Biology subjects

Du, C.

Publications and source records attributed to Du, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

Salicin modifies osteoarthritis progression by binding on IRE1α and inhibiting IRE1α mediated endoplasmic reticulum stress

ObjectivesTo investigate the effect and mechanisms of salicin (SA) on osteoarthritis (OA) progression. MethodsPrimary rat chondrocytes were stimulated with TNF- and treated with or without SA. CCK-8 was utilized to determine the cytotoxicity of SA. RT-qPCR, Western Blotting and immunofluorescence staining were used to detect inflammatory factors, cartilage matrix degeneration markers, cell proliferation and apoptosis markers expression at mRNA and protein levels respectively. EdU assay and flow cytometer analysis were utilized for evaluating cell proliferation and apoptosis. RNA-sequencing, molecular docking, drug affinity responsive target stability and WB were applied to clarify mechanisms. Rat OA model was used to evaluate the effect of intra-articular injection of SA on OA progression. ResultsNo obvious cytotoxicity was found with the treatment of 10 M SA. SA rescued TNF- induced degeneration of cartilage matrix, inhibition of chondrocytes proliferation, and promotion of chondrocytes apoptosis. In mechanism, we clarified SA could directly bind on IRE1 and occupy IRE1 phosphorylation site, followed with inhibiting IRE1 phosphorylation and regulating IRE1 mediated endoplasmic reticulum (ER) stress by IRE1-I{kappa}B-p65 signaling. Finally, intra-articular injection of SA loaded PLGA could ameliorate OA progression by inhibiting IRE1 mediated ER stress in OA model. ConclusionsSA alleviates OA by directly binding on ER stress regulator IRE1 and inhibits IRE1 mediated ER stress by IRE1-I{kappa}B-p65 signaling. Topical use of small molecular drug SA holds the potential of modifying OA progression.

cell biology↗

bioRxiv2022

Two-pore channel blockade by phosphoinositide kinase inhibitors YM201636 and PI-103 determined by a histidine residue near pore-entrance

Human two-pore channels (TPCs) are endolysosomal cation channels and play an important role in NAADP-evoked Ca2+ release and endomembrane dynamics. TPCs are activated by PI(3,5)P2, which is synthesized by PIKfyve. Here, we found that YM201636, a widely used PIKfyve inhibitor, potently inhibits PI(3,5)P2-induced human TPC2 channel Na+ currents in a dose-dependent manner with an IC50 of 0.16 M. YM201636 also effectively inhibits the currents of a constitutively open TPC2 mutant channel, whereas it exerts no effect when applied in the channels closed state. A YM201636 analog, PI-103, an inhibitor of PI3K and mTOR, also inhibits human TPC2 with an IC50 of 0.64 M. Substitution of the pore-constriction residues Leu690, Leu694 and Tyr312 by Ala reduced the effectiveness of YM201636 and PI-103 in channel inhibition. Interestingly, a His699 residue located near the cytosolic pore entrance is a key determinant for the TPC2 channels sensitivity to YM201636 and PI-103, whose substitution with a Phe in the human TPC1 largely accounts for the channels loss of inhibition by YM201636. Molecular dynamic simulation and docking analysis of YM201636s binding to TPC2 indicated that His699 can interact with the inhibitor and facilitate the channel-blockade at the cytosolic end of the pore. We conclude that YM201636 and PI-103 directly block the TPC2s open-state channel pore at the cytosolic entrance where the His699 is a key determinant for the blockers access to the pore. These findings identify two new potent TPC2 channel blockers, reveal a channel pore entrance blockade mechanism, and provide a new protein target in interpreting the pharmacological effects of these two widely used phosphoinositide kinase inhibitors.

biochemistry↗

bioRxiv2022

Hedgehogs are the major amplifying hosts of severe fever with thrombocytopenia syndrome virus

