Biology subjects

Weng, X.

Publications and source records attributed to Weng, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Deletion of CD44 promotes adipogenesis by regulating PPARγ and cell cycle-related pathways

CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPAR{ballotbox} and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

cell biology↗

bioRxiv2023

Complete genome-centric analysis reveals functional divergence and adaptive evolution of uncultured bacteria in anammox community

Anaerobic ammonium-oxidation (anammox) bacteria play a crucial role in global nitrogen cycling and wastewater nitrogen removal, but they share symbiotic relationships with various other microorganisms. No pure culture is available for anammox bacteria so far. Although shotgun metagenomics based on short reads has been widely used in anammox research, metagenome-assembled genomes (MAGs) are often discontinuous and highly contaminated, which limits in-depth analyses of anammox communities. Here, for the first time, we performed Pacific Biosciences high-fidelity (HiFi) long-read sequencing on the anammox granule sludge sample from a lab-scale bioreactor, and obtained 30 accurate and complete metagenome-assembled genomes (cMAGs). These cMAGs were obtained by selecting high-quality circular contigs from initial assemblies of long reads generated by HiFi sequencing, eliminating the need for Illumina short reads, binning, and reassembly. One new anammox species and species from three novel families were found in this anammox community. cMAG-centric analysis revealed divergences in general and nitrogen metabolism among members of the anammox community. Furthermore, we identified mobile genetic elements (MGEs) and putative horizontal gene transfer (HGT) events within these cMAGs to explore the adaptive evolution of the community. The results suggest that MGEs and HGT events, particularly transposons containing tnpA in anammox bacteria, might play important roles in the adaptive evolution of this anammox community. The cMAGs generated in the present study could be used to establish of a comprehensive database for anammox bacteria and associated microorganisms. Our findings highlight the advantages of HiFi sequencing for the studies of complex mixed cultures such as anammox communities and advance our understanding of anammox communities.

microbiology↗

bioRxiv2022

JGI Plant Gene Atlas: An updateable transcriptome resource to improve structural annotations and functional gene descriptions across the plant kingdom

Gene functional descriptions, which are typically derived from sequence similarity to experimentally validated genes in a handful of model species, offer a crucial line of evidence when searching for candidate genes that underlie trait variation. Plant responses to environmental cues, including gene expression regulatory variation, represent important resources for understanding gene function and crucial targets for plant improvement through gene editing and other biotechnologies. However, even after years of effort and numerous large-scale functional characterization studies, biological roles of large proportions of protein coding genes across the plant phylogeny are poorly annotated. Here we describe the Joint Genome Institute (JGI) Plant Gene Atlas, a public and updateable data resource consisting of transcript abundance assays from 2,090 samples derived from 604 tissues or conditions across 18 diverse species. We integrated across these diverse conditions and genotypes by analyzing expression profiles, building gene clusters that exhibited tissue/condition specific expression, and testing for transcriptional modulation in response to environmental queues. For example, we discovered extensive phylogenetically constrained and condition-specific expression profiles across many gene families and genes without any functional annotation. Such conserved expression patterns and other tightly co-expressed gene clusters let us assign expression derived functional descriptions to 64,620 genes with otherwise unknown functions. The ever-expanding Gene Atlas resource is available at JGI Plant Gene Atlas (https://plantgeneatlas.jgi.doe.gov) and Phytozome (https://phytozome-next.jgi.doe.gov), providing bulk access to data and user-specified queries of gene sets. Combined, these web interfaces let users access differentially expressed genes, track orthologs across the Gene Atlas plants, graphically represent co-expressed genes, and visualize gene ontology and pathway enrichments.

