Biology subjects

Datta, S.

Publications and source records attributed to Datta, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2020

Detection of 'relict' western lineage of citrus tristeza virus virulent genotype in declining Arunachal Wakro orange

Eastern Himalayan foothills are known to have optimal agro-climatic conditions for production of quality citrus fruits including oranges. Among the citrus growing regions of eastern Himalayas, Wakro in the far eastern state of Arunachal Pradesh is known for its superior quality oranges, popular as the Wakro orange or the Arunachal orange, which has been included in Geographical Indication Registry by the Government of India. However, during last few years, Arunachal orange orchards have been experiencing severe infestation of aphid associated with rapid decline disease, causing catastrophe to the farmers as well as state economy. Therefore, in 2015, an intensive survey of severely affected orange orchards was carried out to investigate the aetiological factors of citrus decline. RNA samples extracted from leaf and aphid specimens collected from Wakro orchards were subjected to CTV detection through 3-UTR specific RT-PCR. Subsequently, ORF1 and CP genetic regions were amplified and clonal-sequencing was performed. Although, BLAST search showed close homology of the present sequences with other virulent genotype VT sequences, detailed phylogenetic analysis demonstrated affinity and clustering of present sequences with VT sequences belonging to the western lineage. This finding is considerably distinct from CTV sequences reported from citrus growing orchards in India and other neighbouring countries. Additionally, low diversity of CP gene sequences, recombination patterns and presence of sequence segments identical to the present ones in other CTV genotypes was also revealed. Collectively, these observations indicate pristine and primeval nature of present CTV sequences, corroborating well with the proposed origin of CTV in this part of the globe. We here report our finding of western lineage of CTV virulent genotype VT, which is distinct from CTV molecular epidemiology in other parts of India and discuss the implications of these findings.

microbiology↗

bioRxiv2020

Novel mTORC1 inhibitors kill Glioblastoma stem cells

Glioblastoma Multiforme (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. mTORC1 regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed piperazine-mTOR binding strength by two biophysical measurements-- biolayer interferometry and field effect biosensing, and these confirmed each other and demonstrated a structure-activity relationship. Since mTORC1 is reduced in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy--but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, the tight-binding Meclizine provoked ‘synthetic lethality’ in IDH1-mutant GBMSCs. These data tend to support a novel clinical strategy for GBM, i.e. the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM, and IDH1-mutant GBM.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2020

Proximity labeling of Snx14 reveals a functional interaction with delta-9 desaturase SCD1 to maintain ER homeostasis

Fatty acids (FAs) are central cellular metabolites that contribute to lipid synthesis, and can be stored or harvested for metabolic energy. Dysregulation in FA processing and storage causes toxic FA accumulation or altered membrane compositions and contributes to metabolic and neurological disorders. Saturated lipids are particularly detrimental to cells, but how lipid saturation levels are maintained remains poorly understood. Here, we identify the cerebellar ataxia SCAR20-associated protein Snx14, an endoplasmic reticulum (ER)-lipid droplet (LD) tethering protein, as a novel factor required to maintain the lipid saturation balance of cell membranes. We show that SNX14KO cells and SCAR20 disease patient-derived cells are hypersensitive to saturated FA (SFA)-mediated lipotoxic cell death that compromises ER integrity. Using APEX2-based proximity labeling, we reveal the protein composition of Snx14-associated ER-LD contacts and define a functional interaction between Snx14 and {Delta}-9 FA desaturase SCD1. Lipidomic profiling reveals that SNX14KO cells increase membrane lipid saturation following exposure to palmitate, phenocopying cells with reduced SCD1 activity. In line with this, SNX14KO cells manifest delayed FA processing and lipotoxicity, which can be rescued by SCD1 over-expression. Altogether these mechanistic insights reveal a role for Snx14 in FA and ER homeostasis, defects in which may underlie the neuropathology of SCAR20. Significance StatementSCAR20 disease is an autosomal recessive spinocerebellar ataxia primarily affecting children, and results from loss-of-function mutations in the SNX14 gene. Snx14 is an endoplasmic reticulum (ER)-localized protein that localizes to ER-lipid droplet (LD) contacts and promotes LD biogenesis following exogenous FA treatment, but why Snx14 loss causes SCAR20 is unclear. Here, we demonstrate that following exposure to saturated fatty acids, Snx14-deficient cells have defective ER homeostasis and altered lipid saturation profiles. We reveal a functional interaction between Snx14 and fatty acid (FA) desaturase SCD1. Lipidomics shows Snx14-deficient cells contain elevated saturated lipids, closely mirroring SCD1-defective cells. Furthermore, SCD1 over-expression can rescue Snx14 loss. We propose that Snx14 maintains cellular lipid homeostasis, the loss of which underlies the cellular basis for SCAR20 disease.

