Biology subjects

Yan, G.

Publications and source records attributed to Yan, G..

At least 55 records · Page 3Linked to original sources

bioRxiv2021

NAc-DBS corrects depression-like behaviors in CUMS mouse model via disinhibition of DA neurons in the VTA

Major depressive disorder (MDD) is characterized by diverse debilitating symptoms that include loss of motivation and anhedonia. If multiple medications, psychotherapy, and electroconvulsive therapy fail in some patients with MDD, their condition is then termed treatment - resistant depression (TRD). MDD can be associated with abnormalities in the reward-system-dopaminergic mesolimbic pathway, in which the nucleus accumbens (NAc) and ventral tegmental area (VTA) play major roles. Deep brain stimulation (DBS) applied to the NAc alleviates the depressive symptoms of MDD. However, the mechanism underlying the effects of this DBS has remained elusive. In this study, using the chronic unpredictable mild stress (CUMS) mouse model, we investigated the behavioral and neurobiological effects of NAc - DBS on the multidimensional depression - like phenotypes induced by CUMS by integrating behavioral, in vivo microdialysis coupled with high-performance liquid chromatography - electrochemical detector (HPLC - ECD), calcium imaging, pharmacological, and genetic manipulation methods in freely moving mice. We found that long-term and repeated, but not single, NAc-DBS induced robust antidepressant responses in CUMS mice. Moreover, even a single trial NAc-DBS led to the elevation of the {gamma}-aminobutyric acid (GABA) neurotransmitter, accompanied by the increase in dopamine (DA) neuron activity in the VTA. Both the inhibition of the GABAA receptor activity and knockdown of the GABAA-1 gene in VTA-GABA neurons blocked the antidepressant effect of NAc-DBS in CUMS mice. Our results showed that NAc- DBS could disinhibit VTA-DA neurons by regulating the level of GABA and the activity of VTA-GABA in the VTA and could finally correct the depression-like behaviors in the CUMS mouse model.

neuroscience↗

bioRxiv2021

pGlycoQuant with a deep residual network for precise and minuscule-missing-value quantitative glycoproteomics enabling the functional exploration of site-specific glycosylation

Interpreting large-scale glycoproteomic data for intact glycopeptide identification has been tremendously advanced by software tools. However, software tools for quantitative analysis of intact glycopeptides remain lagging behind, which greatly hinders exploring the differential expression and functions of site-specific glycosylation in organisms. Here, we report pGlycoQuant, a generic software tool for accurate and convenient quantitative intact glycopeptide analysis, supporting both primary and tandem mass spectrometry quantitation for multiple quantitative strategies. pGlycoQuant enables intact glycopeptide quantitation with very low missing values via a deep residual network, thus greatly expanding the quantitative function of several powerful search engines, currently including pGlyco 2.0, pGlyco3, Byonic and MSFragger-Glyco. The pGlycoQuant-based site-specific N-glycoproteomic study conducted here quantifies 6435 intact N-glycopeptides in three hepatocellular carcinoma cell lines with different metastatic potentials and, together with in vitro molecular biology experiments, illustrates core fucosylation at site 979 of the L1 cell adhesion molecule (L1CAM) as a potential regulator of HCC metastasis. pGlycoQuant is freely available at https://github.com/expellir-arma/pGlycoQuant/releases/. We have demonstrated pGlycoQuant to be a powerful tool for the quantitative analysis of site-specific glycosylation and the exploration of potential glycosylation-related biomarker candidates, and we expect further applications in glycoproteomic studies.

systems biology↗

bioRxiv2021

A bacterial Argonaute with efficient DNA and RNA cleavage activity guided by small DNA and RNA

