bluuebunny/crossref_metadata_2025_split huggingface dataset:
Public Awareness and Attitude towards Counterfeit Medicines in Sudan: A cross-sectional study
Authors: Wagiella Wala W. , Shantier Shaza W. , Gadkariem Elrasheed A. 
Published: October 2020

AbstractBackgroundCounterfeit medicines (CFMs) are a global problem with significant and well-documented consequences for global health and patient safety, including drug resistance and patient deaths. Reports of counterfeit pharmaceuticals in Africa indicate a wide variety of detrimental effects.ObjectivesThe aim of the present study was to assess the extent, awareness and attitude of public in Sudan towards CFMs.MethodsA cross-sectional study was conducted applying pretested and structured questionnaire. The awareness and attitude were assessed statistically and the association between those and different demographic characteristics was calculated using Fisher exact test and Spearman correlation.ResultsA total of 386 participants have enrolled in the study. The majority of the respondents (58%) were found to be aware about the term CFMs with social media mentioned to be the main source. 73% of the respondents considered CFMs of worse quality suggesting getting the medicine from a trustworthy pharmacist in order to avoid buying CFMs. 56% reported their ability to distinguish CFMs from the side effects rather than the package and cost. Education was suggested by 82% of the respondents to have vital role in combating CFMs spread through workshops and campaigns. 68% of the participants were found to have a fair awareness about CFMs. Furthermore, 80% of them showed a good attitude toward CFMsConclusionCurrent literature includes gaps in knowledge and attitude towards CFMs. Therefore attention and concentrated efforts are required on the part of the government, drug manufacturers and health care providers’ especially pharmaceutical analysts to ensure that only drugs of acceptable quality reach the patient.
Mitigating the transmission of infection and death due to SARS-CoV-2 through non-pharmaceutical interventions and repurposing drugs
Authors: Mondal Chittaranjan , Adak Debadatta , Majumder Abhijit , Bairagi Nandadulal 
Published: October 2020

AbstractThe Covid-19 pandemic has put the world under immeasurable stress. There is no specific drug or vaccine that can cure the infection or protect people from the infection of coronavirus. It is therefore prudent to use the existing resources and control strategies in an optimal way to contain the virus spread and provide the best possible treatments to the infected individuals. Use of the repurposing drugs along with the non-pharmaceutical intervention strategies may be the right way for fighting against the ongoing pandemic. It is the objective of this work to demonstrate through mathematical modelling and analysis how and to what extent such control strategies can improve the overall Covid-19 epidemic burden. The criteria for disease elimination & persistence were established through the basic reproduction number. A case study with the Indian Covid-19 epidemic data is presented to visualize and illustrate the personal hygiene & safe distancing, and repurposing drugs. It is shown that India can significantly improve the overall Covid-19 epidemic burden through the combined use of NPIs and repurposing drugs though containment of spreading is difficult without serious community participation.
Connecting structure and function from organisms to molecules in small animal symbioses through chemo-histo-tomography
Authors: Geier Benedikt , Oetjen Janina , Ruthensteiner Bernhard , Polikarpov Maxim , Gruber-Vodicka Harald , Liebeke Manuel 
Published: October 2020

