Biology subjects

Liu, Z.

Publications and source records attributed to Liu, Z..

At least 1,189 records · Page 66Linked to original sources

bioRxiv2018

TP53 mutations promote immunogenic activity in breast cancer

BackgroundAlthough immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no any immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying the BC patients responsive to immunotherapy. TP53 mutations were often associated with worse clinical outcome in BC, of which the triple-negative BC (TNBC) has a high TP53 mutation rate (approximately 80%). TNBC is high-risk due to its high invasiveness, and lack of targeted therapy. To explore a potentially promising therapeutic option for the TP53-mutated BC subtype, we studied the associations between TP53 mutations and immunogenic activity in BC.\n\nMethodsWe compared enrichment levels of 26 immune gene-sets that indicated activities of diverse immune cells, functions, and pathways between TP53-mutated and TP53-wildtype BCs based on two large-scale BC multi-omics data. Moreover, we explored the molecular cues that were associated with the differences in immunogenic activity between TP53-mutated and TP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis.\n\nResultsWe found that almost all analyzed immune gene-sets had significantly higher enrichment levels in TP53-mutated BCs compared to TP53-wildtype BCs. Moreover, our experiments confirmed that mutant p53 could increase BC immunogenicity. Furthermore, our computational and experimental results showed that TP53 mutations could promote BC immunogenicity via regulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Interestingly, we found that elevated immune activities were likely to be associated with better survival prognosis in TP53-mutated BCs, but not necessarily in TP53-wildtype BCs.\n\nConclusionsTP53 mutations promote immunogenic activity in breast cancer. This finding demonstrates a different effect of p53 dysfunction on tumor immunogenicity from that of previous studies, suggesting that the TP53 mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.

cancer biology↗

bioRxiv2018

MITA couples with PI3K to regulate actin reorganization during BCR activation

As an adaptor protein, MITA has been extensively studied in innate immunity. However, its role in adaptive immunity as well as its underlying mechanism are not completely understood. We used MITA KO mice to study the effect of MITA deficiency on B cell development and differentiation, BCR signaling during BCR activation and humoral immune response. We found that MITA deficiency promotes the differentiation of marginal zone B cells, which is linked to the lupus-like autoimmune disease that develops in MITA KO mice. MITA is involved in BCR activation and negatively regulates the activation of CD19 and Btk and positively regulates the activation of SHIP. Interestingly, we found that the activation of WASP and accumulation of F-actin is enhanced in MITA KO B cells upon stimulation. Mechanistically, we found that MITA uses PI3K mediated by the CD19-Btk axis as a central hub to control the actin remodeling that, in turn, offers feedback to BCR signaling. Overall, our study has provided a new mechanism on how MITA regulates BCR signaling via feedback from actin reorganization, which may contribute to the effects of MITA on the humoral immune response.

immunology↗

bioRxiv2018

The probiotic effectiveness in experimental colitis is correlated with gut microbiome and host genetic features

Current evidence to support extensive use of probiotics in inflammatory bowel disease is limited and factors contribute to the inconsistent effectiveness of clinical probiotic therapy are not completely known. Here, as a proof-of-concept, we utilized Bifidobacterium longum JDM 301, a widely used commercial probiotic strain in China, to study potential factors that may influence the beneficial effect of probiotics in experimental colitis. We found that the probiotic therapeutic effect was varied across individual mouse even with the same genetic background and consuming the same type of food. The different probiotic efficacy was highly correlated with different microbiome features in each mouse. Consumption of a diet rich in fat can change the host sensitivity to mucosal injury-induced colitis but did not change the host responsiveness to probiotic therapy. Finally, the host genetic factor TLR2 was required for a therapeutic effect of B. longum JDM 301. Together, our results suggest that personalized microbiome and genetic features may modify the probiotic therapeutic effect.

microbiology↗

bioRxiv2018

Isolation and characterization of antagonistic bacteria with the potential for biocontrol of soil-borne wheat diseases