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne bandavirus mainly transmitted by Haemaphysalis longicornis in East Asia, mostly in rural areas. To date, the amplifying host involved in the natural transmission of SFTSV remains unidentified. Our epidemiological field survey conducted in endemic areas in China showed that hedgehogs were widely distributed, had heavy tick infestations, and had high SFTSV seroprevalence and RNA prevalence. After experimental infection of Erinaceus amurensis and Atelerix albiventris hedgehogs with SFTSV, robust but transitory viremias were detected, which lasted for around nine to eleven days. The infected hedgehogs experienced light weight loss and histopathology of the spleen showed hemorrhagic necrosis and lymphopenia, with infected hedgehogs recovering after viral clearance. Remarkably, SFTSV transmission cycle between hedgehogs and nymph/adult H. longicornis was easily accomplished under laboratory condition with 100% efficiency. Furthermore, naive H. longicornis ticks could be infected by SFTSV-positive ticks co-feeding on naive hedgehogs, with transstadial transmission of SFTSV also confirmed. We also found that SFTSV viremia remained high in hedgehogs during hibernation, suggesting that this mechanism might contribute to the persistence of SFTSV from one year to the next. Of concern, we recently found evidence of the natural circulation of SFTSV in the urban area of Beijing City in China involving H. longicornis ticks and E. amurensis hedgehogs. Our study suggests that the hedgehogs are the major wildlife amplifying hosts of SFTSV and that urban outbreaks of SFTSV might occur in the future.

microbiology↗

bioRxiv2021

Resting brain activity emerges from wave propagating along spatiotemporal varying hyper-structural connectome

How spontaneous brain activities emerge from the structural connectivity (SC) has puzzled researchers for a long time. The underlying mechanism still remains largely unknown. Previous studies on modeling the resting-state human brain functional connectivity (FC) are normally based on the relatively static structural connectome directly and very few of them concern about the dynamic spatiotemporal variability of FC. Here we establish an explicit wave equation to describe the spontaneous cortical neural activities based on the high-order hypergraph representation of SC. Theoretical solution shows that the dynamic couplings between brain regions fluctuates in the form of an exponential wave regulated by the spatiotemporal varying Laplacian of the hyper-structural connectome (hSC), which orchestrates the cortical activities propagating in both space and time. Ultimately, we present a possible mechanism of how negative correlations emerge during the fluctuation of the hypergraph Laplacian of SC, which helps to further understand the fundamental role of SC in shaping the entire pattern of FC with a new perspective. Comprehensive tests on four connectome datasets with different resolutions confirm our theory and findings.

neuroscience↗

bioRxiv2021

New from old: discovery of the novel antibiotic actinomycin L in Streptomyces sp. MBT27

Streptomycetes are major producers of bioactive natural products, including the majority of the antibiotics. While much if the low-hanging fruit has been discovered, it is predited that less than 5% of the chemical space has been mined. Here, we describe the novel actinomycins L1 and L2, which are produced by Streptomyces sp. MBT27. The molecules were discovered via metabolic analysis combined with molecular networking of cultures grown with different combinations of carbon sources. Actinomycins L1 and L2 are diastereoisomers, and the structure of actinomycin L2 was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via a unique spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X2, prior to the condensation of the actinomycin halves. Feeding anthranilamide to cultures of Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27 but only produces actinomycin X2, resulted in the production of actinomycin L. This shows that actinomycin L results from joining two distinct metabolic pathways, namely those for actinomycin X2 and for anthranilamide. Actinomycins L1 and L2 showed significant antimicrobial activity against Gram- positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families. IMPORTANCEActinomycin was the first antibiotic discovered in an actinobacterium by Selman Waksman and colleagues, as early as 1940. This period essentially marks the start of the golden era of antibiotic discovery. Over time, emerging antimicrobial resistance (AMR) and the declining success rate of antibiotic discovery resulted in the current antibiotic crisis. We surprisingly discovered that under some growth conditions, Streptomyces sp. MBT27 can produce actinomycins that are significantly different from those that have been published so far. The impact of this work is not only that we have discovered a novel molecule with very interesting chemical modifications in one of the oldest antibiotics ever described, but also that this requires the combined action of primary and secondary metabolic pathways, namely the biosynthesis of anthranilamide and of actinomycin X2, respectively. The implication of the discovery is that even the most well-studied families of natural products may still have surprises in store for us.