plant biology↗

bioRxiv2022

Top-down modulation and cortical-AMG/HPC interaction in familiar face processing

Humans can accurately recognize familiar faces in only a few hundred milliseconds, but the underlying neural mechanism remains unclear. Here we recorded intracranial electrophysiological signals from ventral temporal cortex (VTC), superior/middle temporal cortex (STC/MTC), medial parietal cortex (MPC) and amygdala/hippocampus (AMG/HPC) in 20 epilepsy patients while they viewed faces of famous people and strangers as well as common objects. In posterior VTC and MPC, familiarity-sensitive responses emerged significantly later than initial face-selective responses, suggesting that familiarity enhances face representations after they are first being extracted. Moreover, viewing famous faces increased the coupling between cortical areas and AMG/HPC in multiple frequency bands. These findings imply that the top-down modulation in local face-selective response and interactions between cortical face areas and AMG/HPC contribute to the superior recognition of familiar faces. TeaserTop-down modulation and cortical-AMG/HPC interactions contribute to the superior processing of familiar faces.

neuroscience↗

bioRxiv2022

Transcriptome and DNA methylome dynamics reveal differential characteristics of inflorescence development between two ecotypes in Panicum hallii

The morphological diversity of the inflorescence determines flower and seed production, which is critical for plant adaptation and fitness. Cytosine methylation is an epigenetic mark that contributes to gene expression regulation during inflorescence development. Panicum hallii is a wild perennial grass in the subfamily Panicoideae that has been developed as a model to study perennial grass biology and adaptive evolution. Highly divergent inflorescences have evolved between the two major ecotypes in P. hallii, the upland ecotype with compact inflorescence and large seed and the lowland ecotype with an open inflorescence and small seed. Here we performed a comparative transcriptome and DNA methylome analysis across different stages of inflorescence between these two divergent ecotypes of P. hallii. Global transcriptome analysis identified differentially expressed genes (DEGs) involved in panicle divergence, stage-specific expression, and co-expression modules underlying inflorescence development. Comparing DNA methylome profiles revealed a remarkable level of differential DNA methylation associated with the evolution of the P. hallii inflorescence. We found that most differentially methylated regions (DMRs) occurred within the flanking regulatory regions of genes, especially the promoter. Integrative analysis of DEGs and DMRs characterized the global features of DMR-associated DEGs in the divergence of P. hallii inflorescence, which includes homologs of important inflorescence and seed developmental genes that have been previously identified in domesticated crops. Evolutionary analysis measured by Ka/Ks ratio suggested that most DMR-associated DEGs are under relatively strong purifying selection. This study provides insights into the transcriptome and epigenetic landscape of inflorescence divergence in P. hallii and a novel genomic resource for perennial grass biology. One sentence summaryA comparative transcriptome and DNA methylome analysis of inflorescence between upland and lowland ecotypes reveal gene expression and DNA methylation variation underlying inflorescence divergence in Panicum hallii.

evolutionary biology↗

bioRxiv2022

A pleiotropic flowering time QTL exhibits gene-by-environmental interaction for fitness in a perennial grass

Flowering time is crucial for wild plant populations to adapt to their local environments. Although the genetic basis of flowering variation has been studied in many plant species, its mechanisms in non-model organisms and its adaptive value in the field are still poorly understood. Here, we report new insights into the genetic basis of flowering time and its effect on fitness in Panicum hallii, a native perennial grass. We conducted genetic mapping in populations derived from representative inland and coastal ecotypes to identify flowering time QTL and loci exhibited extensive QTL-by-environment interactions. Patterns of segregation within recombinant hybrids provide strong support for directional selection driving ecotypic divergence in flowering time. A major QTL on chromosome 5 (q-FT5) was detected in all experiments and is a key locus controlling flowering variation. Fine-mapping and expression studies identified a FLOWERING LOCUS T orthologue, FT-like 9 (PhFTL9), as the candidate underlying q-FT5. We used reciprocal transplant experiment to test for global local adaptation and the specific impact of q-FT5 on performance. We did not observe local adaptation in terms of fitness tradeoffs when contrasting ecotypes in home versus away habitats. However, we observed that the coastal allele of q-FT5 conferred a fitness advantage only in its local habitat but not at the inland site. Sequence analysis of the PhFTL9 promoter identified ecotypic specific cis-element variation associated with environmental responsiveness. Together, our findings demonstrate the genetic basis of flowering variation in a perennial grass and provide evidence for conditional neutrality underlying flowering divergence.