Argonaute proteins are widespread in prokaryotes and eukaryotes. Most prokaryotic Argonaute proteins (pAgos) use 5P-gDNA to target complementary DNA. However, more and more studies on the properties of pAgos make their functions more diversified. Previously reported pAgos only possess several forms of high activity in all eight cleavage patterns, which limits their practical applications. Here, we described a unique pAgo from Marinitoga hydrogenitolerans (MhAgo) with eight cleavage activities. MhAgo can utilize all four types of guides (5OH-gDNA, 5P-gDNA, 5OH-gRNA, and 5P-gRNA) for ssDNA and RNA cleavage. Further studies demonstrated that MhAgo had high activities with 16-21 nt guides and no obvious preferences for the 5-end nucleotides of 5OH-guides. Unexpectedly, MhAgo had different preferences for the 5-end nucleotides of 5P-guides depending on the types of targets. Although the specificity of MhAgo was related to the types of guides, single mismatches in the central and 3-supplementary regions of guides greatly reduced the cleavage efficiency. Additionally, the electrophoretic mobility shift assay (EMSA) demonstrated MhAgo had the weakest affinity for 5P-gRNA:tRNA duplex, which was consistent with its cleavage efficiency. In conclusion, MhAgo is highly active under a wide range of conditions and can be used for programmable endonucleolytic cleavage of both ssDNA and RNA substrates. The abundant biochemical characteristics of MhAgo broaden our understanding of pAgos and expand the potential application in nucleic acids manipulations.

molecular biology↗

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

THESEUS1 modulates cell wall stiffness and abscisic acid production in Arabidopsis thaliana

Plant cells can be distinguished from animal cells by their cell walls and high turgor pressure. Although changes in turgor and stiffness of cell walls seem coordinated, we know little about the mechanism responsible for coordination. Evidence has accumulated that plants, like yeast, have a dedicated cell wall integrity maintenance mechanism. This mechanism monitors the functional integrity of the wall and maintains it through adaptive responses when cell wall damage occurs during growth, development, and interactions with the environment. The adaptive responses include osmo-sensitive-induction of phytohormone production, defence responses as well as changes in cell wall composition and structure. Here, we investigate how the cell wall integrity maintenance mechanism coordinates changes in cell wall stiffness and turgor in Arabidopsis thaliana. We show that the production of abscisic acid (ABA), the phytohormone modulating turgor pressure and responses to drought, depends on the presence of a functional cell wall. We find that the cell wall integrity sensor THESEUS1 modulates mechanical properties of walls, turgor loss point and ABA biosynthesis. We identify RECEPTOR-LIKE PROTEIN 12 as a new component of cell wall integrity maintenance controlling cell wall damage-induced jasmonic acid production. Based on the results we propose that THE1 is responsible for coordinating changes in turgor pressure and cell wall stiffness. Significance statementPlants need to constantly adapt to a changing environment. This includes responses to biotic and abiotic stress. Key elements influencing the response to abiotic stress are the plant cell walls surrounding all cells and the phytohormone abscisic acid, which influences turgor pressure in plants. Turgor pressure in plant cells is much higher than in animal cells and a key driver of plant growth and development. Here we investigate the mechanism regulating cell wall stiffness and coordinating changes in stiffness and turgor. We characterize key elements of the mechanism and dissect its mode of action. This knowledge will enable us to pursue novel approaches to improve plant resistance to drought stress, which is crucial in a rapidly changing environment.

plant biology↗

bioRxiv2021

Targeting Adaptation to Cancer Treatment by Drug Combinations

Adaptation of tumors to therapeutic interventions contributes to dismal long-term patient outcomes. Adaptation to therapy involves co-action of functionally related proteins that together activate cell survival programs and compensate for the therapeutic impact. Oncogenic dependencies to such adaptive events, however, can generate new therapeutic vulnerabilities that can be targeted with drug combinations. The precision medicine approaches in which targeted drugs are matched to pre-existing genomic aberrations fail to address the adaptive responses and resulting vulnerabilities. Here, we provide the mathematical formulation, implementation and validation of the TargetScore method. The TargetScore identifies collective adaptive responses to targeted interventions as concurrent changes of phospho-proteins that are connected within a signaling network. Based on the adaptive responses, the method predicts drug-induced vulnerabilities. Using TargetScore, we inferred the adaptive responses with short-term (i.e., days) stress and long-term (i.e., months) acquired resistance to inhibitors of anti-apoptotic mediators, MCL1 and BCL2. With experiments guided by the predictions, we identified synergistic interactions between inhibitors of PARP, SHP2, and MCL1 in breast cancer cells. TargetScore is readily applicable to existing precision oncology efforts by matching targeted drug combinations to emerging molecular signatures under therapeutic stress.