cell biology↗

bioRxiv2020

CGGBP1-regulated cytosine methylation at CTCF-binding motifs resists stochasticity

The human CGGBP1 is implicated in a variety of cellular functions. It regulates genomic integrity, cell cycle, gene expression and cellular response to growth signals. Evidence suggests that these functions of CGGBP1 manifest through binding to GC-rich regions in the genome and regulation of interspersed repeats. Recent works show that CGGBP1 is needed for cytosine methylation homeostasis and genome-wide occupancy patterns of the epigenome regulator protein CTCF. It has remained unknown if cytosine methylation regulation and CTCF occupancy regulation by CGGBP1 are independent or interdependent processes. By sequencing immunoprecipitated methylated DNA, we have found that some transcription factor-binding sites resist stochastic changes in cytosine methylation. Of these, we have analyzed the CTCF-binding sites thoroughly and show that cytosine methylation regulation at CTCF-binding DNA sequence motifs by CGGBP1 is deterministic. These CTCF-binding sites are positioned at locations where the spread of cytosine methylation in cis depends on the levels of CGGBP1. Our findings suggest that CTCF occupancy and functions are determined by CGGBP1-regulated cytosine methylation patterns.

genomics↗

bioRxiv2020

HDAC inhibitor Givinostat targets DNA-binding of human CGGBP1

The antineoplastic agent Givinostat inhibits histone deacetylases. We present here our finding that the DNA-binding of human CGGBP1 is also inhibited by Givinostat. CGGBP1, a DNA-binding protein, is required for cancer cell proliferation. In our quest to exploit the potential anti-proliferative effects of CGGBP1 inhibition, we have developed a simple screening assay to identify chemical inhibitors of DNA-protein interactions. We have applied this screen for human CGGBP1 on a library of 1685 compounds and found that Givinostat is a direct inhibitor of CGGBP1-DNA interaction. The mechanism of action of Givinostat should thus extend beyond HDACs to include the inhibition of the myriad functions of CGGBP1 that depend on its binding to the DNA.

cancer biology↗

bioRxiv2019

Maximization of non-nitrogenous metabolite production in E. coli using population systems biology

The E. coli metabolome is an interconnected set of enzymes that has measurable kinetic parameters ascribed for the production of most of its metabolites. Flux Balance Analysis (FBA) or Ordinary Differential Equation (ODE) models are used to increase product yield using defined media. However, they either give a range (FBA) or exact amount (ODE) of metabolite yield which isnt true as the transcriptome diversity of individual cells isnt considered. We formulate the metabolic-behaviour of individual cells by using a POpulation SYstems-Biology ALgorithm (POSYBAL) which predicts multiple-gene knockouts for increasing industrially relevant metabolites. We validate this prediction for producing isobutanol (Heterogenous metabolite) and shikimate (Homogenous metabolite) where, the product-yield was increased by 40 times (~2000 ppm) and 42 times (~3000 ppm) respectively. Also, we introduce a nitrogen-swap in standard media to its low-nitrogen counterpart during post-growth phase to redistribute flux towards non-nitrogenous pathways for increasing overall product-yield. Further, our model shows growth-phase diversity in bacterial population even under normal glucose-uptake, portraying a real-world scenario of diverse and robust environment thus, making it evolutionarily favourable to threats such as anti-bacterial attack.