Bacillus amyloliquefaciens subsp. plantarum XH-9 is a plant-beneficial rhizobacterium that shows good antagonistic potential against phytopathogens by releasing diffusible and volatile antibiotics, and secreting hydrolytic enzymes. Furthermore, the XH-9 strain possesses important plant growth-promoting characteristics, including nitrogen fixation (7.92 {+/-} 1.05 mg/g), phosphate solubilization (58.67 {+/-} 4.20 g/L), potassium solubilization (10.07 {+/-} 1.26 g/mL), and the presence of siderophores (4.92 {+/-} 0.46 g/mL), indole-3-acetic acid (IAA) (7.76 {+/-} 0.51 g/mL) and 1-aminocyclopropane-1-carboxylic acid deaminase (ACC-deaminase) (4.67 {+/-} 1.21 nmol/[mg*h]). Moreover, the XH-9 strain showed good capacities for wheat, corn, and chili root colonization, which are critical prerequisites for controlling soil-borne diseases as a bio-control agent. Real-time quantitative polymerase chain reaction experiments showed that the amount of Fusarium oxysporum DNA associated with the XH-9 strain after treatment significantly decreased compared with control group. Accordingly, wheat plants inoculated with the XH-9 strain showed significant increases in the plant shoot heights (14.20%), root lengths (32.25%), dry biomass levels (11.93%), and fresh biomass levels (16.28%) relative to the un-inoculated plants. The results obtained in this study suggest that the XH-9 strain has potential as plant-growth promoter and biocontrol agent when applied in local arable land to prevent damage caused by F. oxysporum and other phytopathogens.\n\nImportancePlant diseases, particularly soilborne pathogens, play a significant role in the destruction of agricultural resources. Although these diseases can be controlled to some extent with crop and fungicides, while these measures increase the cost of production, promote resistance, and lead to environmental contamination, so they are being phased out. Plant growth-promoting rhizobacteria are an alternative to chemical pesticides that can play a key role in crop production by means of siderophore and indole-3-acetic acid production, antagonism to soilborne root pathogens, phosphate and potassium solubilization, and nitrogen fixation. These rhizobacteria can also promote a beneficial change in the microorganism community by significantly reducing its pathogenic fungi component. Their use is fully in accord with the principles of sustainability.

microbiology↗

bioRxiv2018

C. albicans Zn Cluster Transcription Factors Tac1 and Znc1 are Activated by Farnesol to Up Regulate a Transcriptional Program Including the Multi-Drug Efflux Pump CDR1

Farnesol, a quorum-sensing molecule, inhibits C. albicans hyphal formation, affects its biofilm formation and dispersal, and impacts its stress response. Several aspects of farnesols mechanism of action remain incompletely uncharacterized. Among these are a thorough accounting of the cellular receptors and transporters for farnesol. This work suggests these themes are linked through the Zn cluster transcription factors Tac1 and Znc1, and their induction of the multi-drug efflux pump Cdr1. Specifically, we have demonstrated that Tac1 and Znc1 are functionally activated by farnesol through a mechanism that mimics other means of hyperactivation of Zn cluster transcription factors. This is consistent with our observation that many genes acutely induced by farnesol are dependent on TAC1, ZNC1, or both. A related molecule, 1-dodecanol, invokes a similar TAC1/ZNC1 response, while several other proposed C. albicans quorum sensing molecules do not. TAC1 and ZNC1 both bind to and up-regulate the CDR1 promoter in response to farnesol. Differences in inducer and DNA binding specificity lead to Tac1 and Znc1 having overlapping, but non-identical, regulons. TAC1 and ZNC1 dependent farnesol induction of their target genes was inversely related to the level of CDR1 present in the cell, suggesting a model in which induction of CDR1 by Tac1 and Znc1 leads to an increase in farnesol efflux. Consistent with this premise, our results show that CDR1 expression, and its regulation by TAC1 and ZNC1, facilitates growth in the presence of high farnesol concentrations in C. albicans, and certain strains of its close relative C. dubliniensis.

molecular biology↗

bioRxiv2018

HIV-1 antisense protein of different clades induces autophagy and associates to the autophagy factor p62