systems biology↗

bioRxiv2021

GproDIA enables data-independent acquisition glycoproteomics with comprehensive statistical control

Large-scale profiling of intact glycopeptides is critical but challenging in glycoproteomics. Data independent acquisition (DIA) is an emerging technology with deep proteome coverage and accurate quantitative capability in proteomics studies, but is still in the early stage of development in the field of glycoproteomics. We propose GproDIA, a framework for the proteome-wide characterization of intact glycopeptides from DIA data with comprehensive statistical control by a 2-dimentional false discovery rate approach and a glycoform inference algorithm, enabling accurate identification of intact glycopeptides using wide isolation windows. We further adapt a semi-empirical spectrum prediction strategy to expand the coverage of spectral libraries of glycopeptides. We benchmark our method for N-glycopeptide profiling on DIA data of yeast and human serum samples, demonstrating that DIA with GproDIA outperforms the data dependent acquisition (DDA) based methods for glycoproteomics in terms of capacity and data completeness of identification, as well as accuracy and precision of quantification. We expect that this work can provide a powerful tool for glycoproteomic studies.

bioinformatics↗

bioRxiv2021

IHRW: An Improved Hypergraph Random Walk Model for Predicting Three-Drug Therapy

Drug combination therapy is a well-established concept in the treatment of complex diseases due to its fewer side effects, lower toxicity, and better efficacy. However, it is challenging to identify efficacious drug combinations from many drug candidates. Computational models could greatly reduce the cost, but most models did not use data for more than two-drug combinations and could not predict three-drug therapy. However, three-drug combinations account for about 21% of the known combinations, which is a very important type of treatment. Here, we utilized higher-order information and developed an improved hypergraph random walk model (IHRW) for three-drug therapy prediction. This is the first method to explore the combination of three drugs. As a result, the case studies of breast cancer, lung cancer, and colon cancer showed that IHRW had a powerful ability to predict potential efficacious three-drug combinations, which provides new prospects for complex disease treatment. The code of IHRW is freely available at https://github.com/wangqi27/IHRW.

bioinformatics↗

bioRxiv2021

Data-driven analysis of COVID-19 reveals specific severity patterns distinct from the temporal immune response

Key immune signatures of SARS-CoV-2 infection may associate with either adverse immune reactions (severity) or simply an ongoing anti-viral response (temporality); how immune signatures contribute to severe manifestations and/or temporal progression of disease and whether longer disease duration correlates with severity remain unknown. Patient blood was comprehensively immunophenotyped via mass cytometry and multiplex cytokine arrays, leading to the identification of 327 basic subsets that were further stratified into more than 5000 immunotypes and correlated with 28 plasma cytokines. Low-density neutrophil abundance was closely correlated with hepatocyte growth factor levels, which in turn correlated with disease severity. Deep analysis also revealed additional players, namely conventional type 2 dendritic cells, natural killer T cells, plasmablasts and CD16+ monocytes, that can influence COVID-19 severity independent of temporal progression. Herein, we provide interactive network analysis and data visualization tools to facilitate data mining and hypothesis generation for elucidating COVID-19 pathogenesis.

immunology↗

bioRxiv2021

Comparative genomics of Chinese and international isolates of Escherichia albertii: population structure and evolution of virulence and antimicrobial resistance

