Biology subjects

Zhou, G.

Publications and source records attributed to Zhou, G..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

Latitude influences stability via stabilizing mechanisms in naturally-assembled forest ecosystems at different spatial grains

Ecosystem stability reveals how ecosystems respond to global change over time. Yet, the focus of past research on small spatial grains and extents overlooks scale dependence and how broad-scale environmental gradients shape stability. Here, we use forest inventory data covering a broad latitudinal gradient from the temperate to the tropical zone to examine cross-scale variation in stability of aboveground biomass and underlying stabilizing mechanisms. While stability did not shift systematically with latitude at either spatial grain, we found evidence that species asynchrony increased towards the tropics at the small spatial grain while species stability decreased at both spatial grains. Moreover, latitude stabilized forest communities via its effects on both stabilizing mechanisms, which compensated for the weak and destabilizing effects of species richness. Yet, the trade-off in the relative importance of species stability and species asynchrony for stability was not mediated by latitude, suggesting that context-dependent factors - to a greater extent than macroecological ones - underlie large-scale patterns of stability. Our results highlight the crucial role of species asynchrony and species stability in determining ecosystem stability across broad-scale environmental gradients, suggesting that conserving biodiversity alone may not be sufficient for stabilizing naturally-assembled forest ecosystems.

ecology↗

bioRxiv2022

Mapping potential malaria vector larval habitats for larval source management: Introduction to multi-model ensembling approaches

Mosquito larval source management (LSM) is a viable supplement to the currently implemented first-line malaria control tools for use under certain conditions for malaria control and elimination. Implementation of larval source management requires a carefully designed strategy and effective planning. Identification and mapping of larval sources is a prerequisite. Ensemble modeling is increasingly used for prediction modeling, but it lacks standard procedures. We proposed a detailed framework to predict potential malaria vector larval habitats using ensemble modeling, which includes selection of models, ensembling method and predictors; evaluation of variable importance; prediction of potential larval habitats; and assessment of prediction uncertainty. The models were built and validated based on multi-site, multi-year field observations and climatic/environmental variables. Model performance was tested using independent multi-site, multi-year field observations. Overall, we found that the ensembled model predicted larval habitats with about 20% more accuracy than the average of the individual models ensembled. Key larval habitat predictors were elevation, geomorphon class, and precipitation 2 months prior. Mapped distributions of potential malaria vector larval habitats showed different prediction errors in different ecological settings. This is the first study to provide a detailed framework for the process of multi-model ensemble modeling. Mapping of potential habitats will be helpful in LSM planning. Authors summaryMosquito larval source management (LSM) is a viable supplement to the currently implemented first-line malaria control tools. Implementation of LSM requires a carefully designed strategy and effective planning. Identification and mapping of larval sources is a prerequisite. Ensemble modeling is increasingly used for prediction modeling, but it lacks standard procedures. We proposed a detailed framework for such a process, including selection of models, ensembling methods and predictors; evaluation of variable importance; and assessment of prediction uncertainty. We used predictions of potential malaria vector larval habitats as an example to demonstrate how the procedure works, specifically, we used multi-site multi-year field observations to build and validate the model, and model performance was further tested using independent multi-site multi-year field observations - this training-validation-testing is often missing from previous studies. The proposed ensemble modeling procedure provides a framework for similar biological studies.