bioengineering↗

bioRxiv2019

The anti-leishmanial activity of Spergulin-A involves P2X7R-P38MAPK axis

Current drugs are inadequate for the treatment of visceral leishmaniasis an immunosuppressive ailment caused by Leishmania donovani. Regrettably, there is no plant-origin antileishmanial drug present. P2X7R is constitutively present on macrophage surfaces and can be a putative therapeutic target in intra-macrophage pathogens with function attributes towards inflammation, host cell apoptosis, altered redox, and phagolysosomal maturation by activating p38MAPK. Here we demonstrated that the initial interaction of Spergulin-A (SpA), a triterpenoid saponin with RAW 264.7 macrophages was mediated through P2X7R involving the signaling cascade intermediates Ca++, P38MAPK, and NF-{kappa}{beta}. P38MAPK involvement is shown to have specific and firm importance in leishmanial killing with increased NF-{kappa}Bp65. Phago-lysosomal maturation by Sp A also campaigns for another contribution of P2X7R. In vivo evaluation of the anti-leishmanial activity of Sp A was monitored through expression analyses of P2X7R, P38MAPK, and NF-{kappa}{beta} in murine spleen and bone-marrow macrophages and advocated Sp A of being a natural compound of leishmanicidal functions which acted through the P2X7R-P38MAPK axis. SIGNIFICANCE OR IMPORTANCEPreciously, this manuscript demonstrated previously unreported initial interaction of Spergulin-A, a triterpenoid saponin isolated from Glinus oppositifolius with macrophages through P2X7R involving the signaling cascade intermediates Ca++, P38MAPK, and NF-{kappa}{beta}. Signaling interaction is shown to have specific importance in the leishmanial killing. Phago-lysosomal maturation also campaigns for another contribution of P2X7R. In vivo evaluation was monitored through P2X7R, P38MAPK, and NF-{kappa}{beta} in murine spleen and bone-marrow macrophages and advocated Sp A of being a natural compound of leishmanicidal functions which acted through the P2X7R-P38MAPK axis. The result supports that Spergulin-A can provide new lead molecules for the development of alternative drugs against VL. We feel very strongly that this work can be very interesting as it describes a detailed evaluation of leishmanicidal effect by Sp A and thus has every potential to attract a lot of workers especially in the fields of pharmacology, drug development, immunology, as well as parasitology.

molecular biology↗

bioRxiv2019

Elucidating the regulation of glucose tolerance through the interaction between the reaction product and active site pocket residues of a β-glucosidase from Halothermothrix orenii

{beta}-glucosidase catalyzes the hydrolysis of {beta}-1,4 linkage between two glucose molecules in cello-oligosaccharides and is prone to inhibition by the reaction product glucose. Relieving the glucose inhibition of {beta}-glucosidase is a significant challenge. Towards the goal of understanding how glucose interacts with {beta}-glucosidase, we expressed in Escherichia coli, the Hore_15280 gene encoding a {beta}-glucosidase in Halothermothrix orenii. Our results show that the enzyme is glucose tolerant, and its activity stimulated in the presence of up to 0.5 M glucose. NMR analyses show the unexpected interactions between glucose and the {beta}-glucosidase at lower concentrations of glucose that however does not lead to enzyme inhibition. We identified non-conserved residues at the aglycone-binding and the gatekeeper site and show that increased hydrophobicity at the pocket entrance and a reduction in steric hindrances are critical towards enhanced substrate accessibility and significant improvement in activity. Analysis of structures and in combination with molecular dynamics simulations show that glucose increases the accessibility of the substrate by enhancing the structural flexibility of the active site pocket and may explain the stimulation in specific activity up to 0.5 M glucose. Such novel regulation of {beta}-glucosidase activity by its reaction product may offer novel ways of engineering glucose tolerance.

biochemistry↗

bioRxiv2019

Diverse Species-Specific Phenotypic Consequences of Loss of Function Sorting Nexin 14 Mutations