Escherichia albertii is a newly recognized species in the genus Escherichia that causes diarrhea. The population structure, genetic diversity and genomic features has not been fully examined. Here, 169 E. albertii isolates from different sources and regions in China were sequenced and combined with 312 publicly available genomes for phylogenetic and genomic analyses. The E. albertii population was divided into 2 clades and 8 lineages, with lineage 3 (L3), L5 and L8 more common in China. Clinical isolates were observed in all clades/lineages. Virulence genes were found to be distributed differently among lineages: subtypes of the intimin encoding gene eae and the cytolethal distending toxin (Cdt) gene cdtB were lineage associated, the second type three secretion system (ETT2) island was truncated in L3 and L6. Seven new eae subtypes and 1 new cdtB subtype (cdtB-VI) were found. Alarmingly, 85.9% of the Chinese E. albertii isolates were predicted to be multidrug resistant (MDR) with 35.9% harboured genes capable of conferring resistance to 10 to 14 different drug classes. By in silico multi-locus sequence typing, majority of the MDR isolates belonged to 4 STs (ST4638, ST4479, ST4633 and ST4488). Thirty-four intact plasmids carrying MDR and virulence genes, and 130 intact prophages were identified from 17 complete E. albertii genomes. Ten plasmid replicon types were found to be significantly associated with MDR. The 130 intact prophages were clustered into 5 groups, with group 5 prophages harbouring more virulence genes. Our findings provided fundamental insights into the population structure, virulence variation and MDR of E. albertii. Impact statementE. albertii is newly recognized foodborne pathogen causing diarrhea. Elucidation of its genomic features is important for surveillance and control of E. albertii infections. In this work, 169 E. albertii genomes from difference sources and regions in China were collected and sequenced, which contributed to the currently limited genomic data pool of E. albertii. In combination with 312 publicly available genomes from 14 additional countries, the population structure of E. albertii was defined. The presence and subtypes of virulence genes in different lineages were significantly different, indicating potential pathogenicity variation. Additionally, the presence of multidrug resistance (MDR) genes was alarmingly high in the Chinese dominated lineages. MDR associated STs and plasmid subtypes were identified, which could be used as sentinels for MDR surveillance. Moreover, the subtypes of plasmids and prophages were distributed differently across lineages, and were found to contribute to the acquisition of virulence and MDR genes of E. albertii. Altogether, this work reveals the diversity of E. albertii and characterized its genomic features in unprecedented detail. Data SummaryAll newly sequenced data in this work were deposited in National Center for Biotechnology Information (NCBI) under the BioProject of PRJNA693666, including 6 complete genomes and raw reads of 164 E. albertii isolates.

genomics↗

bioRxiv2020

HRWR: Predicting Potential Efficacious Drug Combination Based on Hypergraph Random Walk with Restart

Some studies have shown that efficacious drug combination can increase the therapeutic effect, and decrease drug toxicity and side-effects. Thus, drug combinations have been widely used in the treatment of complex diseases, especially cancer. However, experiment-based methods are extremely costly in time and money. Computational models can greatly reduce the cost, but most of the models do not use the data of more than two drugs and lose a lot of useful information. Here, we used high-order drug combination information and developed a hypergraph random walk with restart model (HRWR) for efficacious drug combination prediction. As a result, compared with the other methods by leave-one-out cross-validation (LOOCV), the Area Under Receiver Operating Characteristic Curve (AUROC) of the HRWR algorithm were higher than others. Moreover, the case studies of lung cancer, breast cancer, and colorectal cancer showed that HRWR had a powerful ability to predict potential efficacious combinations, which provides new prospects for cancer treatment. The code and dataset of HRWR are freely available at https://github.com/wangqi27/HRWR.