ecology↗

bioRxiv2022

Kinetic and Structural Analysis of Ribonucleotide Extension by DNA Polymerase η

DNA polymerases catalyze DNA synthesis with high fidelity, which is essential for all life. Extensive kinetic and structural efforts have been executed in exploring mechanisms of DNA polymerases, surrounding their kinetic pathway, catalytic mechanisms, and factors that dictate polymerase fidelity. Recent time-resolved crystallography studies on DNA polymerase {eta} (Pol {eta}) and {beta} have revealed essential transient events during DNA synthesis reaction, such as mechanisms of primer deprotonation, separated roles of the three metal ions, and conformational changes that disfavor incorporation of the incorrect substrate. DNA-embedded ribonucleotides (rN) are the most common lesion on DNA and a major threat to genome integrity. While kinetics of rN incorporation has been explored and structural studies have revealed that DNA polymerases have a steric gate that destabilizes rNTP binding, mechanism of extension upon rN addition remains poorly characterized. Using steady-state kinetics, static and time-resolved X-ray crystallography with Pol {eta} as a model system, we showed that the extra hydroxyl group on the primer terminus does not reduce the catalytic efficiency of Pol {eta}. However, rN ended primers alter the dynamics of the polymerase active site as well as the catalysis and fidelity of DNA synthesis. During rN extension, Pol {eta} fidelity drops significantly across different sequence context. Systematic structural studies suggest that the rN at the primer end improved primer alignment and reduced barriers in C2-endo to C3-endo sugar conformation change. Our work provides important insights for rN extension and implicates a possible mechanism for rN removal.

biochemistry↗

bioRxiv2022

MAM-STAT3-induced upregulation of mitochondrial Ca+2 causes immunosenescence in patients with type A mandibuloacral dysplasia

Homozygous lamina/c p.R527C mutations result in severe mandibuloacral dysplasia (MAD) and progeroid syndrome, but the underlying molecular pathology remains unknown. Here, we report on three patients with MAD, all displaying severe systemic inflammaging and characterized the major molecular pathways involved in the manifestation of this disease. Analysis of induced pluripotent stem cell (IPSC)-derived mesenchymal stem cells (MAD-iMSCs) obtained from the patients revealed that increased mitochondrial Ca+2 loading was the root cause of lost mitochondrial membrane potential, abnormal fission/fusion and fragmentation, which then participated in inflammaging by inducing the inflammasome. These alterations in Ca+2 homeostasis were mediated by signal transducer and activator of transcription 3 (STAT3), which is located on the mitochondrial associated membrane (MAM). STAT3 function could be rescued by treatment with clinically-approved IL-6 blockers, or by correction of R527C mutations. In addition, extracellular vesicles (EVs) obtained from MAD-iMSCs displayed reduced immunomodulatory function, being unable to rescue bleomycin-induced lung fibrosis and triggering mitochondrial dysfunction, senescence, and fibrosis in healthy cells. Our results provide new insights into the pathology of complex lamin-associated MAD with systemic immunosenescence, and suggest that targeting defective mitochondrial Ca+2 homeostasis may represent a promising novel therapy for this condition.

cell biology↗

bioRxiv2022

Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps

Advances in cryo-electron microscopy (cryoEM) and deep-learning guided protein structure prediction have expedited structural studies of protein complexes. However, methods for accurately determining ligand conformations are lacking. In this manuscript, we develop a tool for automatically determining ligand structures guided by medium-resolution cryoEM density. We show this method is robust at predicting ligands in maps as low as 6[A] resolution, and is able to correct receptor sidechain errors. Combining this with a measure of placement confidence, and running on all protein/ligand structures in EMDB, we show that 58% of ligands replicate the deposited model, 16% confidently find alternate conformations, 22% have ambiguous density where multiple conformations might be present, and 4% are incorrectly placed. For five cases where our approach finds an alternate conformation with high confidence, high-resolution crystal structures validate our placement. This tool and the resulting analysis should prove critical in using cryoEM to investigate protein-ligand complexes.

biochemistry↗

bioRxiv2022

Oscillatory mechanisms of intrinsic brain networks

Neuroimaging studies of hemodynamic fluctuations have shown specific network-based organization of the brain at rest, yet the neurophysiological underpinning of these networks in human brain remain unclear. Here, we recorded resting-state activities of neuronal populations in the key regions of default mode network (DMN, posterior cingulate cortex and medial prefrontal cortex), frontoparietal network (FPN, dorsolateral prefrontal cortex and inferior parietal lobule), and salience network (SN, anterior insula and dorsal anterior cingulate cortex) from 42 human participants using intracranial electroencephalogram (iEEG). We observed stronger within-network connectivity of the DMN, FPN and SN in broadband iEEG power, stronger phase synchronization within the DMN across theta and alpha bands, and weaker phase synchronization within the FPN in delta, theta and alpha band. We also found positive power correlations in high frequency band (70-170Hz) and negative power correlations in alpha and beta band for FPN-DMN and FPN-SN. Robust negative correlations in DMN-SN were found in alpha, beta and gamma band. These findings provide intracranial electrophysiological evidence in support of the network model for intrinsic organization of human brain and shed light on the way how the brain networks communicate at rest.