AbstractOur understanding of metabolic interactions between small symbiotic animals and bacteria or parasitic eukaryotes that reside within their body is extremely limited. This gap in knowledge originates from a methodological challenge, namely to connect histological changes in host tissues induced by beneficial and parasitic (micro)organisms to the underlying metabolites. To close this gap, we developed chemo-histo-tomography (CHEMHIST), a culture-independent approach to connect anatomic structure and metabolic function in millimeter-sized symbiotic animals. CHEMHIST combines spatial metabolomics based on mass spectrometry imaging (MSI) and microanatomy-based micro-computed X-ray tomography (microCT) on the same animal. Both high-resolution MSI and microCT allowed us to correlate the distribution of metabolites to the same animal’s three-dimensional (3D) histology down to sub-micrometer resolutions. Our protocol is compatible with tissue specific DNA sequencing and fluorescence in situ hybridization (FISH) for the taxonomic identification and localization of the associated micro(organisms). Building CHEMHIST upon in situ imaging, we sampled an earthworm from its natural habitat and created an interactive 3D model of its physical and chemical interactions with bacteria and parasitic nematodes in its tissues. Combining MSI and microCT, we introduce a workflow to connect metabolic and anatomic phenotypes of small symbiotic animals that often represent keystone species for ecosystem-functioning.SignificanceMetabolites mediate the establishment and persistence of most inter-kingdom symbioses. Still, to pinpoint the metabolites each partner displays upon interaction remains the biggest challenge in studying multi-organismal assemblages. Addressing this challenge, we developed a correlative imaging workflow to connect the in situ production of metabolites with the organ-scale and cellular 3D distributions of mutualistic and pathogenic (micro)organisms in the same host animal. Combining mass spectrometry imaging and micro-computed X-ray tomography provided a culture-independent approach, which is essential to include the full spectrum of naturally occurring interactions. To introduce the potential of combining high-resolution tomography with metabolite imaging, we resolve the metabolic interactions between an invertebrate host, its symbiotic bacteria and tissue parasites at unprecedented detail for model and non-model symbioses.
Boolean Implication Analysis Improves Prediction Accuracy of In Silico Gene Reporting of Retinal Cell Types
Authors: Subramanian Rohan , Sahoo Debashis 
Published: October 2020

AbstractThe retina is a complex tissue containing multiple cell types that is essential for vision. Understanding the gene expression patterns of various retinal cell types has potential applications in regenerative medicine. Retinal organoids (optic vesicles) derived from pluripotent stem cells have begun to yield insights into the transcriptomics of developing retinal cell types in humans through single cell RNA-sequencing studies. Previous methods of gene reporting have relied upon techniques in vivo using microarray data, or correlational and dimension reduction methods for analyzing single cell RNA-sequencing data in silico. Here, we present a bioinformatic approach using Boolean implication to discover retinal cell type-specific genes. We apply this approach to previously published retina and retinal organoid datasets and improve upon previously published correlational methods. Our method improves the prediction accuracy and reproducibility of marker genes of retinal cell types and discovers several new high confidence cone and rod-specific genes. Furthermore, our method is general and can impact all areas of gene expression analyses in cancer and other human diseases.Significance StatementEfforts to derive retinal cell types from pluripotent stem cells to the end of curing retinal disease require robust characterization of these cell types’ gene expression patterns. The Boolean method described in this study improves prediction accuracy of earlier methods of gene reporting, and allows for the discovery and validation of retinal cell type-specific marker genes. The invariant nature of results from Boolean implication analysis can yield high-value molecular markers that can be used as biomarkers or drug targets.
Exploring the niche ofRickettsia montanensis(Rickettsiales: Rickettsiaceae) infection of the American dog tick (Acari: Ixodidae), using multiple species distribution model approaches
Authors: Lippi Catherine A. , Gaff Holly D. , White Alexis L. , John Heidi K. St. , Richards Allen L. , Ryan Sadie J. 
Published: October 2020

AbstractThe American dog tick,Dermacentor variabilis(Say), is a vector for several human disease causing pathogens such as tularemia, Rocky Mountain spotted fever, and the understudied spotted fever group rickettsiae (SFGR) infection caused byRickettsia montanensis. It is important for public health planning and intervention to understand the distribution of this tick and pathogen encounter risk. Risk is often described in terms of vector distribution, but greatest risk may be concentrated where more vectors are positive for a given pathogen. When assessing species distributions, the choice of modeling framework and spatial layers used to make predictions are important. We first updated the modeled distribution ofD. variabilisandR. montanensisusing MaxEnt, refining bioclimatic data inputs, and including soils variables. We then compared geospatial predictions from five species distribution modeling (SDM) frameworks. In contrast to previous work, we additionally assessed whether theR. montanensispositiveD. variabilisdistribution is nested within a larger overallD. variabilisdistribution, representing a fitness cost hypothesis. We found that 1) adding soils layers improved the accuracy of the MaxEnt model; 2) the predicted ‘infected niche’ was smaller than the overall predicted niche across all models; and 3) each model predicted different sizes of suitable niche, at different levels of probability. Importantly, the models were not directly comparable in output style, which could create confusion in interpretation when developing planning tools. The random forest (RF) model had the best measured validity and fit, suggesting it may be most appropriate to these data.
Drought duration determines the recovery dynamics of rice root microbiomes
Authors: Santos-Medellin Christian , Liechty Zachary , Edwards Joseph , Nguyen Bao , Huang Bihua , Weimer Bart C. , Sundaresan Venkatesan 
Published: October 2020