bioinformatics↗

bioRxiv2020

Predicting Brain Regions Related to Alzheimer's Disease Based on Global Feature

Alzheimers disease (AD) is a common neurodegenerative disease in the elderly, early diagnosis and timely treatment are very important to delay the course of the disease. In the past, most of the brain regions related to AD were identified based on the imaging method, which can only identify some atrophic brain regions. In this work, we used mathematical models to find out the potential brain regions related to AD. First, diffusion tensor imaging (DTI) was used to construct the brain structural network. Next, we set a new local feature index 2hop-connectivity to measure the correlation among different areas. The 2hop-connectivity utilizes the higher-order information of the graph structure relative to the traditional graph theory metrics. And for this, we proposed a novel algorithm named 2hopRWR to measure 2hop-connectivity. At last, we proposed a new index GFS (Global Feature Score) based on a global feature by combing 5 local features: degree centrality, betweenness centrality, closeness centrality, the number of maximal cliques, and 2hop-connectivity, to judge which brain regions are likely related to Alzheimers Disease. As a result, all the top ten brain regions in the GFS scoring difference between the AD group and the non-AD group were related to AD by literature verification. Literature validation results comparing GFS with local features showed that GFS outperforms individual local features. Finally, the results of the canonical correlation analysis showed that the GFS was significantly correlated with the scores of the mini-mental state examination (MMSE) scale and the Montreal cognitive assessment (MoCA) scale. So, we believe the GFS can also be used as a new index to assist in diagnosis and objective monitoring of disease progression. Besides, the method proposed in this paper can be used as a differential network analysis method in other areas of network analysis.

neuroscience↗

bioRxiv2020

An improved comprehensive strategy for deep and quantitative N-glycomics based on optimization of sample preparation, isotope-based data quality control and quantification, new N-glycan libraries and new algorithms

Withdrawal statement"The authors have withdrawn their manuscript because the authors need to re-organize the data and writing, meanwhile more experimental evidence from human cellular N-glycome will be added to support their viewpoints. In this preprint, only one human cell line, Acute Promyelocytic Leukemia (APL) cells, was deeply investigated to show the N-glycome landscape. To provide the shared features of human N-glycome, more human cells should be investigated. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author."

biochemistry↗

bioRxiv2020

Insecticide resistance status of indoor and outdoor resting malaria vectors in a highland and lowland site in Western Kenya

BackgroundLong Lasting Insecticidal Nets (LLINs) and indoor residual spraying (IRS) represent powerful tools for controlling malaria vectors in sub-Saharan Africa. The success of these interventions relies on their capability to inhibit indoor feeding and resting of malaria mosquitoes. This study sought to understand the interaction of insecticide resistance with indoor and outdoor resting behavioral responses of malaria vectors from Western Kenya. MethodsThe status of insecticide resistance among indoor and outdoor resting anopheline mosquitoes was compared in Anopheles mosquitoes collected from Kisumu and Bungoma counties in Western Kenya. The level and intensity of resistance were measured using WHO-tube and CDC-bottle bioassays, respectively. The synergist piperonyl butoxide (PBO) was used to determine if metabolic activity (monooxygenase enzymes) explained the resistance observed. The mutations at the voltage-gated sodium channel (Vgsc) gene and Ace 1 gene were characterized using PCR methods. Microplate assays were used to measure levels of detoxification enzymes if present. ResultsA total of 1094 samples were discriminated within Anopheles gambiae s.l. and 289 within An. funestus s.l. In Kisian (Kisumu county), the dominant species was Anopheles arabiensis 75.2% (391/520) while in Kimaeti (Bungoma county) collections the dominant sibling species was Anopheles gambiae s.s 96.5% (554/574). The An. funestus s.l samples analysed were all An. funestus s.s from both sites. Pyrethroid resistance of An.gambiae s.l F1 progeny was observed in all sites. Lower mortality was observed against deltamethrin for the progeny of indoor resting mosquitoes compared to outdoor resting mosquitoes (Mortality rate: 37% vs 51%, P=0.044). The intensity assays showed moderate-intensity resistance to deltamethrin in the progeny of mosquitoes collected from indoors and outdoors in both study sites. In Kisian, the frequency of vgsc-L1014S and vgsc-L1014F mutation was 0.14 and 0.19 respectively in indoor resting malaria mosquitoes while those of the outdoor resting mosquitoes were 0.12 and 0.12 respectively. The ace 1 mutation was present in higher frequency in the F1 of mosquitoes resting indoors (0.23) compared to those of mosquitoes resting outdoors (0.12). In Kimaeti, the frequencies of vgsc-L1014S and vgsc-L1014F were 0.75 and 0.05 respectively for the F1 of mosquitoes collected indoors whereas those of outdoor resting ones were 0.67 and 0.03 respectively. The ace 1 G119S mutation was present in progeny of mosquitoes from Kimaeti resting indoors (0.05) whereas it was absent in those resting outdoors. Monooxygenase activity was elevated by 1.83 folds in Kisian and by 1.33 folds in Kimaeti for mosquitoes resting indoors than those resting outdoors respectively. ConclusionThe study recorded high phenotypic, metabolic and genotypic insecticide resistance in indoor resting populations of malaria vectors compared to their outdoor resting counterparts. The indication of moderate resistance intensity for the indoor resting mosquitoes is alarming as it could have an operational impact on the efficacy of the existing pyrethroid based vector control tools. The use of synergist (PBO) in LLINs may be a better alternative for widespread use in these regions recording high insecticide resistance.