Over recent years, strong support argues for the existence of an HIV-1 protein encoded by antisense transcripts and termed Antisense Protein (ASP). Furthermore, a recent in silico analysis has provided evidence for its recent appearance in the genome of HIV-1. We have previously detected ASP in various mammalian cell lines by Western blot (WB), flow cytometry and confocal microscopy analyses and reported that it induced autophagy, potentially through multimer formation. The aim of the current study was to examine autophagy induction by testing ASP from different clades, and to identify the implicated autophagy factors. We firstly confirmed that NL4.3-derived ASP was interacting with itself and that multimer formation was dependent on its amino region. Removal of this region was associated with reduced level of induced autophagy, as assessed by autophagosome formation but deletion of the most amino cysteine triplet did not totally abrogate multimer and autophagosome formation. Expression vectors of ASP from different clades were next tested and led to detection of monomers and varying levels of multimers with concomitant induced autophagy, as determined by increased LC3-II and decreased p62 (SQSTM1) levels. Through confocal microscopy, ASP was noted to co-localize with p62 and LC3-II in autophagosome-like cellular structures. CRISPR-based knock-out of ATG5, ATG7 and p62 genes led to increased stability in the levels of ASP. Furthermore, co-immunoprecipitation experiments demonstrated the interaction between p62 and ASP, which was dependent on the PB1 domain of p62. Interestingly, immunoprecipitation experiments further supported that ASP is ubiquitinated and that ubiquitination was also responsible for the modulation of its stability. We are thus suggesting that ASP induces autophagy through p62 interaction and that its abundance is controlled by autophagy- and Ubiquitin/Proteasome System (UPS)-mediated degradation in which ubiquitin is playing an important role. Understanding the mechanisms underlying the degradation of ASP is essential to better assess its function.\n\nAuthor SummaryIn the present study, we provide the first evidence that a new HIV-1 protein termed ASP when derived from different clades act similarly in inducing autophagy, an important cellular process implicated in the degradation of excess or defective material. We have gained further knowledge on the mechanism mediate the activation of autophagy and have identified an important interacting partner. Our studies have important ramification in the understanding of viral replication and the pathogenesis associated with HIV-1 in infected individuals. Indeed, autophagy is implicated in antigen presentation during immune response and could thus be rendered inefficient in infected cells, such as dendritic cells. Furthermore, a possible link with HIV-1-associated Neurological Disorder (HAND) might also be a possible association with the capacity of ASP to induce autophagy. Our studies are thus important and demonstrate the importance in conducting further studies on this protein, as it could represent a new interesting target for antiretroviral therapies and vaccine design.

microbiology↗

bioRxiv2018

Genetic Dissection of Haploid Male Fertility in Maize (Zea mays L.)

Haploid genome doubling is a key limiting step of haploid breeding in maize. Spontaneous restoration of haploid male fertility (HMF) provides a method by which costs can be saved and which does not require the use of toxic chemicals, in contrast to the artificial doubling process. To reveal the genetic basis of HMF, haploids were obtained from the offspring of 285 F2:3 families, derived from the cross Zheng58x K22. The F2:3 families were used as female donor and YHI-1 as the male inducer line. The rates of HMF from each family line were evaluated at two field sites over two planting seasons. Quantitative trait loci (QTL) for HMF were identified using a genetic linkage map containing 157 simple sequence repeat (SSR) markers. QTL for HMF displayed incomplete dominance. Transgressive segregation of haploids from F2:3 families was observed relative to haploids derived from the two parents of the mapping population. A total of nine QTL were detected, which were distributed on chromosomes 1, 3, 4, 7, and 8. Three QTL, qHMF3b, qHMF7a, and qHMF7b were detected in both locations, respectively. In our mapping population, HMF was controlled by three major QTL. These QTL could be useful to predict the ability of spontaneous haploid genome doubling in related breeding materials, and to accelerate the haploid breeding process by introgression or aggregation of those QTL.

genetics↗

bioRxiv2018

Comparison of antioxidant activity between cyanidin-3-O-glucoside (C3G) liposome and cyanidin-3-O-glucoside (C3G) in 2D and 3D cell cultures

The 2D cell culture is the predominant in vitro model for numerous studies. However, 2D cell cultures may not accurately reflect the functions of three-dimensional (3D) tissues, which have extensive cell-cell and cell-matrix interactions; thus, using 2D cell cultures may lead to inaccurate experimental results. Therefore, to obtain adequate and detailed information about the antioxidant activity of cyanidin-3-O-glucoside (C3G) and C3G liposomes in the 2D and 3D cell culture models, we used in this study H2O2 to construct the cell damage model and assess the antioxidant activity of C3G and C3G liposomes on Caco-2 cells cultured in the 3D model. We also measured the cell viability, cell morphology, and activity of glutathione (GSH), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) content of Caco-2 cells treated with H2O2, C3G, and C3G liposomes. Results showed that cells cultured in the 3D culture model formed a 3D structure and tight spheroids and showed increased cell activity and IC50. The C3G and C3G liposomes can enhance the activity of GSH, SOD, and T-AOC but decrease the MDA content. At the same time, the effect was more obvious in the 3D cell culture model than in the cells cultured in the 2D model. This study revealed that the results obtained from the 2D cell model may be inaccurate compared with the results obtained from the 3D cell model. A realistic mechanism study of antioxidant activity of C3G and C3G liposomes in the 3D cell model, which acts as an intermediate stage bridging the in vitro 2D and in vivo models, was observed.