microbiology↗

bioRxiv2021

Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense

The Nrf2/Keap1 axis plays a complex role in viral susceptibility, virus-associated inflammation and immune regulation. However, whether or how the Nrf2/Keap1 axis is involved in the interactions between equine lentiviruses and their hosts remains unclear. Here, we demonstrate that the Nrf2/Keap1 axis was activated during EIAV infection. Mechanistically, EIAV-Rev competitively binds to Keap1 and releases Nrf2 from Keap1-mediated repression, leading to the accumulation of Nrf2 in the nucleus and promoting Nrf2 responsive genes transcription. Subsequently, we demonstrated that the Nrf2/Keap1 axis represses EIAV replication via two independent molecular mechanisms: directly increasing antioxidant enzymes to promote effective cellular resistance against EIAV infection, and repression of Rev-mediated RNA transport through direct interaction between Keap1 and Rev. Together, these data suggest that activation of the Nrf2/Keap1 axis mediates a passive defensive response to combat EIAV infection. The Nrf2/Keap1 axis could be a potential target for developing the strategies for combating EIAV infection. Author summaryHere we report that the Nrf2/Keap1 axis acts as an antiviral effector on EIAV replication through two-way regulation of Rev. On the one hand, EIAV-Rev activates the Nrf2/Keap1 axis by competitive interaction with Keap1, which promotes the transcription of cytoprotective genes implicated in the antiviral response. On the other hand, Keap1 restricts Rev/RRE-dependent RNA transport, leading to inhibition of viral protein synthesis and reduction in viral replication. This study highlights the importance of the Nrf2/Keap1 axis in controlling EIAV replication, and identifies this pathway as a potential new entry-point for treating lentivirus infection. Importantly, this report provides new insights into the regulation of viral replication by the Nrf2/Keap1 axis.

microbiology↗

bioRxiv2021

Inhibiting adenine synthesis attenuates glioblastoma cell stemness and temozolomide resistance

Glioblastoma (GBM) is a lethal brain cancer exhibiting high levels of drug resistance, a feature partially imparted by tumor cell stemness. Recent work shows that homozygous MTAP deletion, a genetic alteration occurring in about half of all GBMs, promotes stemness in GBM cells. Exploiting MTAP loss-conferred deficiency in adenine salvage, we demonstrate that transient adenine blockade via treatment with L-Alanosine (ALA), an inhibitor of de novo adenine synthesis, attenuates stemness of MTAP-deficient GBM cells. This ALA-induced reduction in stemness is accompanied by compromised mitochondrial function, highlighted by diminished spare respiratory capacity. Direct pharmacological inhibition of mitochondrial respiration recapitulates the effect of ALA on GBM cell stemness, suggesting ALA targets stemness partially via affecting mitochondrial function. Finally, in agreement with diminished stemness and compromised mitochondrial function, we show that ALA sensitizes GBM cells to temozolomide (TMZ) in vitro and in an orthotopic GBM model. Collectively, these results identify critical roles of adenine supply in maintaining mitochondrial function and stemness of GBM cells, highlight a critical role of mitochondrial function in sustaining GBM stemness, and implicate adenine synthesis inhibition as a complementary approach for treating MTAP-deleted GBMs.

cancer biology↗

bioRxiv2021

Changes in splicing and neuromodulatory gene expression programs in sensory neurons with pheromone signaling and social experience

Social experience and pheromone signaling in olfactory neurons affect neuronal responses and male courtship behaviors in Drosophila. We previously showed that social experience and pheromone signaling modulate chromatin around behavioral switch gene fruitless, which encodes a transcription factor necessary and sufficient for male behaviors. Fruitless drives social experience dependent modulation of courtship behaviors and pheromone responses in sensory neurons, however, the molecular mechanisms underlying this neuromodulation remain less clear. To identify the molecular mechanisms driving social experience-dependent neuromodulation, we performed RNA-seq from antennal samples of mutants in pheromone receptors and fruitless, as well as grouped or isolated wild-type males. We found that loss of pheromone detection differentially alters the levels of fruitless exons suggesting changes in splicing patterns. In addition, many Fruitless target neuromodulatory genes, such as neurotransmitter receptors, ion channels, ion and membrane transporters, and odorant binding proteins are differentially regulated by social context and pheromone signaling. Recent studies showed that social experience and juvenile hormone signaling coregulate fru chromatin to modify pheromone responses in olfactory neurons. Interestingly, genes involved in juvenile hormone metabolism are also misregulated in different social contexts and mutant backgrounds. Our results suggest that modulation of neuronal activity and behaviors in response to social experience and pheromone signaling likely arise due to large-scale changes in transcriptional programs for neuromodulators downstream of behavioral switch gene function.