neuroscience↗

bioRxiv2022

Micropatterned Organoids Enable Modeling of the Earliest Stages of Human Cardiac Vascularization

Although model organisms have provided insight into the earliest stages of cardiac vascularization, we know very little about this process in humans. Here we show that spatially micropatterned human pluripotent stem cells (hPSCs) enable in vitro modeling of this process, corresponding to the first three weeks of in vivo human development. Using four hPSC fluorescent reporter lines, we create cardiac vascular organoids (cVOs) by identifying conditions that simultaneously give rise to spatially organized and branched vascular networks within endocardial, myocardial, and epicardial cells. Using single-cell transcriptomics, we show that the cellular composition of cVOs resembles that of a 6.5 post-conception week (PCW) human heart. We find that NOTCH and BMP pathways are upregulated in cVOs, and their inhibition disrupts vascularization. Finally, using the same vascular-inducing factors to create cVOs, we produce hepatic vascular organoids (hVOs). This suggests there is a conserved developmental program for creating vasculature within different organ systems. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/499233v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17b265org.highwire.dtl.DTLVardef@1c1113eorg.highwire.dtl.DTLVardef@531c18org.highwire.dtl.DTLVardef@596bd2_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Flavivirus prM interacts with MDA5 and MAVS to inhibit RLR antiviral signaling

Vector-borne flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKA), West Nile virus (WNV), yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), pose a growing threat to public health worldwide, and have evolved complex mechanisms to overcome host antiviral innate immunity. However, the underlying mechanisms of flavivirus structural proteins to evade host immune response remain elusive. Here we show that TBEV structural proteins, including pre-membrane (prM), envelope, and capsid proteins, could inhibit type I interferon (IFN-I) production. Mechanically, TBEV prM interacted with both MDA5 and MAVS and interfered with the formation of MDA5-MAVS complex, thereby impeded the nuclear translocation and dimerization of IRF3 to inhibit RLR antiviral signaling. ZIKA and WNV prM was also demonstrated to interact with both MDA5 and MAVS, while dengue virus serotype 2 (DENV2) and YFV prM associated only with MDA5 or MAVS to suppress IFN-I production. In contrast, JEV prM could not suppress IFN-I production. Overexpression of TBEV and ZIKA prM significantly promoted the replication of Sendai virus. Our findings reveal the immune evasion mechanisms of flavivirus prM, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention and vaccine development. Author SummaryAll flaviviruses must overcome the antiviral innate immunity to infect vertebrate host. The non-structural proteins of flaviviruses are mainly responsible for viral replication and host innate immune escape, and the structural proteins are involved in the virus assembly, which are potential targets for prevention and treatment of flaviviral infections. Whether flavivirus structural proteins participate in host innate immune escape remains to be determined. Here, we found that tick-borne encephalitis virus structural proteins precursor membrane (prM), capsid, and envelope proteins can antagonize type I interferon production, in which prM interacts with both MDA5 and MAVS to inhibit RLR antiviral signaling. Additionally, Zika virus and West Nile virus prMs also interact with both MDA5 and MAVS, while dengue virus serotype 2 and yellow fever virus prMs associate only with MDA5 or MAVS to suppress type I interferon production. In contrast, Japanese encephalitis virus prM cannot antagonize type I interferon production. Our findings reveal that flavivirus prM inhibits type I interferon production via interacting with MDA5 and/or MAVS in a species-dependent manner, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention, and vaccine development.

microbiology↗

bioRxiv2022

OTTERS: A powerful TWAS framework leveraging summary-level reference data

Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.

genetics↗

bioRxiv2022

Sex-specific transcription and DNA methylation landscapes of the Asian citrus psyllid, a vector of huanglongbing pathogens.