AbstractAs extreme droughts become more frequent, dissecting the responses of root-associated microbiomes to drying-wetting events is essential to understand their influence on plant performance. Here, we show that rhizosphere and endosphere communities associated with drought-stressed rice plants display compartment-specific recovery trends. Rhizosphere microorganisms were mostly affected during the stress period, whereas endosphere microorganisms remained altered even after irrigation was resumed. The duration of drought stress determined the stability of these changes, with more prolonged droughts leading to decreased microbiome resilience. Drought stress was also linked to a permanent delay in the temporal development of root microbiomes, mainly driven by a disruption of late colonization dynamics. Furthermore, a root-growth-promotingStreptomycesbecame the most abundant community member in the endosphere during drought and early recovery. Collectively, these results reveal that severe drought results in enduring impacts on root-associated microbiomes that could potentially reshape the recovery response of rice plants.
Eusociality through conflict dissolution
Authors: González-Forero Mauricio , Peña Jorge 
Published: October 2020

AbstractEusociality, where largely unreproductive offspring help their mothers reproduce, is a major form of social organization. An increasingly documented feature of eusociality is that mothers induce their offspring to help by means of hormones, pheromones, or behavioral displays, with evidence often indicating that offspring help voluntarily. The co-occurrence of maternal influence and offspring voluntary help may be explained by what we call the converted helping hypothesis, whereby maternally manipulated helping subsequently becomes voluntary. Such hypothesis requires that parent-offspring conflict is eventually dissolved—for instance, if the benefit of helping increases sufficiently over evolutionary time. We show that help provided by maternally manipulated offspring can enable the mother to sufficiently increase her fertility to transform parent-offspring conflict into parent-offspring agreement. This conflict-dissolution mechanism requires that helpers alleviate maternal life-history trade-offs, and results in reproductive division of labor, high queen fertility, and honest queen signaling suppressing worker reproduction—thus exceptionally recovering diverse features of eusociality. As such trade-off alleviation seemingly holds widely across eusocial taxa, this mechanism offers a potentially general explanation for the origin of eusociality, the prevalence of maternal influence, and the offspring’s willingness to help. Overall, our results explain how a major evolutionary transition can happen from ancestral conflict.
Modeling multifunctionality of genes with secondary gene co-expression networks in human brain provides novel disease insights
Authors: Sánchez Juan A. , Gil-Martinez Ana L. , Cisterna Alejandro , García-Ruíz Sonia , Gómez Alicia , Reynolds Regina , Nalls Mike , Hardy John , Ryten Mina , Botía Juan A. 
Published: October 2020

AbstractMotivationCo-expression networks are a powerful gene expression analysis method to study how genes co-express together in clusters with functional coherence that usually resemble specific cell type behaviour for the genes involved. They can be applied to bulk-tissue gene expression profiling and assign function, and usually cell type specificity, to a high percentage of the gene pool used to construct the network. One of the limitations of this method is that each gene is predicted to play a role in a specific set of coherent functions in a single cell type (i.e. at most we get a single <gene, function, cell type> for each gene). We present here GMSCA (Gene Multifunctionality Secondary Co-expression Analysis), a software tool that exploits the co-expression paradigm to increase the number of functions and cell types ascribed to a gene in bulk-tissue co-expression networks.ResultsWe applied GMSCA to 27 co-expression networks derived from bulk-tissue gene expression profiling of a variety of brain tissues. Neurons and glial cells (microglia, astrocytes and oligodendrocytes) were considered the main cell types. Applying this approach, we increase the overall number of predicted triplets <gene, function, cell type> by 46.73%. Moreover, GMSCA predicts that theSNCAgene, traditionally associated to work mainly in neurons, also plays a relevant function in oligodendrocytes.AvailabilityThe tool is available at GitHub,https://github.com/drlaguna/GMSCAas open source software.ImplementationGSMCA is implemented in R.
Structural insights on the substrate-binding proteins of theMycobacterium tuberculosismammalian-cell-entry (Mce) 1 and 4 complexes
Authors: Asthana Pooja , Singh Dhirendra , Pedersen Jan Skov , Hynönen Mikko J. , Sulu Ramita , Murthy Abhinandan V. , Laitaoja Mikko , Jänis Janne , Riley Lee W. , Venkatesan Rajaram 
Published: October 2020