cell biology↗

bioRxiv2018

CRISPRCloud2: A cloud-based platform for deconvoluting CRISPR screen data

The simplicity and cost-effectiveness of CRISPR technology have made high-throughput pooled screening approaches available to many. However, the large amount of sequencing data derived from these studies yields often unwieldy datasets requiring considerable bioinformatic resources to deconvolute data; a feature which is simply not accessible to many wet labs. To address these needs, we have developed a cloud-based webtool CRISPRCloud2 that provides a state-of-the-art accuracy in mapping short reads to CRISPR library, a powerful statistical test that aggregates information across multiple sgRNAs targeting the same gene, a user-friendly data visualization and query interface, as well as easy linking to other CRISPR tools and bioinformatics resources for target prioritization. CRISPRCloud2 is a one-stop shop for labs analyzing CRISPR screen data.

bioinformatics↗

bioRxiv2018

Insufficient fumarase contributes to generating reactive oxygen species in Dahl salt sensitive rats

Dahl SS rats exhibit greater levels of renal medullary oxidative stress and lower levels of fumarase activities. Fumarase insufficiencies can increase reactive oxygen species (ROS), the mechanism of which, however, is not clear. A proteomic analysis indicated fumarase knockdown in HK-2 cells resulted in changes in the expression or activity of NADPH oxidase, mitochondrial respiratory chain complex I and III, ATP synthase subunits, and -oxoglutarate dehydrogenase, all of which are sites of ROS formation. Meantime, the activities of key antioxidant enzymes such as G6PD, 6PGD, GR, GPx and GST increased significantly too. The apparent activation of antioxidant defense appeared insufficient as glutathione precursors, glutathione and GSH/GSSG ratio were decreased. SS rats exhibited changes in redox metabolism similar to HK-2 cells with fumarase knockdown. Supplementation with fumarate and malate, the substrate and product of fumarase, increased and decreased, respectively, blood pressure and the levels of H2O2 and MDA in kidney tissues of SS rats. These results indicate fumarase insufficiencies cause a wide range of changes at several sites of ROS production and antioxidant mechanisms.

molecular biology↗

bioRxiv2018

Clusters of fatty acids in the serum triacylglyceride fraction associate with the disorders of type 2 diabetes

AimsOur aim was to examine longitudinal associations of triacylglyceride fatty acid (TGFA) composition with insulin sensitivity (IS) and beta-cell function.\n\nMethodsAdults at-risk for T2D (n=477) had glucose and insulin measured from a glucose challenge at 3 time points over 6 years. The outcome variables Matsuda index (ISI), HOMA2-%S, Insulinogenic Index over HOMA-IR (IGI/IR), and Insulin Secretion-Sensitivity Index-2 (ISSI-2) were computed from the glucose challenge. Gas chromatography quantified TGFA composition from the baseline. We used adjusted generalized estimating equations (GEE) models and partial least squares (PLS) regression for the analysis.\n\nResultsIn adjusted GEE models, four TGFA (14:0, 16:0, 14:1n-7, 16:1n-7 as mol%) had strong negative associations with IS while others (e.g. 18:1n-7, 18:1n-9, 20:2n-6, 20:5n-3) had strong positive associations. Few associations were seen for beta-cell function, except for 16:0, 18:1n-7, and 20:2n-6. PLS analysis indicated four TGFA (14:0, 16:0, 14:1n-7, 16:1n-7) that clustered together and strongly related with lower IS. These four TGFA also correlated highly (r>0.4) with clinically measured TG.\n\nConclusionsWe found that higher proportions of a cluster of four TGFA strongly related with lower IS as well as hypertriglyceridemia, suggesting only a few fatty acids within the TGFA composition may primarily explain lipids role in glucose dysregulation.