Mutations in the SNX14 gene cause spinocerebellar ataxia, autosomal recessive 20 (SCAR20) in both humans and dogs. SCAR20 is understood to involve subcellular disruption to autophagy and lipid metabolism. Previously reported studies on the phenotypic consequences of SNX14 mutations have been limited to in vitro investigation of patient-derived dermal fibroblasts, laboratory engineered cell lines and developmental analysis of zebrafish morphants. In addition, studies have investigated the biochemical roles of SNX14 homologues Snz (Drosophila) and Mdm1 (yeast) which have demonstrated an important role during lipid biogenesis. This study investigates the impact of constitutive Snx14 mutations in laboratory species: mice and zebrafish. Loss of SNX14 in mice was found to be embryonic lethal around mid-gestation. This is due to placental pathology that involves severe disruption to syncytiotrophoblast cell differentiation. Zebrafish carrying a homozygous, maternal zygotic snx14 genetic loss-of-function mutation contrasts with other vertebrates, being both viable and anatomically normal. Whilst no obvious behavioural effects were observed, elevated levels of neutral lipids and phospholipids resemble previously reported effects on lipid homeostasis in other species. The biochemical role of SNX14 therefore appears largely conserved through evolution while the overall consequences of loss of function varies considerably between species. New mouse and zebrafish models therefore provide valuable insights into the functional importance of SNX14 with distinct opportunities for investigating its cellular and metabolic function in vivo.

developmental biology↗

bioRxiv2019

Excavating New Facts from Ancient Hepatitis B Virus Sequences

Recently, Muhlemann et al. (2018) and Krause-Kyora et al. (2018) discovered 15 ancient Hepatitis B virus (aHBV) sequences dating back to the Neolithic age (NA) and the Bronze age (BA). Being published simultaneously, neither of these studies could include sequences from the other for analyses. In the present research, aHBV sequences from these studies were collective re-analysed with reference to a comprehensive database comprising extant HBV diversity to understand their relatedness and role in the evolution of extant HBV diversity. Present analyses revealed several interesting findings on distribution, dispersal, phylogenetic and recombinational relatedness of ancient HBV to extant genotypes, which were not recognized previously. Several interesting recombination patterns were observed, which corroborated well with ancient human migration, shown by the human genetic studies. Present analyses suggest that comparable to the replacement of the Neolithic European farmer associated Y chromosome haplogroups by haplogroups associated with the steppe people during Steppe migration, HBV genotype associated with the early Neolithic European farming cultures was also replaced by the ancestral HBV genotype A probably carried by the migrating steppe people, and a variant of this genotype is the prevalent HBV genotype in contemporary European populations. Additionally, based on recent literature, this research also indicates that HBV genotype divergence estimates proposed by Muhlemann et al., and others cannot sufficiently explain distribution of certain extant HBV genotypes. Hence, an alternative possibility to explain long distance and trans-oceanic distribution of phylogenetically related HBV genotypes was reviewed and discussed in the light of currently available knowledge. Through this manuscript, novel and important findings of the present analyses are communicated.

evolutionary biology↗

bioRxiv2019

Benchmarking workflows to assess performance and suitability of germline variant calling pipelines in clinical diagnostic assays.

Benchmarking the performance of complex analytical pipelines is an essential part of developing Laboratory Developed Assays (LDT). Reference samples and benchmark calls published by Genome in a Bottle (GIAB) Consortium have enabled the evaluation of analytical methods. However, the performance of such methods is not uniform across the different regions of the genome/exome and different variant types and lengths. Here we present a scalable and reproducible, cloud-based benchmarking workflow that can be used by clinical laboratories to rapidly access and validate the performance of LDT assays, across their regions of interest and reportable range, using a broad set of benchmarking samples.

bioinformatics↗

bioRxiv2019

Drosophila Snazarus regulates a lipid droplet population at plasma membrane-droplet contacts in adipocytes

Adipocytes store nutrients as lipid droplets (LDs), but how they organize their LD stores to balance lipid uptake, storage, and mobilization remains poorly understood. Here, using Drosophila fat body (FB) adipocytes we characterize spatially distinct LD populations that are maintained by different lipid pools. We identify peripheral LDs (pLDs) that make close contact with the plasma membrane (PM) and are maintained by lipophorin-dependent lipid trafficking. pLDs are distinct from larger cytoplasmic medial LDs (mLDs) which are maintained by FASN1-dependent de novo lipogenesis. We find that sorting nexin CG1514/Snazarus (Snz) associates with pLDs and regulates LD homeostasis at ER-PM contact sites. Loss of SNZ perturbs pLD organization whereas Snz over-expression drives LD expansion, triacylglyceride production, starvation resistance, and lifespan extension through a DESAT1-dependent pathway. We propose that Drosophila adipocytes maintain spatially distinct LD populations and identify Snz as a novel regulator of LD organization and inter-organelle crosstalk.