The relationship of DNA methylation and sex-biased gene expression is of high interest, it allows research into mechanisms of sexual dimorphism and the development of potential novel strategies for insect pest control. The Asian citrus psyllid, Diaphorina citri Kuwayama, is a major vector for the causative agents of Huanglongbing (HLB), which presents an unparalleled challenge to citrus production worldwide. Here, we identify the X chromosome of D. citri and investigate differences in the transcription and DNA methylation landscapes between adult virgin males and females. We find a large number of male-biased genes on the autosomes and a depletion of such on the X chromosome. We have also characterised the methylome of D. citri, finding low genome-wide levels, which is unusual for an hemipteran species, as well as evidence for both promoter and TE methylation. Overall, DNA methylation profiles are similar between the sexes but with a small number of differentially methylated genes found to be involved in sex differentiation. There also appears to be no direct relationship between differential DNA methylation and differential gene expression. Our findings lay the groundwork for the development of novel epigenetic-based pest control methods, and given the similarity of the D. citri methylome to other insect species, these methods could be applicable across agricultural insect pests.

evolutionary biology↗

bioRxiv2022

Comparative analysis of cattle breeds as satellite cells donors for cultured beef

BackgroundCultured meat is a promising new field with the potential for considerable environmental and animal welfare benefits. One technological approach to cultured meat production utilises the proliferative and differentiative capacity of muscle-derived satellite cells (SCs) to produce large volumes of cultured muscle tissue from small biopsies of donor animals. Differing genotypes between cattle breeds lead to predictable phenotypic traits, resulting in breeds being favoured for their respective meat or milk production characteristics in the livestock industry. However, whilst these breeds show significant differences in muscle growth, it is unclear whether the physiological differences observed between them in vivo are reflected in differences in SC behaviour in vitro, particularly with respect to proliferation, differentiation and cellular longevity, and hence whether particular breeds might represent preferred SC donors for a cultured beef bioprocess. ResultsComparing SCs isolated from five breeds (Belgian Blue, Holstein Friesian, Galloway, Limousin and Simmental), we found that the proliferation rates were largely unaffected by the donor breed. In contrast, potentially meaningful differences were observed in the kinetics and extent of myogenic differentiation. Furthermore, whilst differentiation dropped for all breeds with increasing population doublings (PDs), SCs from Belgian Blue and Limousin cattle showed significantly longer retention of differentiation capacity over long-term passaging. ConclusionSCs from all breeds were able to proliferate and differentiate, although Limousin and (particularly) Belgian Blue cattle, both breeds commonly used for traditional meat production, may represent preferred donors for cultured beef production.

cell biology↗

bioRxiv2021

Effect of gastrointestinal alterations mimicking elderly conditions on in vitro digestion of meat and soy proteins

We evaluated the digestion of meat (chicken, beef, and pork) and soy proteins under in vitro conditions mimicking gastrointestinal (GI) conditions of adults (control, C) and elderly with achlorhydria (EA). The changes in degree of hydrolysis (DH), SDS-PAGE profiles, peptide concentration, and proteomics profiles during the digestion process were investigated. Digestion under the EA condition markedly decreased the DH of all protein sources, especially for soy protein. SDS-PAGE profiling and proteomics showed that myofibrillar/sarcoplasmic protein from meat and glycinin/beta-conglycinin from soy were the proteins most affected by the different digestive conditions. Our results indicated that the difference in the digestibility of meat protein between EA and control conditions gradually narrowed from the gastric to the intestinal phase, while a pronounced difference between control and EA conditions was maintained also in the intestinal phase. This work provides new insights of value for future dietary recommendations for elderly individuals.