evolutionary biology↗

bioRxiv2022

Metabolome and transcriptome analysis reveal components regulating soapberry triterpenoid saponin biosynthesis

Soapberry (Sapindus mukorossi Gaertn.) pericarps are rich in valuable bioactive triterpenoid saponins. However, the saponin content dynamics and the molecular regulatory network of saponin biosynthesis in soapberry pericarps remain largely unclear. Here, we performed combined metabolite profiling and transcriptome analysis to identify saponin accumulation kinetic patterns, investigate gene networks, and characterize key candidate genes and transcription factors involved in saponin biosynthesis in soapberry pericarps. A total of 54 saponins were tentatively identified, including 25 that were differentially accumulated. Furthermore, 49 genes putatively involved in sapogenin backbone biosynthesis and some candidate genes assumed to be responsible for the backbone modification, including 41 cytochrome P450s and 45 glycosyltransferases, were identified. Saponin-specific clusters/modules were identified by Mfuzz clustering and weighted gene co-expression network analysis, and one TF-gene regulatory network underlying saponin biosynthesis was proposed. The results of yeast one-hybrid assay and electrophoretic mobility shift assay suggested that SmbHLH2, SmTCP4, and SmWRKY27 may play important roles in the triterpenoid saponin biosynthesis by directly regulating the transcription of SmCYP71D-3 in soapberry pericarp. Overall, these findings provide valuable information for understanding the molecular regulatory mechanism of saponin biosynthesis, enriching the gene resources, and guiding further research on triterpenoid saponin accumulation in soapberry pericarps. One-sentence summaryCombining metabolome and transcriptome analysis to identify saponin kinetic patterns, gene networks, and key candidate genes and transcription factors involved in saponin biosynthesis of soapberry.

molecular biology↗

bioRxiv2021

Efficient and Rapid generation of neural stem cells by direct conversion Fibroblasts with A Single microRNA

Neural stem cells (NSCs) have great potential in the application of neurodegenerative disease therapy, drug screening and disease modeling. NSC can be generated by reprogramming from terminally differentiated cells with transcription factors or small molecules. However, current methods for producing NSCs involve the danger of integrating foreign genes into the genome and the problem of low efficiency. Here, we report an efficient method to generate NSCs from human skin-derived fibroblasts with microRNA (mir-302a) in 2-3 days. The induced NSCs (iNSCs) have more than 90% of purity. Their morphology is similar to regular NSCs, expressing key markers including Nestin, Pax6 and Sox2, and can be expanded for more than 20 passages in vitro. They can also differentiate into functional neuron progeny, astrocytes and oligodendrocytes as well. Those cells can elicit action potential, can be xeno-transplanted into the brain of immune-deficient mice, and can survive and differentiate in vivo without tumor formation. This study shows that a single part of pluripotency-inducing mir-302 cluster can drive fibroblasts reprogramming, providing a general platform for high-efficiency generation of individual-specific human NSCs for studies of neuron system development and regenerative cell therapy.

neuroscience↗

bioRxiv2021

Pre-stimulus alpha activities predict the confidence in subjective judgment by modulating post-stimulus theta oscillation

Even when making arbitrary decisions, people tend to feel varying levels of confidence, which is associated with the pre-stimulus neural oscillation of the brain. We investigated varying confidence in a pure subjective judgment task, and how this confidence was predicted by pre-stimulus alpha oscillations. Participants made pure subjective judgments where their prior experience seems to be helpful but actually useless, and their fluctuating confidence was related to the choice boundary process rather than the evidence accumulation process, suggesting participants underwent varying confidence resulting from the internal signals. With EEG and MEG analyses, we not only revealed the linkage between confidence and pre-stimulus alpha activities, but also successfully located this linkage onto decision-making relevant brain areas, i.e. MCC/PCC and SMA. Moreover, we unveiled a specific pathway underlying such linkage, that is, the influence of pre-stimulus alpha activities on decision confidence was fulfilled through modulating post-stimulus theta activities of SMA.

neuroscience↗

bioRxiv2021

DeepHBV: A deep learning model to predict hepatitis B virus (HBV) integration sites.