cell biology↗

bioRxiv2019

Deciphering the structural intricacy in virulence effectors for proton-motive force mediated unfolding and type-III protein secretion

Many gram-negative pathogenic bacteria use type III secretion system (T3SS) to inject virulence effectors directly into the cytosol of targeted host cells. Given that the protein unfolding requisite for secretion via nano-size pore of T3SS injectisome is an energetically unfavorable process, "How do pathogenic bacteria unfold and secrete hundreds of toxic proteins in seconds" remain largely unknown. In this study, first, from an in-depth analysis of folding and stability of T3SS effector ExoY, we show that the proton-concentration gradient ([~]pH 5.8-6.0) generated by proton-motive force (PMF) can significantly amortize tertiary structural folding and stability of effectors without significant entropic cost. Strikingly, it was found that the lower energetic cost associated with the global unfolding of ExoY is mainly due to its weakly folded geometry and abundance of geometrical frustrations stemming from buried water molecules and native-like folded intermediates in the folded cores. From in-silico structural analysis of 371 T3SS effectors, it can be curtained that T3SS effectors belong to typical class (disorder globules) of IDPs and have evolved similar conserved intrinsic structural archetypes to mediate early-stage unfolding. The slower folding kinetics in effector proteins requisite for efficient T3SS-mediated secretion mostly stems from reduced hydrophobic density and enhanced polar-polar repulsive interactions in their sequence landscapes. Lastly, the positively evolved histidine-mediated stabilizing interactions and gate-keeper residues in effector proteins shed light on collaborative role of evolved structural chemistry in T3SS effectors and PMF in the spatial-temporal regulation of effector folding and stability essential for maintaining balance in secretion and function trade-off.

biophysics↗

bioRxiv2019

De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population.

de novo Mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T[->]C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish. SignificanceHere we provide one of the largest and most diverse human de novo mutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.

genetics↗

bioRxiv2019

Visible light-triggered NO generation from Naphthalimide-based probe for photoreceptor-mediated plant root growth regulation

An efficient visible light-triggered nitric oxide (NO) releasing fluorescent molecule is designed and synthesized by coupling 2,6-dimethyl nitrobenzene moiety at the peri-position of 1, 8-naphthalimide through an alkene bond. The NO-releasing ability is investigated in details using various spectroscopic techniques, and the photoproduct was also characterized. Further, the photo-generated NO has been employed to examine the effect of photoreceptor-mediated NO uptake on plant root growth regulation.

plant biology↗

bioRxiv2018

A triterpenoid saponin, Spergulin-A from Glinus oppositifolius is a potent immunostimulator and antileishmanial agent