biochemistry↗

bioRxiv2021

Causal Haplotype Block Identification in Plant Genome-Wide Association Studies

Genome wide association studies (GWAS) can play an essential role in understanding genetic basis of complex traits in plants and animals. Conventional SNP-based linear mixed models (LMM) used in many GWAS that marginally test single nucleotide polymorphisms (SNPs) have successfully identified many loci with major and minor effects. In plants, the relatively small population size in GWAS and the high genetic diversity found many plant species can impede mapping efforts on complex traits. Here we present a novel haplotype-based trait fine-mapping framework, HapFM, to supplement current GWAS methods. HapFM uses genotype data to partition the genome into haplotype blocks, identifies haplotype clusters within each block, and then performs genome-wide haplotype fine-mapping to infer the causal haplotype blocks of trait. We benchmarked HapFM, GEMMA, BSLMM, and GMMAT in both simulation and real plant GWAS datasets. HapFM consistently resulted in higher mapping power than the other GWAS methods in simulations with high polygenicity. Moreover, it resulted in higher mapping resolution, especially in regions of high LD, by identifying small causal blocks in the larger haplotype block. In the Arabidopsis flowering time (FT10) datasets, HapFM identified four novel loci compared to GEMMAs results, and its average mapping interval of HapFM was 9.6 times smaller than that of GEMMA. In conclusion, HapFM is tailored for plant GWAS to result in high mapping power on complex traits and improved mapping resolution to facilitate crop improvement.

bioinformatics↗

bioRxiv2021

Emerging mosquito resistance to piperonyl butoxide-synergized pyrethroid insecticide and its mechanism

Piperonyl butoxide (PBO)-synergized pyrethroid products are widely available for the control of pyrethroid-resistant mosquitoes. To date, no study has formally examined mosquito resistance to PBO-synergized insecticides. We used Culex quinquefasciatus as a model mosquito examined the insecticide resistance mechanisms of mosquitoes to PBO-synergized pyrethroid using modified World Health Organization tube bioassays and biochemical analysis of metabolic enzyme expressions prior- and post-PBO exposure. We measured mosquito mortalities and metabolic enzyme expressions in mosquitoes with/without pre-exposure to different PBO concentrations and exposure durations. We found that field Culex quinquefasciatus mosquitoes were resistant to all insecticides tested, including PBO-synergized pyrethroids (mortality ranged from 3.7{+/-}4.7% to 66.7{+/-}7.7%), except malathion. Field mosquitoes had elevated levels of carboxylesterase (COE, 3.8-fold) and monooxygenase (P450, 2.1-fold) but not glutathione S-transferase (GST) compared to susceptible mosquitoes. When the field mosquitoes were pre-exposed to 4% PBO, the 50% lethal concentration of deltamethrin was reduced from 0.22% to 0.10%, compare to 0.02% for susceptible mosquitoes. Knockdown resistance gene mutation (L1014F) rate was 62% in field mosquitoes. PBO pre-exposure suppressed P450 enzyme expression levels by 25[~]34%, GST by 11%, and had no impact on COE enzyme expression. Even with the optimal PBO concentration and exposure duration, field mosquitoes had significantly higher P450 enzyme expression levels after PBO exposure compared to laboratory controls. These results demonstrate that PBO alone may not be enough to control highly pyrethroid resistant mosquitoes due to the multiple resistance mechanisms. Mosquito resistance to PBO-synergized insecticide should be closely monitored. Authors SummaryMosquitoes are vectors of many major infectious diseases globally. Insecticides and related products are widely used for mosquito controls and disease preventions. Over time and following repeated use, mosquitoes (including Aedes, Anopheles and Culex) have developed very high resistance to multiple insecticides all over the world. Target site insensitivity due to mutations in the voltage-gated sodium channel gene and overproduction of metabolic detoxification enzymes such as cytochrome P450 (CYP) monooxygenases play critical role in insecticide resistance in mosquitoes. To enhance the killing power of insecticides, synergized insecticides were developed by mixing insecticide synergists with pyrethroids. Discovered in the 1940s, piperonyl butoxide (PBO) is one of the earliest and most commonly used insecticide synergists. Field application of PBO-synergized insecticides performed far better than mono-pyrethroids. PBO-treated long-lasting insecticidal nets (PBO-LLINs), which also use pyrethroids, outperformed regular LLIN for malaria control in many African countries. PBO-LLIN is soon to be rolled out on a large scale for malaria control in Africa. One important question regarding the use of synergized insecticides is whether they will select for vector population resistance to synergized insecticide products, in other words, are PBO-synergized pyrethroids effective against highly insecticide-resistant mosquitoes? To date, no study has formally examined mosquito resistance to PBO-synergized insecticides. Here, we used Culex quinquefasciatus as a model mosquito, we examined its resistance status to different insecticides including PBO-synergized pyrethrins and tested how PBO exposure affect mosquito mortality and the expressions of metabolic enzymes. We found that field Culex quinquefasciatus mosquitoes were resistant to multiple insecticides tested, including PBO-synergized pyrethroids. Field mosquitoes had elevated levels of carboxylesterase (COE) and monooxygenase (P450) but not glutathione S-transferase (GST) enzyme expressions compared to susceptible mosquitoes. Even with optimal PBO concentration and exposure duration, field mosquitoes had significantly higher P450 enzyme expression levels after PBO exposure compared to laboratory controls, and PBO exposure had no impact on COE enzyme expressions. The phenomena of the insecticide-resistant mosquitoes insensitivity to PBO exposure or PBO-synergized insecticides and multiple-resistance mechanisms have also been reported from Aedes and Anopheles mosquitoes in different countries. These results demonstrate that PBO alone is not enough to control highly pyrethroid resistant mosquitoes due to multiple resistance mechanisms. Mosquito resistance to PBO-synergized insecticide should be closely monitored