Hepatitis B virus (HBV) is one of the main causes for viral hepatitis and liver cancer. Previous studies showed HBV can integrate into host genome and further promote malignant transformation. In this study, we developed an attention-based deep learning model DeepHBV to predict HBV integration sites by learning local genomic features automatically. We trained and tested DeepHBV using the HBV integration sites data from dsVIS database. Initially, DeepHBV showed AUROC of 0.6363 and AUPR of 0.5471 on the dataset. Adding repeat peaks and TCGA Pan Cancer peaks can significantly improve the model performance, with an AUROC of 0.8378 and 0.9430 and an AUPR of 0.7535 and 0.9310, respectively. On independent validation dataset of HBV integration sites from VISDB, DeepHBV with HBV integration sequences plus TCGA Pan Cancer (AUROC of 0.7603 and AUPR of 0.6189) performed better than HBV integration sequences plus repeat peaks (AUROC of 0.6657 and AUPR of 0.5737). Next, we found the transcriptional factor binding sites (TFBS) were significantly enriched near genomic positions that were paid attention to by convolution neural network. The binding sites of AR-halfsite, Arnt, Atf1, bHLHE40, bHLHE41, BMAL1, CLOCK, c-Myc, COUP-TFII, E2A, EBF1, Erra and Foxo3 were highlighted by DeepHBV attention mechanism in both dsVIS dataset and VISDB dataset, revealing the HBV integration preference. In summary, DeepHBV is a robust and explainable deep learning model not only for the prediction of HBV integration sites but also for further mechanism study of HBV induced cancer. Author summaryHepatitis B virus (HBV) is one of the main causes for viral hepatitis and liver cancer. Previous studies showed HBV can integrate into host genome and further promote malignant transformation. In this study, we developed an attention-based deep learning model DeepHBV to predict HBV integration sites by learning local genomic features automatically. The performance of DeepHBV model significantly improves after adding genomic features, with an AUROC of 0.9430 and an AUPR of 0.9310. Furthermore, we enriched the transcriptional factor binding sites of proteins by convolution neural network. In summary, DeepHBV is a robust and explainable deep learning model not only for the prediction of HBV integration sites but also for the further study of HBV integration mechanism.

bioinformatics↗

bioRxiv2020

Higher-order sensorimotor circuit of the brain' global network supports human consciousness

The neural correlates of consciousness, defined as the minimum neuronal mechanisms sufficient for any conscious percept, are usually subject to different interpretations depending on whether one uses measures of local or global brain activities. We argue that the local regions may support consciousness by serving as hubs within the brains global network. We adopt a unique functional magnetic resonance imaging resting state dataset that encompasses various conscious states, including non-rapid eye movement (NREM)-sleep, rapid eye movement (REM)-sleep, anesthesia, and brain injury patients. Using a graph-theoretical measure for detecting local hubs within the brains global network, we identify various higher-order sensory and motor regions as hubs with significantly reduced degree centrality during unconsciousness. Additionally, these regions form a sensorimotor circuit which correlates with levels of consciousness. Our findings suggest that integration of higher-order sensorimotor function may be a key mechanism of consciousness. This opens novel perspectives for therapeutic modulation of unconsciousness.

neuroscience↗

bioRxiv2020

CTLA-4 blockade reverses the Foxp3+ T-regulatory-cell suppression of anti-tuberculosis T-cell effector responses