epidemiology↗

bioRxiv2018

Single-step Enzymatic Glycoengineering for the Construction of Antibody-cell Conjugates

Employing live cells as therapeutics is a direction of future drug discovery. An easy and robust method to modify the surfaces of cells directly to incorporate novel functionalities is highly desirable. However, many current methods for cell-surface engineering interfere with cells endogenous properties. Here we report an enzymatic approach that enables the transfer of biomacromolecules, such as a full length IgG antibody, to the glycocalyx on the surfaces of live cells when the antibody is conjugated to the enzymes natural donor substrate GDP-fucose. This method is fast and biocompatible with little interference to cells endogenous functions. We applied this method to construct two antibody-cell conjugates (ACCs) using different immune cells, and the modified cells exhibited specific tumor targeting and resistance to inhibitory signals produced by tumor cells, respectively. Remarkably, Herceptin-NK-92MI conjugates exhibits enhanced activities to induce the lysis of HER2+ cancer cells both ex vivo and in a murine tumor model, indicating its potential for further development as a clinical candidate.

bioengineering↗

bioRxiv2018

The universally-conserved transcription factor RfaH is recruited to a hairpin structure of the non-template DNA strand

RfaH, a transcription regulator of the universally conserved NusG/Spt5 family, utilizes a unique mode of recruitment to elongating RNA polymerase to activate virulence genes. RfaH function depends critically on an ops sequence, an exemplar of a consensus pause, in the non-template DNA strand of the transcription bubble. We used structural and functional analyses to elucidate the role of ops in RfaH recruitment. Our results demonstrate that ops induces pausing to facilitate RfaH binding and establishes direct contacts with RfaH. Strikingly, the non-template DNA forms a hairpin in the RfaH: ops complex structure, flipping out a conserved T residue that is specifically recognized by RfaH. Molecular modeling and genetic evidence support the notion that ops hairpin is required for RfaH recruitment. We argue that both the sequence and the structure of the non-template strand are read out by transcription factors, expanding the repertoire of transcriptional regulators in all domains of life.

biochemistry↗

bioRxiv2018

Adaptive and Wireless Recordings of Electrophysiological Signals during Concurrent Magnetic Resonance Imaging

Strong electromagnetic fields that occur during functional magnetic resonance imaging (fMRI) presents a challenging environment for concurrent electrophysiological recordings. Here, we present a miniaturized, wireless platform - \"MR-Link\" (Multimodal Recording Link) that provides a hardware solution for simultaneous electrophysiological and fMRI signal acquisition. The device detects the changes in the electromagnetic field during fMRI to synchronize amplification and sampling of electrophysiological signals with minimal artifacts. It wirelessly transmits the recorded data at a frequency detectable by the MR-receiver coil. The transmitted data is readily separable from MRI in the frequency domain. To demonstrate its efficacy, we used this device to record electrocardiograms and somatosensory evoked potential during concurrent fMRI scans. The device minimized the fMRI-induced artifacts in electrophysiological data and wirelessly transmitted the data back to the receiver coil without compromising fMRI signal quality. The device is compact (22 mm dia., 2gms) and can be placed within the MR-bore to precisely synchronize with fMRI. Therefore, MR-Link offers an inexpensive system by eliminating the need for amplifiers with a high dynamic range, high-speed sampling, additional storage or synchronization hardware for electrophysiological signal acquisition. It is expected to enable a broader range of applications of simultaneous fMRI and electrophysiology in animals and humans.

bioengineering↗

bioRxiv2018

Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration ofinflammatory immune cells in EGFR mutant lung tumors

Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment. We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. Erlotinib treatment also led to increased maturation of myeloid cells and an increase in CD40+ dendritic cells. Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlights potential avenues for investigation of targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.

cancer biology↗

bioRxiv2018

Vagus Nerve Stimulation Promotes Gastric Emptying by Increasing Pyloric Opening Measured with Magnetic Resonance Imaging