AbstractTuberculosis (Tb), caused byMycobacterium tuberculosis(Mtb), is responsible for more than a million deaths annually. In the latent phase of infection,Mtbuses lipids as the source of carbon and energy for its survival. The lipid molecules are transported across the cell wall via multiple transport systems. One such set of widely present and less-studied transporters is the Mammalian-cell-entry (Mce) complexes. Here, we report the properties of the substrate-binding proteins (SBPs; MceA-F) of the Mce1 and Mce4 complexes fromMtbwhich are responsible for the import of mycolic acid/fatty acids, and cholesterol respectively. MceA-F are composed of four domains namely, transmembrane, MCE, helical and tail domains. Our studies show that MceA-F are predominantly monomeric when purified individually and do not form homohexamers unlike the reported homologs (MlaD, PqiB and LetB) from other prokaryotes. The crystal structure of MCE domain ofMtbMce4A (MtMce4A39-140) determined at 2.9 Å shows the formation of an unexpected domain-swapped dimer in the crystals. Further, the purification and small-angle X-ray scattering (SAXS) analysis on MtMce1A, MtMce4A and their domains suggest that the helical domain requires hydrophobic interactions with the detergent molecules for its stability. Combining all the experimental data, we propose a heterohexameric arrangement of MtMceA-F SBPs, where the soluble MCE domain of the SBPs would remain in the periplasm with the helical domain extending to the lipid layer forming a hollow channel for the transport of lipids across the membranes. The tail domain would reach the cell surface assisting in lipid recognition and binding.
The CXCL12gamma chemokine immobilized by heparan sulfate on stromal niche cells controls adhesion and mediates drug resistance in multiple myeloma
Authors: Ren Zemin , Lantermans Hildo , Kuil Annemieke , Kraan Willem , Arenzana-Seisdedos Fernando , José Kersten Marie , Spaargaren Marcel , Pals Steven T. 
Published: October 2020

AbstractThe homing/retention, survival and proliferation of multiple myeloma (MM) cells critically depends on interaction with CXCL12 expressing stromal cells in the bone marrow (BM) niche. Here, we report a unique role in this interaction for the recently characterized CXCL12gamma isoform, which contains an extended C-terminal domain that binds heparan-sulfate proteoglycans (HSPGs) with an extraordinary high affinity. We observed that CXCL12γ is expressedin situby reticular stromal cells in both normal and MM BM, as well as by primary BM stromal-cell (BMSC) isolates and BMSC lines. Importantly, upon secretion, CXCL12γ, unlike the CXCL12α isoform, was retained on the surface of these BMSCs. This membrane retention of CXCL12γ is HSPG-mediated, since it was completely annulated by CRISPR-Cas9 mediated deletion of the heparan-sulfate (HS) co-polymerase EXT1. Recombinant CXCL12γ was found to induce strong adhesion of MM cells to vascular cell-adhesion molecule 1 (VCAM-1) coated plates. Furthermore, CXCL12γ expressed by BMSCs and membrane-retained by HSPGs, supported robust adhesion of MM cells to the BMSCs. Specific genetic deletion of either CXCL12γ or of EXT1 significantly attenuated the ability of BMSCs to support MM cell adhesion and, in addition, impaired their capacity to protect MM cells from bortezomib-induced cell death. Our data indicate that CXCL12γ functions as a membrane-bound ‘niche chemokine’, which plays a unique role in the interaction of MM cells with the stromal niche by controlling adhesion/retention as well as cell adhesion-mediated drug resistance (CAM-DR). These findings designate CXCL12γ and associated HSPGs as potential therapeutic targets in MM.
Integrating cyanobacterial flavodiiron proteins within the chloroplast photosynthetic electron transport chain maintains carbohydrate turnover and enhances drought stress tolerance in barley
Authors: Shahinnia Fahimeh , Tula Suresh , Hensel Goetz , Reiahisamani Narges , Nasr Nasrin , Kumlehn Jochen , Gómez Rodrigo , Lodeyro Anabella F. , Carrillo Néstor , Hajirezaei Mohammad R. 
Published: October 2020