BackgroundsIt has been well described that Foxp3+ T regulatory (Treg) cells suppress immune responses and that murine cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can control the function of Foxp3+Treg cells. However, it remains unknown about the role of CTLA-4 pathway in Treg suppression of T cell responses in tuberculosis (TB). MethodsWe assessed TB-driven changes in CTLA-4-expressing Foxp3+ Treg and conducted CTLA-4 blocking mechanistic studies ex vivo in 126 subjects with active TB, latent TB or uninfected statuses. ResultsFrequencies of CTLA-4-expressing Treg cells were increased in the circulation of pulmonary TB patients and in the pleural compartment of TB pleuritis. Six-month anti-TB treatment significantly reduced CTLA-4+ Treg subset. Notably, antibody blocking of CTLA-4 pathway (CTLA-4 blockade) reversed the ability of Treg cells to suppress anti-TB Th1 responses and abrogated the Treg-mediated suppression of TB antigen-stimulated proliferative response. The CTLA-4 blockade reversed the Treg suppression of the ability of T cells to restrict intracellular BCG and M. tuberculosis growth in macrophages. InterpretationThe study uncovered previously-unreported observations implicating that the CTLA-4 blockade abrogates the capability of Treg cells to suppress anti-TB immune responses or immunity. Findings support the rationale for exploring the CTLA-4 blockade as potential host-directed therapy against TB. FundThis work is supported in part by the National Natural Science Foundation of China (30901277, 81671553, 81501359), and the Key Technologies Research and Development Program for Infectious Diseases of China (2017ZX10201302-004).

immunology↗

bioRxiv2019

Single molecule tracking reveals the role of transitory dynamics of nucleoid-associated protein HU in organizing the bacterial chromosome

HU is the most conserved nucleoid-associated protein in eubacteria and has been implicated as a key player in global chromosome organization. The mechanism of HU-mediated nucleoid organization, however, remains poorly understood. Using single molecule tracking coupled with genetic manipulations, we characterized the dynamics of HU in live Escherichia coli cells. We found that native HU dimers bind and unbind chromosomal DNAs weakly and transitorily across the entire nucleoid volume but remain nucleoid-localized, reminiscent of random diffusion in a liquid phase-separated, membrane-less "macro-compartment" distinct from the remaining cytosol. Mutating three key surface lysine residues of HU nearly entirely abolished the weak and transitory interactions of HU with DNA and led to severe cell growth and DNA segregation defects, suggesting the importance of HUs interactions with chromosomal DNA mediated by the positively charged surface. A conserved proline residue important for recognizing bent and cruciform DNAs such as that in recombination intermediates, similarly abolished HUs rapid and transitory DNA interaction dynamics but had little impact on its apparent binding stability with nonspecific chromosomal DNAs. Interestingly, the proline residue appeared to be important for HU{beta} dimer formation as mutating this residue makes HU{beta} behave similarly to HU2 dimers. Finally, we find that while prior evidence has found HU capable of depositing nucleoid-associated noncoding RNAs onto cruciform DNA structures, deletion of these specific naRNAs or inhibition of global transcription had a relatively minor effect on HU dynamics irrespective altered nucleoid compaction. Our results suggest a model of chromosome organization mediated by weak, transient interactions of HU, a substantial deviation from nucleoid-like proteins such as histones. Such collective sum of the numerous weak, transitory binding events of HU with nonspecific chromosome DNAs could generates a "force" to maintain a dynamic, fluid nucleoid with enough flexibility to rapidly facilitate global topological processes such as replication or nucleoid segregation.

biophysics↗

bioRxiv2019

A Pairwise Distance Distribution Correction (DDC) algorithm for blinking-free super-resolution microscopy