neuroscience↗

bioRxiv2021

The nucleoid-associated protein Gbn binds to GATC sequences and affects sporulation and antibiotic production in Streptomyces

Bacterial chromosome structure is organized by a diverse group of proteins collectively referred to as nucleoid-associated proteins (NAPs). Many NAPs have been well studied in Streptomyces, including Lsr2, HupA, HupS, and sIHF. Here, we show that SCO1839 represents a novel family of Actinobacteria NAPs and recognizes a consensus sequence consisting of GATC followed by (A/T)T. The protein was designated Gbn for GATC-binding NAP. Deletion of gbn led to alterations in development and antibiotic production in Streptomyces coelicolor. Chromatin immunoprecipitation sequencing (ChIP-Seq) detected more than 2800 binding regions, encompassing some 3600 GATCWT motifs, which comprise 55% of all such motifs in the S. coelicolor genome. DNA binding of Gbn in vitro increased DNA stiffness but not compaction, suggesting a role in regulation rather than chromosome organization. Transcriptomics analysis showed that Gbn binding generally leads to reduced gene expression. The DNA binding profiles were nearly identical between vegetative and aerial growth. Exceptions are SCO1311 and SCOt32, for a tRNA editing enzyme and a tRNA that recognises the rare leucine codon CUA, respectively, which nearly exclusively bound during vegetative growth. Taken together, our data show that Gbn is a highly pleiotropic NAP that impacts growth and development in streptomycetes. IMPORTANCEA large part of the chemical space of bioactive natural products is derived from Actinobacteria. Many of the biosynthetic gene clusters for these compounds are cryptic, in others words, they are expressed in nature but not in the laboratory. Understanding the global regulatory networks that control gene expression is key to the development of approaches to activate this biosynthetic potential. Chromosome structure has a major impact on the control of gene expression. In bacteria, the organization of chromosome structure is mediated by a diverse group of proteins referred to collectively as nucleoid-associated proteins (NAPs), which play an important role in the control of gene expression, nucleoid structure and DNA repair. We here present the discovery of a novel and extremely pleiotropic NAP, which we refer to as Gbn. Gbn is a sporulation-specific protein that occurs only in the Actinobacteria and binds to GATC sequences, with a subtle but broad effect on global gene expression. The discovery of Gbn is a new step towards better understanding of how gene expression and chromosome structure is governed in antibiotic-producing streptomycetes.

molecular biology↗

bioRxiv2020

lncRNA-RMST functioned as a SOX2 transcription co-regulator to regulate miR-1251 in the progression of Hirschsprung's disease

Hirschsprungs disease (HSCR) is a congenital disorder characterized by the absence of enteric neural crest cells (ENCCs). Non-coding RNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been authenticated as important regulators of biological functions. We conducted a microarray analysis and found lncRNA Rhabdomyosarcoma 2-associated transcript (RMST) was down-regulated in the stenotic segment of HSCR patients. MiR-1251 is transcribed from the intron region of RMST and was also low-expressed. When the expression of RMST or miR-1251 was reduced, the cell proliferation and migration were attenuated. However, RMST didnt affect the expression of miR-1251 directly found in this study. Through bioinformatic analysis, transcription factor SOX2 was predicted to bind to the promoter region of miR-1251 which was confirmed by CHIP assay. Herein, we demonstrated that RMST exerted as a co-regulator of SOX2 to regulate the expression of miR-1251. Furtherly, AHNAK was proved to be the target gene of miR-1251 in this study. Taken together, we revealed the role of RMST/SOX2/miR-1251/AHNAK pathway in the occurrence of Hirschsprungs disease and provided a potential therapeutic target for this disease. SUMMARY STATEMENTHirschsprung disease (HSCR) is characterized by a deficit in enteric neurons, however, the underlying mechanism remains unclear. This study revealed the role of lnc-RMST during the occurrence of HSCR.