ecology↗

bioRxiv2021

Larval ecology and bionomics of Anopheles funestus in highland and lowland sites in western Kenya

BackgroundAn. funestus is a major Afrotropical vector of human malaria. This study sought to investigate the larval ecology, sporozoite infection rates and blood meal sources of An. funestus in western Kenya. MethodsLarval surveys were carried out in Bungoma (Highland) and Kombewa (lowland) of western Kenya. Aquatic habitats were identified, characterized, georeferenced and carefully examined for mosquito larvae and predators. Indoor resting mosquitoes were sampled using pyrethrum spray catches. Adults and larvae were morphologically and molecularly identified to species. Sporozoite infections and blood meal sources were detected using real-time PCR and ELISA respectively. ResultsOf the 151 aquatic habitats assessed, 62/80 (78%) in Bungoma and 58/71(82%) in Kombewa were positive for mosquito larvae. Of the 3,193 larvae sampled, An. funestus larvae constitute 38% (1224/3193). Bungoma recorded a higher number of An. funestus larvae (85%, 95%, CI, 8.722-17.15) than Kombewa (15%, 95%, CI, 1.33-3.91). Molecular identification of larvae showed that 89% (n=80) were An. funestus. Approximately 59%, 35% and 5% of An. funestus larvae co-existed with An. gambiae s.l, Culex spp and An. coustani in the same habitats respectively. Of 1,221 An. funestus s.l adults sampled, molecular identifications revealed that An. funestus constituted 87% (n=201) and 88% (n=179) in Bungoma and Kombewa, respectively. The Plasmodium falciparum sporozoite rate of An. funestus in Bungoma and Kombewa was 2% (3/174) and 1% (2/157), respectively, and the human blood index of An. funestus was 84% (48/57) and 89% (39/44) and for Bungoma and Kombewa, respectively. ConclusionMan-made ponds had the highest abundance of An. funestus larvae. Multiple regression and principal component analyses identified the distance to the nearest house as the key environmental factor associated with the abundance of An. funestus larvae in aquatic habitats. This study serves as a guide for the control of An. funestus and other mosquito species to complement existing vector control strategies.

ecology↗

bioRxiv2021

Effects of Guangzhou seasonal climate change on the development of Aedes albopictus and its susceptibility to DENV-2