zoology↗

bioRxiv2020

ERWR: Predicting Efficacious Drug Combinations in Cancer Based on Random Walk with Restart

(1) BackgroundCompared with monotherapy, efficacious drug combinations can increase the therapeutic effect, decrease drug resistance of experimental subjects and the side effects of drugs. Therefore, efficacious drug combinations are widely used in the treatment of complex diseases, such as various cancers. However, compared with the mathematical model and computational method, experimental screening efficacious drug combinations is time-consuming, costly, laborious, and inefficient; (2) Methodswe predicted efficacious drug combinations in cancer based on random walk with restart (RWRDC). An efficacious score can be obtained between any two individual drugs by RWRDC; (3) ResultsAs a result, we analyzed the rationality of the efficacious score first. Besides, compared with the other methods by leave-one-out cross-validation, all the Area Under Receiver Operating Characteristic Curves (AUROCs) of RWRDC were higher for data sets of breast cancer, colorectal cancer, and lung cancer. Moreover, the case study of breast cancer showed that RWRDC could discover potential efficacious drug combinations; (4) ConclusionsThese results suggest that RWRDC is a novel way to discover efficacious drug combinations in cancer, which provides new prospects for cancer treatment. Furthermore, RWRDC is a semi-supervised learning framework that can be used to predict combinations of drugs for other complex diseases.

bioinformatics↗

bioRxiv2020

Plasmodium falciparum increases its investment in gametocytes in the wet season in asymptomatic individuals

In many regions, malaria transmission is seasonal, but it is not well understood whether P. falciparum modulates its investment in transmission in response to seasonal vector abundance. In two sites in western Kenya (Chulaimbo and Homa Bay), we sampled 1116 asymptomatic individuals in the wet season, when vectors are abundant, and 1743 in the dry season. We screened for P. falciparum by qPCR, and gametocytes by pfs25 RT-qPCR. Parasite prevalence in Chulaimbo and Homa Bay was 27.1% and 9.4% in the dry season, and 48.2% and 7.8% in the wet season respectively. Mean parasite densities did not differ between seasons (P=0.562). A contrasting pattern of gametocyte carriage was observed. In the wet season, fewer infections harbored gametocytes (22.3% vs. 33.8%, P=0.009), but densities were 3-fold higher (P<0.001). Thus, in the wet season, among gametocyte positive individuals, higher proportion of all parasites were gametocytes, reflecting an increased investment in transmission.

microbiology↗

bioRxiv2020

A reference-guided approach for epigenetic characterization of single cells

The recent advancements in single-cell technologies, including single-cell chromatin accessibility sequencing (scCAS), have enabled profiling the epigenetic landscapes for thousands of individual cells. However, the characteristics of scCAS data, including high dimensionality, high degree of sparsity and high technical variation, make the computational analysis challenging. Reference-guided approach, which utilizes the information in existing datasets, may facilitate the analysis of scCAS data. We present RA3 (Reference-guided Approach for the Analysis of single-cell chromatin Acessibility data), which utilizes the information in massive existing bulk chromatin accessibility and annotated scCAS data. RA3 simultaneously models 1) the shared biological variation among scCAS data and the reference data, and 2) the unique biological variation in scCAS data that identifies distinct subpopulations. We show that RA3 achieves superior performance in many scCAS datasets. We also present several approaches to construct the reference data to demonstrate the wide applicability of RA3.

bioinformatics↗