In single-molecule localization based super-resolution microscopy (SMLM), a fluorophore stochastically switches between fluorescent- and dark-states, leading to intermittent emission of fluorescence, a phenomenon known as blinking. Intermittent emissions create multiple localizations belonging to the same molecule, resulting in blinking-artifacts within SMLM images. These artifacts are often interpreted as true biological assemblies, confounding quantitative analyses and interpretations. Multiple methods have been developed to eliminate these artifacts, but they either require additional experiments, arbitrary thresholds, or specific photo-kinetic models. Here we present a method, termed Distance Distribution Correction (DDC), to eliminate blinking-caused repeat localizations without any additional calibrations. The approach relies on the finding that the true pairwise distance distribution of different fluorophores in an SMLM image can be naturally obtained from the imaging sequence by using distances between localizations separated by a time much longer than the average fluorescence survival time. We show that using the true pairwise distribution we can define and then maximize the likelihood of obtaining a particular set of localizations void of blinking-artifacts, generating an accurate reconstruction of the underlying cellular structure. Using both simulated and experimental data, we show that DDC surpasses all previous existing blinking-artifact correction methodologies, resulting in drastic improvements in obtaining the closest estimate of the true spatial organization and number of fluorescent emitters in a wide range of applications. The simplicity and robustness of DDC will allow it to become the field standard in SMLM imaging, enabling the most accurate reconstruction and quantification of SMLM images to date.

biophysics↗

bioRxiv2019

A novel xenograft model of human HCC in immunocompetent mouse

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors that threaten human health; thus, the establishment of an animal model with clinical features similar to human liver cancer is of important practical significance. Taking advantage of the novel microcarrier-6, human HCC cells was injected into immunocompetent mice to establish a novel human HCC patient-derived xenograft (PDX) model. Primary HCC cells were isolated from fresh liver cancer tissues, which were subsequently co-cultured with microcarrier-6 to construct a three-dimensional tumor cell culture model in vitro. The HCC-microcarrier complex was implanted into mice by subcutaneous inoculation, and the tumor formation time, tumor formation rate, and pathological manifestation were recorded. Changes of immune parameters in mice were detected by flow cytometry. The success rate was 60% (6/10) in the establishment of liver cancer PDX mouse model, and the total tumor formation rate of the tumor-forming model is 80-100%. H&E staining and immunohistochemical experiments indicate that the model well retained the characteristics of the primary tumor. Interestingly, M2 macrophages in tumor-bearing mice increased significantly, and the levels of CD4+ T cells were significantly reduced. Through the application of the microcarrier-6 in immunocompetent mice, we successfully established a novel human HCC PDX model, which can be used to better study and further elucidate the occurrence and pathogenic mechanism of HCC.

cancer biology↗

bioRxiv2019

Generating Templates and Growth Charts for School-Aged Brain Development

Standard brain templates and growth charts provide an invaluable resource for basic science research, with the eventual goal of contributing to the clinical care of neuropsychiatric conditions. Here, we report on a protocol to generate MRI brain templates in children and adolescents at one-year intervals from 6-to-18 years of age, with their corresponding growth charts, using a large-scale neuroimaging data resource (948 brain images from China and United States). To assure that the brain templates and growth charts are reliable and accurate, we developed a refined pipeline consisting of template construction, image registration, brain area labeling and growth chart modeling. The pipeline comprises multiple modular workflows that can be used for multiple applications. In our approach, population- and age-specific templates were first constructed to avoid systemic bias in registration. Brain areas were then labeled based on the appropriate templates, and their morphological metrics were extracted for modeling associated growth curves. We implemented warp cost as a function of age differences between individual brains and template brains. A strong U-shaped cost function was revealed, indicating larger age differences are associated with greater registration errors. This validates the necessity of age-specific reference templates in pediatric brain imaging studies. Growth chart analyses revealed preferential shape differences between Chinese and US samples in lateral frontal and parietal areas, aspects of cortex which are most variable across individuals with regard to structure and function as well as associated behavioral performance. This growth distinction is largely driven by neurodevelopmental differences between Chinese and US age-specific brain templates. The pipeline together with the brain templates and charts are publicly available and integrated into the Connectome Computation System.

neuroscience↗

bioRxiv2019

Powerful solution for experimental cerebral malaria treatment: artesunate and tetramethylpyrazine