Present chemotherapeutics are inadequate against visceral leishmaniasis (VL) an immunosuppressive ailment caused by Leishmania donovani. Despite the interest in plant-based drug development, an antileishmanial drug from plant source is unavailable. Glinus oppositifolius had been reported in favor of being immunomodulators along with other traditional uses. Novel anti-VL therapies can rely on host immune-modulation with associated leishmanicidal action. With this rationale, an n-BuOH fraction of the methanolic extract of the plant and isolated triterpenoid saponin Spergulin-A were evaluated against acellular and intracellular L. donovani. Immunostimulatory activity of them was confirmed by elevated TNF-a and extracellular NO production from treated M{Phi}s and was found nontoxic to the host cells. Identification and structure confirmation for isolated Spergulin-A was performed by ESI-MS,13C, and 1H NMR. Spergulin-A was found ineffective against the acellular forms while, against the intracellular parasites at 30g/ml, the reduction was 92.6% after 72h. Spergulin-A enhanced ROS and nitric oxide (NO) release and changes in Gp91-phox, i-NOS, and pro and anti-inflammatory cytokines elaborated its intracellular anti-leishmanial activity. The results supported that G. oppositifolius and Spergulin-A can potentiate new lead molecules for the development of alternative drugs against VL.\n\nAuthor summaryVisceral Leishmaniasis (VL) is prevalent in tropical and temperate regions and is endemic in 88 countries with an estimated yearly incidence of 1-1.5 million cases of cutaneous leishmaniasis and 500,000 cases of VL, of which 70,000 people die every year. More than 90% of cases occur in India, Bangladesh, Nepal, Sudan, Ethiopia, and Brazil with an estimated incidence of at least 500,000 new cases and 50,000 deaths each year.\n\nThis work highlights the anti-leishmanial effect of a triterpenoid saponin that was extracted from a tropical plant, Glinus oppositifolius, commonly found in Asian and parts of African countries. The drug showed potent Leishmanicidal activity against Leishmania donovani at very low concentration. As the application of the conventional drugs (pentavalent antimoniates, amphotericin B, and pentamidine) is limited due to low efficacy, life-threatening side effects, high toxicity, induction of parasite resistance, length of treatment and high cost and anti-leishmanial vaccines may not become available in the near future, so plant extracts or plant compounds, represent a valuable source of new medicinal agents and alternative, effective and less toxic treatments, leading to a search for natural products with a potential leishmanicidal action. Being an immunosuppressive disease efficacy against VL can be demonstrated against intracellular parasites in the lights of emphasizing host M{Phi} immunostimulation as elaborated precisely in the present study.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC=\"FIGDIR/small/458653_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (30K):\norg.highwire.dtl.DTLVardef@f93fa1org.highwire.dtl.DTLVardef@1c073f0org.highwire.dtl.DTLVardef@1fbb86aorg.highwire.dtl.DTLVardef@1085c11_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2018

Spatio-temporal modelling of Leishmania infantum infection among domestic dogs: a simulation study and sensitivity analysis applied to rural Brazil

BackgroundThe parasite Leishmania infantum causes zoonotic visceral leishmaniasis (VL), a potentially fatal vector-borne disease of canids and humans. Zoonotic VL poses a significant risk to public health, with regions of Latin America being particularly afflicted by the disease.\n\nLeishmania infantum parasites are transmitted between hosts during blood feeding by infected female phlebotomine sand flies. With a principal reservoir host of L. infantum being domestic dogs, limiting prevalence in this reservoir may result in a reduced risk of infection for the human population. To this end, a primary focus of research efforts has been to understand disease transmission dynamics among dogs. One way this can be achieved is through the use of mathematical models.\n\nMethodsWe have developed a stochastic, spatial, individual-based mechanistic model of L. infantum transmission in domestic dogs. The model framework was applied to a rural Brazilian village setting with parameter values informed by fieldwork and laboratory data. To ensure household and sand fly populations were realistic, we statistically fit distributions for these entities to existing survey data. To identify the model parameters of highest importance, we performed a stochastic parameter sensitivity analysis of the prevalence of infection among dogs to the model parameters.\n\nResultsWe computed parametric distributions for the number of humans and animals per household and a non-parametric temporal profile for sand fly abundance. The stochastic parameter sensitivity analysis determined prevalence of L. infantum infection in dogs to be most strongly affected by the sand fly associated parameters and the proportion of immigrant dogs already infected with L. infantum parasites.\n\nConclusionsEstablishing the model parameters with the highest sensitivity of average L. infantum infection prevalence in dogs to their variation helps motivate future data collection efforts focusing on these elements. Moreover, the proposed mechanistic modelling framework provides a foundation that can be expanded to explore spatial patterns of zoonotic VL in humans and to assess spatially targeted interventions.

epidemiology↗

bioRxiv2018

SciReader*: A Cloud-based Recommender System for Biomedical Literature

With the growing number of biomedical papers published each year, keeping up with relevant literature has become increasingly important, and yet more challenging. SciReader (www.scireader.com) is a cloud-based personalized recommender system that specifically aims to assist biomedical researchers and clinicians identify publications of interest to them. SciReader uses topic modeling and other machine learning algorithms to provide users with recommendations that are recent, relevant, and of high quality1.

scientific communication and education↗