cell biology↗

bioRxiv2020

Integration of machine learning and pan-genomics expands the biosynthetic landscape of RiPP natural products

Most clinical drugs are based on microbial natural products, with compound classes including polyketides (PKS), non-ribosomal peptides (NRPS), fluoroquinones and ribosomally synthesized and post-translationally modified peptides (RiPPs). While variants of biosynthetic gene clusters (BGCs) for known classes of natural products are easy to identify in genome sequences, BGCs for new compound classes escape attention. In particular, evidence is accumulating that for RiPPs, subclasses known thus far may only represent the tip of an iceberg. Here, we present decRiPPter (Data-driven Exploratory Class-independent RiPP TrackER), a RiPP genome mining algorithm aimed at the discovery of novel RiPP classes. DecRiPPter combines a Support Vector Machine (SVM) that identifies candidate RiPP precursors with pan-genomic analyses to identify which of these are encoded within operon-like structures that are part of the accessory genome of a genus. Subsequently, it prioritizes such regions based on the presence of new enzymology and based on patterns of gene cluster and precursor peptide conservation across species. We then applied decRiPPter to mine 1,295 Streptomyces genomes, which led to the identification of 42 new candidate RiPP families that could not be found by existing programs. One of these was studied further and elucidated as a novel subfamily of lanthipeptides, designated Class V. Two previously unidentified modifying enzymes are proposed to create the hallmark lanthionine bridges. Taken together, our work highlights how novel natural product families can be discovered by methods going beyond sequence similarity searches to integrate multiple pathway discovery criteria. Code and data availabilityThe source code of DecRiPPter is freely available online at https://github.com/Alexamk/decRiPPter. Results of the data analysis are available online at http://www.bioinformatics.nl/~medem005/decRiPPter_strict/index.html and http://www.bioinformatics.nl/~medem005/decRiPPter_mild/index.html (for the strict and mild filters, respectively). All training data and code used to generate these, as well as outputs of the data analyses, are available on Zenodo at doi:10.5281/zenodo.3834818.

microbiology↗

bioRxiv2020

Potential host range of multiple SARS-like coronaviruses and an improved ACE2-Fc variant that is potent against both SARS-CoV-2 and SARS-CoV-1

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a currently uncontrolled pandemic and the etiological agent of coronavirus disease 2019 (COVID-19). It is important to study the host range of SARS-CoV-2 because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. Here we show that ACE2 orthologs of a wide range of domestic and wild animals support entry of SARS-CoV-2, as well as that of SARS-CoV-1, bat coronavirus RaTG13, and a coronavirus isolated from pangolins. Some of these species, including camels, cattle, horses, goats, sheep, pigs, cats, and rabbits may serve as potential intermediate hosts for new human transmission, and rabbits in particular may serve as a useful experimental model of COVID-19. We show that SARS-CoV-2 and SARS-CoV-1 entry could be potently blocked by recombinant IgG Fc-fusion proteins of viral spike protein receptor-binding domains (RBD-Fc) and soluble ACE2 (ACE2-Fc). Moreover, an ACE2-Fc variant, which carries a D30E mutation and has ACE2 truncated at its residue 740 but not 615, outperforms all the other ACE2-Fc variants on blocking entry of both viruses. Our data suggest that RBD-Fc and ACE2-Fc could be used to treat and prevent infection of SARS-CoV-2 and any new viral variants that emerge over the course of the pandemic.

microbiology↗

bioRxiv2020

C Terminus of DJ-1 Determines Its Homodimerization, Deglycation Activity and Suppression of Ferroptosis

DJ-1 is a multi-functional protein related to cancer and autosomal early-onset Parkinson disease (PD). Besides the well-documented antioxidative stress activity, recent studies suggest that DJ-1 has the deglycation enzymatic activity and the anti-ferroptosis function. Although it has been demonstrated that DJ-1 forms the homodimerization, which dictates its antioxidative stress activity, the relationship between the dimeric structure and newly reported activities remains largely elusive. In this study, we find that the deletion mutation of the last 3 amino acids at C terminus of DJ-1 disrupts its homodimerization in both transfected and purified DJ-1 protein. Further study shows that hydrophobic L187 residue is of great importance for DJ-1 homodimerization. In addition, the ability in methylglyoxal detoxification is almost abolished in the mutation of deleting last 3 residues at C terminus ({Delta}C3) and point mutant L187E compared with wild type DJ-1 (DJ-1 WT). We also find that the suppression of ferroptosis is fully inhibited by {Delta}C3 and L187E while partially suppressed by V51C. Thus, our findings show that C terminus of DJ-1 is crucial for its homodimerization, deglycation activity and suppression of ferroptosis.