ABSTRACTChloroplasts, the sites of photosynthesis in higher plants, have evolved several means to tolerate short episodes of drought stress through biosynthesis of diverse metabolites essential for plant function, but these become ineffective when the duration of the stress is prolonged. Cyanobacteria are the closest bacterial homologs of plastids with two photosystems to perform photosynthesis and to evolve oxygen as a byproduct. The presence ofFlvgenes encoding flavodiiron proteins has been shown to enhance stress tolerance in cyanobacteria. Here, the products ofSynechocystisgenesFlv1andFlv3were expressed in chloroplasts of barley in an attempt to support the growth of plants exposed to drought. The heterologous expression of bothFlv1 and Flv3accelerated days to heading, increased biomass, promoted the number of spikes and grains per plant, and improved grain yield of barley plants exposed to drought. Improved growth correlated with enhanced availability of soluble sugars, a higher turnover of amino acids and the accumulation of lower levels of proline in the leaf.Flv1andFlv3maintained the energy status of the leaves in the stressed plants by converting sucrose to glucose and fructose, immediate precursors for energy production to support plant growth under drought. The results suggest that sugars and amino acids play a fundamental role in the maintenance of the energy status and metabolic activity to ensure growth and survival under stress conditions, that is, water limitation in this particular case. Engineering chloroplasts by introducingFlvgenes, therefore, has the potential to improve plant productivity wherever drought stress represents a significant production constraint.
Population-level consequences of inheritable somatic mutations and the evolution of mutation rates in plants
Authors: Lesaffre Thomas 
Published: October 2020

ABSTRACTInbreeding depression, that is the decrease in fitness of inbred relative to outbred individuals, was shown to increase strongly as life expectancy increases in plants. Because plants are thought to not have a separated germline, it was proposed that this pattern could be generated by somatic mutations accumulating during growth, since larger and more long-lived species have more opportunities for mutations to accumulate. A key determinant of the role of somatic mutations is the rate at which they occur, which likely differs between species because mutation rates may evolve differently in species with constrasting life-histories. In this paper, we study the evolution of the mutation rates in plants, and consider the population-level consequences of inheritable somatic mutations given this evolution. We show that despite substantially lower per year mutation rates, more long-lived species still tend to accumulate larger amounts of deleterious mutations because of higher per generation, leading to higher levels of inbreeding depression in these species. However, the magnitude of this increase depends strongly on how mutagenic meiosis is relative to growth.
Cell intrinsic signaling inMEN1mutant pancreatic neuroendocrine tumors unveils novel signaling pathways associated with de-differentiation
Authors: Rheinheimer Brenna A. , Heimark Ronald L. , Grant Adam D. , Camacho Luis , Padi Megha , Jie Tun 
Published: October 2020

AbstractObjectivesPreliminary genomic analysis of primary pancreatic neuroendocrine tumors revealed a complex mutational landscape with four common oncogenic events; however, critical activation pathways responsible for pancreatic neuroendocrine tumor progression and metastasis have yet to be elucidated. Here, we analyzed six primary pancreatic neuroendocrine tumors to determine which pathways are deregulated and responsible for progression.MethodsSelected genomic profiling of six primary pancreatic neuroendocrine tumors was performed using the Ion Torrent Comprehensive Cancer Panel with matched transcriptomes analyzed by Affymetrix Clariom D arrays. Validation of gene expression changes were measured by quantitative PCR using TaqMan assays and immunohistochemistry on tumor specimens.ResultsMEN1was mutated in half (50%) of our sequenced tumors whileFGFR3was mutated in 2/6 (33%). Transcriptome analysis revealed thatITGA2andEZH2were overexpressed inMEN1mutant tumors whereasALKandVEGFAwere overexpressed inFGFR3mutant tumors. Immunohistochemistry revealed increased nuclear ITGA2 and EZH2 staining along with increased VE-Cadherin staining and loss of membranous E-cadherin localization inMEN1andFGFR3mutant tumors.ConclusionsOur results suggest that pancreatic neuroendocrine tumors containingMEN1andFGFR3mutations are more aggressive and de-differentiated than their wild-type counterparts. Additionally, we provide novel chemotherapeutic target FGFR3 for patients with this disease.