BackgroundVagus nerve stimulation (VNS) is an emerging electroceutical therapy for remedying gastric disorders that are poorly managed by pharmacological treatments and/or dietary changes. Such therapy seems promising since the vagovagal neurocircuitry controlling the enteric nervous system strongly influences gastric functions.\n\nMethodsHere, the modulatory effects of left cervical VNS on gastric emptying in rats was quantified using a 1) feeding protocol in which the animal voluntarily consumed a post-fast, gadolinium-labeled meal and 2) newly developed, robust, sensitive and non-invasive imaging strategy to measure antral motility, pyloric activity and gastric emptying based on contrast-enhanced magnetic resonance imaging (MRI) and computer-assisted image processing pipelines.\n\nKey ResultsVNS significantly accelerated gastric emptying (control vs. VNS: 24.9{+/-}3.5% vs. 40.7{+/-}3.9% of meal emptied per 4hrs, p<0.05). This effect resulted from a greater relaxation of the pyloric sphincter (control vs. VNS: 1.4{+/-}0.2 vs. 2.5{+/-}0.5 mm2 cross-sectional area of lumen, p<0.05), without notable changes in antral contraction amplitude (control vs. VNS: 30.6{+/-}3.0% vs. 32.5{+/-}3.0% occlusion), peristaltic velocity (control vs. VNS: 0.67{+/-}0.03 vs. 0.67{+/-}0.03 mm/s), or frequency (control vs. VNS: 6.3{+/-}0.1 vs. 6.4{+/-}0.2 cpm). The degree to which VNS relaxed the pylorus positively correlated with gastric emptying rate (r = 0.5465, p<0.01).\n\nConclusions & InferencesThe MRI protocol employed in this study is expected to enable advanced preclinical studies to understand stomach pathophysiology and its therapeutics. Results from this study suggest an electroceutical treatment approach for gastric emptying disorders using cervical VNS to control the degree of pyloric sphincter relaxation.\n\nKey PointsO_LIVagus nerve stimulation is emerging as a new electroceutical therapy for treating gastric disorders. However, its underlying mechanism(s) and therapeutic effect(s) remain incompletely understood.\nC_LIO_LIVagus nerve stimulation significantly accelerated gastric emptying by promoting the relaxation of the pyloric sphincter.\nC_LIO_LIMRI offers high spatial and temporal resolution to non-invasively characterize gastric motility and physiology in preclinical animal models.\nC_LI

bioengineering↗

bioRxiv2018

Task-Evoked Functional Connectivity Does Not Explain Functional Connectivity Differences Between Rest and Task Conditions

During complex tasks, patterns of functional connectivity (FC) differ from those in the resting state. What accounts for such differences remains unclear. Brain activity during a task reflects an unknown mixture of spontaneous activity and task-evoked responses. The difference in FC between a task state and resting state may reflect not only task-evoked connectivity, but also changes in spontaneously emerging networks. Here, we characterized the difference in apparent functional connectivity between the resting state and when human subjects were watching a naturalistic movie. Such differences were marginally (3-15%) explained by the task-evoked networks directly involved in processing the movie content, but mostly attributable to changes in spontaneous networks driven by ongoing activity during the task. The execution of the task reduced the correlations in ongoing activity among different cortical networks, especially between the visual and non-visual sensory cortices. Our results suggest that the interaction between spontaneous and task-evoked activities is not mutually independent or linearly additive, and that engaging in a task may suppress ongoing activity.

neuroscience↗

bioRxiv2018

Epigenetic Drift of H3K27me3 in Aging Links Glycolysis to Healthy Longevity

Epigenetic alteration has been implicated in aging. However, the mechanism by which epigenetic change impacts aging is unclear. H3K27me3, a highly conserved histone modification signifying transcriptional repression, is marked and maintained by Polycomb Repressive Complexes (PRCs). Here, we explore the mechanism by which age-modulated increase of H3K27me3 impacts adult lifespan. Using Drosophila, we reveal that aging leads to loss of fidelity in epigenetic marking and drift of H3K27me3 and consequential reduction in the expression of glycolytic genes with negative effects on energy production and redox state. Moreover, we show that a reduction of H3K27me3 by PRCs-deficiency promotes glycolysis and healthy lifespan. While perturbing glycolysis by gene mutation diminishes the pro-lifespan benefits mediated by PRCs-deficiency, transgenic increase of glycolytic genes in wild-type animals extends longevity. Together, we propose that epigenetic drift of H3K27me3 defines a new aging mechanism and that stimulation of glycolysis promotes metabolic health and longevity.

molecular biology↗