molecular biology↗

bioRxiv2019

Juvenile hormone regulation on the flight capability of Bactrocera dorsalis (Diptera: Tephritidae)

The oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae), is considered a major economic threat in many regions worldwide. In order to better understand the flight capacity of B. dorsalis and its physiological basis, the functions and regulatory roles of juvenile hormone (JH) in the flight muscle of B. dorsalis were studied under a controlled environment. JH titer of B. dorsalis varied with age and sex. Females, irrespective of age, have higher JH than males for ovarian development and maturation in addition to better flight capabilities. The flight duration and distance of both males and females increased with the gradual increase of JH titer after adult emergences. JH titer peaked in 15-d-old adult and declined subsequently with age. Flight activity stimulated the production of JH as adults flown for 24 hours on the flight mills have the highest JH titers compare to adults tethered on shorter flight durations. Furthermore, JH III-treated adults were able to perform long-duration and long-distance flights. The mutual reinforcement of JH and flight activity provides fundamental understanding on the physiological aspects of the flight capability and dispersal, which facilitates strategies for the long-term control of this destructive pest.

animal behavior and cognition↗

bioRxiv2019

Neural Encoding for Human Visual Cortex with Deep Neural Networks Learning "What" and "Where"

Neural encoding, a crucial aspect to understand human brain information processing system, aims to establish a quantitative relationship between the stimuli and the evoked brain activities. In the field of visual neuroscience, with the ability to explain how neurons in primary visual cortex work, population receptive field (pRF) models have enjoyed high popularity and made reliable progress in recent years. However, existing models rely on either the inflexible prior assumptions about pRF or the clumsy parameter estimation methods, severely limiting the expressiveness and interpretability. In this paper, we propose a novel neural encoding framework by learning "what" and "where" with deep neural networks. The modeling approach involves two separate aspects: the spatial characteristic ("where") and feature selection ("what") of neuron populations in visual cortex. Specifically, we use the receptive field estimation and multiple features regression to learn these two aspects respectively, which are implemented simultaneously in a deep neural network. The two forms of regularizations: sparsity and smoothness, are also adopted in our modeling approach, so that the receptive field can be estimated automatically without prior assumptions about shapes. Furthermore, an attempt is made to extend the voxel-wise modeling approach to multi-voxel joint encoding models, and we show that it is conducive to rescuing voxels with poor signal-to-noise characteristics. Extensive empirical results demonstrate that the method developed herein provides an effective strategy to establish neural encoding for human visual cortex, with the weaker prior constraints but the higher encoding performance. Author summaryCharacterizing the quantitative relationship between the stimuli and the evoked brain activities usually involves learning the spatial characteristic ("where") and feature selection ("what") of neuron populations. As an effective strategy, we propose a novel end-to-end "what" and "where" architecture to perform neural encoding. The proposed modeling approach consists of receptive field estimation and multiple features regression, which learns "where" and "what" simultaneously in a deep neural network. Different from previous methods, we use the sparsity and smoothness regularizations in the deep neural network to guide the receptive field estimation, so that the receptive field for each voxel can be estimated automatically. Moreover, in consideration of computational similarities between adjacent voxels, we made an attempt to extend the proposed modeling approach to multi-voxel joint encoding models, improving the encoding performance of voxels with poor signal-to-noise characteristics. Empirical evaluations show that the proposed method outperforms other baselines to achieve the state-of-the-art performance.

neuroscience↗

bioRxiv2019

Genome-scale Model Constrained by Proteomics Reveals Metabolic Rearrangements in the Heterologous Host Streptomyces coelicolor