The susceptibility of Asian tiger mosquitoes to DENV-2 in different seasons was observed in simulated field environments as a reference to design dengue fever control strategies in Guangzhou. The life table experiments of mosquitoes in four seasons were carried out in the field. The susceptibility of Ae. albopictus to dengue virus was observed in both environments in Guangzhou in summer and winter. Ae. albopictus was infected with dengue virus by oral feeding. On day 7 and 14 after infection, the viral load in the head, ovary, and midgut of the mosquito was detected using real-time fluorescent quantitative PCR. Immune-associated gene expression in infected mosquitoes was performed using quantitative real-time reverse transcriptase PCR. The hatching rate and pupation rate of Ae. albopictus larvae in different seasons differed significantly. The winter hatching rate of larvae was lower than that in summer, and the incubation time was longer than in summer. In the winter field environment, Ae. albopictus still underwent basic growth and development processes. Mosquitoes in the simulated field environment were more susceptible to DENV-2 than those in the simulated laboratory environment. In the midgut, viral RNA levels on day 7 in summer were higher than those on day 7 in winter (F = 14.459, P = 0.01); ovarian viral RNA levels on day 7 in summer were higher than those on day 7 in winter (F = 8.656, P < 0.001), but there was no significant difference in the viral load at other time points (P > 0.05). Dicer-2 mRNA expression on day 7 in winter was 4.071 times than that on day 7 in summer: the viral load and Dicer-2 expression correlated moderately. Ae. albopictus could still develop and transmit dengue virus in winter in Guangzhou. Mosquitoes under simulated field conditions were more susceptible to DENV-2 than those under simulated laboratory conditions. Author summaryAe. albopictus is the only vector of dengue fever in Guangzhou. Observational data of Ae. albopictus development under natural conditions is important for monitoring vector population expansion, dengue virus transmission, and disease outbreak prevention. We found that Ae. albopictus could still develop in winter in Guangzhou. In addition, the viral load of mosquitoes in the simulated winter environment was lower than that in summer on the 7th day after infection; however, the difference in the viral load of mosquitoes in winter and summer on the 14th day after infection was not statistically significant. Mosquitoes in simulated field conditions were more susceptible to DENV-2 than those in simulated laboratory conditions. The results suggested that Ae. albopictus retains the ability to transmit dengue virus in winter in Guangzhou, and that improved dengue epidemic prevention and control measures are required. The findings of this study represent an important reference for the design of dengue fever control strategies in Guangzhou in response to global climate change.

ecology↗

bioRxiv2021

Tumor PD-L1 selectively suppresses type I interferon in myeloid cells to suppress CTL recruitment to promote lung metastasis

The mechanism underlying tumor cell PD-L1 (tPD-L1) induction of immune suppression through T cell PD-1 is well-known, but the mechanism underlying tPD-L1 induction of immune suppression via an intermediate cell is incompletely understood. We report here that tPD-L1 does not suppress cytotoxic T lymphocyte (CTL) activation and lytic function when only tumor cells and CTLs are present. Strikingly, knocking out PD-L1 in tumor cells has no effect on primary tumor growth, but significantly decreases lung metastasis in a CTL-dependent manner. Depletion of myeloid cells impaired tPD-L1 promotion of lung metastasis. Single-cell RNA sequencing revealed that tPD-L1 engages myeloid PD-1 (mPD-1) to antagonize type I interferon (IFN-I) and STAT1 signaling to repress Cxcl9 and Cxcl10 expression to impair CTL recruitment to lung metastases. Human patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. Our data determines that the tPD-L1/mPD-1/IFN-I/STAT1/Cxcl9/10 axis controls CTL tumor infiltration in lung metastasis.

cancer biology↗

bioRxiv2021

RegVar: Tissue-specific Prioritization of Noncoding Regulatory Variants

Noncoding genomic variants constitute the majority of trait-associated genome variations; however, identification of functional noncoding variants is still a challenge in human genetics, and a method systematically assessing the impact of regulatory variants on gene expression and linking them to potential target genes is still lacking. Here we introduce a deep neural network (DNN)-based computational framework, RegVar, that can accurately predict the tissue-specific impact of noncoding regulatory variants on target genes. We show that, by robustly learning the genomic characteristics of massive variant-gene expression associations in a variety of human tissues, RegVar vastly surpasses all current noncoding variants prioritization methods in predicting regulatory variants under different circumstances. The unique features of RegVar make it an excellent framework for assessing the regulatory impact of any variant on its putative target genes in a variety of tissues. RegVar is available as a webserver at http://regvar.cbportal.org/.

bioinformatics↗