFV have been concentrated in Xinjiang province. However, the CCHFV strain has never been reported in Inner Mongolia, China. This study reports new CCHFV strains, HANM-18, from Hyalomma asiaticum and Hyalomma dromedarii collected in Alxa Left Banner and Alxa Right Banner in Inner Mongolia. Complete sequences of CCHFV were obtained by the nested PCR technique and used for analyzing the identity and evolutionary relationship with other CCHFV strains. Interestingly, our results showed that the S and L fragments of the HANM-18 strain had high degrees of identity with Xingjiang isolate strains, and the M fragment had significant identity with South African isolates. These analyses also indicate that the HANM-18 strain may have been prevalent in northwest Inner Mongolia for many years. This discovery will be helpful in CCHF prevention and control in Inner Mongolia, and it also adds new evidence to the epidemiology of CCHF in China.

microbiology↗