Many biosynthetic gene clusters (BGCs) require heterologous expression to realize their genetic potential, including silent and metagenomic BGCs. Although the engineered Streptomyces coelicolor M1152 is a widely used host for heterologous expression of BGCs, a systemic understanding of how its genetic modifications affect the metabolism is lacking and limiting further development. We performed a comparative analysis of M1152 and its ancestor M145, connecting information from proteomics, transcriptomics, and cultivation data into a comprehensive picture of the metabolic differences between these strains. Instrumental to this comparison was the application of an improved consensus genome-scale metabolic model (GEM) of S. coelicolor. Although many metabolic patterns are retained in M1152, we find that this strain suffers from oxidative stress, possibly caused by increased oxidative metabolism. Furthermore, precursor availability is likely not limiting polyketide production, implying that other strategies could be beneficial for further development of S. coelicolor for heterologous production of novel compounds.

systems biology↗

bioRxiv2019

Epidemiology of drug-resistant tuberculosis in Chongqing, China: a retrospective observational study from 2010 to 2017

China is one of the top 30 countries with high multidrug-resistant tuberculosis (MDR-TB) and rifampin-resistant tuberculosis (RR-TB) burden. Chongqing is a southwest city of China with a large rural population. A retrospective observational study has been performed based on routine tuberculosis (TB) surveillance data in Chongqing from 2010 to 2017. The MDR/RR-TB notification rate increased from 0.03 cases per 100,000 population in 2010 to 2.09 cases per 100,000 population in 2017. The extensively drug-resistant TB (XDR-TB) notification rate has increased to 0.09 cases per 100,000 population in 2017. There was a decreasing detection gap between the number of notified MDR/RR-TB cases and the estimate number of MDR/RR-TB cases among all notified TB cases. The treatment success rate of MDR/RR-TB was 50.66% in this period. The rate of MDR/RR-TB in new TB cases was 6.23%, and this rate in previously treated TB cases was 32.7%. Despite the progress achieved, the prevalence of MDR/RR-TB was still high facing challenges including detection gaps, the regional disparity, and the high risk for MDR/RR-TB in elderly people and farmers. Sustained government financing and policy support should be guaranteed in the future.

epidemiology↗

bioRxiv2019

ANP32A and ANP32B are key factors in the Rev dependent CRM1 pathway for nuclear export of HIV-1 unspliced mRNA

The nuclear export receptor CRM1 is an important regulator involved in the shuttling of various cellular and viral RNAs between the nucleus and the cytoplasm. HIV-1 Rev interacts with CRM1 in the late phase of HIV-1 replication to promote nuclear export of unspliced and single spliced HIV-1 transcripts. However, the knowledge of cellular factors that are involved in the CRM1-dependent viral RNA nuclear export remains inadequate. Here, we identified that ANP32A and ANP32B mediate the export of unspliced or partially spliced viral mRNA via interacting with Rev and CRM1. We found that double, but not single, knockout of ANP32A and ANP32B, significantly decreased the expression of gag protein. Reconstitution of either ANP32A or ANP32B restored the viral production equally. Disruption of both ANP32A and ANP32B expression led to a dramatic accumulation of unspliced viral mRNA in the nucleus. We further identified that ANP32A and ANP32B interact with both Rev and CRM1 to promote RNA transport and that this function is Rev/RRE-dependent, but not CTE-dependent. Together our data suggests that ANP32A and ANP32B are required for HIV-1 unspliced RNA export in the Rev-CRM1 pathway. Author summaryPosttranscriptional regulation of HIV-1 genome is very important for viral protein expression and viral replication. HIV-1 Rev protein bind to RRE structure of viral RNA and interacts with the mammalian nuclear export factor Chromosomal Maintenance 1 (CRM1) in the late phase of HIV-1 replication to promote nuclear export of unspliced and single spliced HIV-1 transcripts. The REV/RRE-CRM1 pathway has been investigated for years and many host factors have been reported to be involved, but the complicated complex and procedure remain largely unknown. Here the authors report that two host proteins, ANP32A and ANP32B, are novel key factors that support export of unspliced and partial spliced viral RNA from the nucleus to the cytosol. ANP32A/B can interact with both Rev and CRM1, and this interaction is necessary for Rev/RRE-CRM1 dependent viral RNA export. These results suggest that ANP32A and ANP32B are important in viral replication and could be potential targets for novel antiviral strategy.

microbiology↗