BackgroundCerebral malaria (CM) is a kind of serious neurological complication caused by the acute Plasmodium falciparum infection. About 300000 patients including children under 5 years old died from this disease every year. Even intravenous artesunate (Art) is employed as the most effictive drug in the treatment of CM, high incidence of death and neurological sequelae are still inevitable. Therefore, we assessed the combination of Art and tetramethylpyrazine (TMP), to treat experimental CM (ECM) in C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). A non-biased whole brain quantitative proteomic analysis was also conducted to get some insight of the mechanism of the combinational treatment.\n\nResultsTreatment of (ECM)-C57BL/6 mice with the combination of Art and TMP increased the survival, improved clinical signs and prevented neurological manifestations. These effects were related to reduction of parasitised red blood cells (pRBC) adhesion, sequestration, maintaining brain microvascular integrity, increasing nerve growth factor, neurotrophin levels, and alleviating hippocampal neuronal damage and astrocyte activation. The pharmacological effects of Art-TMP combination therapy were analyzed by ECM mice brain proteomic function enrichment. Based on an isobaric tag for relative and absolute quantitation (iTRAQ) fold-change of 1.2 (P-value < 0.05), 217 down-regulated and 177 up-regulated proteins were identified, presenting a significantly altered proteome profile of the combined Art and TMP group as compared to the group treated with Art or TMP alone. These results suggested that the Art-TMP combination could be used as a powerful solution for CM and its neurologic damage.\n\nConclusionsAn effictive therapy for CM with low mortality rate and protect against ECM-induced neurocognitive impairment has been proposed through the combination of Art and TMP, which can provide an effective adjuvant treatment in the clinic. iTRAQ proteomics provide a resource for further mechanistic studies to examine the synergistic effects of Art and TMP and their potential to serve as an adjunctive treatment method and intervention targets.\n\nAuthor SummaryCerebral malaria (CM) is the most serious neurological complication caused by Plasmodium falciparum infection. Even after antimalarial treatment, severe neurological sequelae still exist. We used tetramethylpyrazine (TMP), the main ingredient of the traditional Chinese medicine Chuanxiong, and artesunate (Art) as a combination of drugs. We found that Art-TMP combination could improve the clinical symptoms of CM and protect the nervous system. At the same time, proteomics was used to analyze the protective mechanism of Art-TMP combination administration on ECM mice. This study suggests that the combination of Art and TMP may be used as an adjuvant therapy for clinical CM and iTRAQ proteomics provides resources for further study of Art-TMP combination and provides potential prognostic biomarkers for this therapeutic intervention.

pathology↗

bioRxiv2018

(-)-Epigallocatechin-3-gallate inhibition of Epstein-Barr virus lytic replication involves latent membrane protein 1-mediated MAPK signaling pathways

AbstractEBV lytic replication has been shown to be important for carcinogenesis. Latent membrane protein 1 (LMP1) plays an important role in the viral latent infection and is abundantly expressed after EBV entry into the lytic cycle. However, the biological significance of LMP1 continuous expression in EBV lytic cycle is still not completely understood. We found that LMP1 promotes EBV reactivation by activating the downstream MAPK signaling in both AGS-EBV and B95.8 cells. In AGS-EBV cells, LMP1 induces EBV the initiation of the EBV lytic cycle in a p53 dependent manner. Activation of c-Jun by LMP1 through JNKs appears to be involved in EBV reactivation in p53 mutant B95.8 cells. We also demonstrated that EGCG, an anti-EBV agent, inhibits LMP1 expression and the activation of the downstream MAPK signaling pathways, followed by downregulation of EBV lytic protein expression level. Together, this study provides the first evidence that LMP1 promotes EBV reactivation via activation of the MAPK signaling pathways. Our findings further demonstrate that the mechanisms underlying EGCG inhibition of the EBV lytic replication involve the suppression of LMP1-mediated MAPK signaling pathways.\n\nSummary statementThis study definitely confirms the role of LMP1 in EBV reactivation and further explores the mechanism by which EGCG inhibits EBV lytic replication.

molecular biology↗