bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADAM protease inhibition overcomes resistance of breast cancer stem-like cells to γδ T cell immunotherapy
Authors: Dutta Indrani , Dieters-Castator Dylan , Papatzimas James W. , Medina Anais , Schueler Julia , Derksen Darren J. , Lajoie Gilles , Postovit Lynne-Marie , Siegers Gabrielle M. 
Published: July 2020

AbstractBreast cancer stem cells (BCSC) are highly resistant to current therapies, and are responsible for metastatic burden and relapse. Gamma delta T cells (γδTc) are immunosurveillance cells with tremendous anti-tumoral activity, and a growing number of clinical trials have confirmed the safety of γδTc immunotherapy for various malignancies. Herein, we demonstrate that γδTc can kill BCSC, but to a lesser extent than non-cancer stem cells (NSC). Immune evasion was orchestrated by several mechanisms. The BCSC secretome rendered γδTc hypo-responsive by reducing proliferation, cytotoxicity and IFN-γ production, while increasing expression of co-inhibitory receptors on γδTc. BCSC and target cells surviving γδTc cytotoxicity had higher PD-L1 co-inhibitory ligand expression, and blocking PD-1 on γδTc significantly overcame BCSC resistance to γδTc killing. Fas/FasL signaling was dysfunctional in BCSC due to upregulation of the anti-apoptotic protein MCL-1, which could be partially overcome using dMCL1-2, an MCL-1 degrader. Moreover, the BCSC fraction shed higher levels of the NKG2D ligand MICA compared to NSC. Inhibiting MICA shedding using the ADAM inhibitor GW280264X overcame BCSC resistance to γδTc killing, rendering BCSC as sensitive to γδTc cytotoxicity as NSC. Collectively, our data unravel multiple mechanisms exploited by BCSC to evade γδTc killing, which may also come into play in BCSC resistance to other cytotoxic lymphocytes. Developing strategies to overcome this resistance will increase the efficacy of cancer immunotherapy and lead to improved outcomes for cancer patients.One Sentence SummaryBreast cancer stem-like cells are resistant to γδ T cell targeting, which can be overcome by inhibiting ADAM proteases that facilitate MICA/B shedding.
Time-dependent inhibition of covert shift of attention
Authors: Buonocore Antimo , Dietze Niklas , McIntosh Robert D. 
Published: July 2020

AbstractVisual transients can interrupt overt orienting by abolishing the execution of a planned eye movement due about 90 ms later, a phenomenon known as saccadic inhibition (SI). It is not known if the same inhibitory process might influence covert orienting in the absence of saccades, and consequently alter visual perception. In Experiment 1 (n=14), we measured orientation discrimination during a covert orienting task in which an uninformative exogenous visual cue preceded the onset of an oriented probe by 140 to 290 ms. In half of the trials the onset of the probe was accompanied by a brief irrelevant flash, a visual transient that would normally induce SI. We report a time-dependent inhibition of covert orienting in which the irrelevant flash impaired orientation discrimination accuracy when the probe followed the cue by 190 and 240 ms. The interference was more pronounced when the cue was incongruent with the probe location, suggesting an impact on the reorienting component of the attentional shift. In Experiment 2 (n=12), we tested whether the inhibitory effect of the flash could occur within an earlier time range, or only within the later, reorienting range. We presented probes at congruent cue locations in a time window between 50 to 200 ms. Similarly to Experiment 1, discrimination performance was altered at 200 ms after the cue. We suggest that covert attention may be susceptible to similar inhibitory mechanisms that generate SI, especially in later stages of attentional shifting (> 200ms after a cue), typically associated with reorienting.
Biodiversity and niche partitioning in an anaerobic benzene degrading culture
Authors: Melkonian Chrats , Fillinger Lucas , Atashgahi Siavash , da Rocha Ulisses Nunes , Kuiper Esther , Olivier Brett , Braster Martin , Gottstein Willi , Helmus Rick , Parsons John , Smidt Hauke , van der Waals Marcelle , Gerritse Jan , Brandt Bernd W , Molenaar Douwe , van Spanning Rob 
Published: July 2020

ABSTRACTA key question in microbial ecology is what the driving forces behind the persistence of large biodiversity in natural environments are. We studied a microbial community with more than 100 different types of species which evolved in a 15-years old bioreactor with benzene as the main carbon and free energy source and nitrate as the electron acceptor. We demonstrate that only a few community members are able to degrade benzene, and that most of the others feed on the metabolic left-overs or on the contents of dead cells making up a food web with different trophic levels. As a result of niche partitioning, a high species richness is maintained and the complexity of a natural community is stabilized in a relatively simple environment. This view highlights the importance of species interactions and interdependencies, which drive microbial community structure and function. These mechanisms may well be conserved across ecosystems.
Transcriptional Signatures of Synaptic Vesicle Genes Define Myotonic Dystrophy Type I Neurodegeneration
Authors: Jimenez-Marin Antonio , Diez Ibai , Labayru Garazi , Sistiaga Andone , Sepulcre Jorge , Lopez de Munain Adolfo , Cortes Jesus M. 
Published: July 2020

AbstractDespite significant research, the biological mechanisms underlying the brain degeneration in Myotonic Dystrophy Type I (DM1) remain largely unknown. Here we have assessed brain degeneration by measuring the volume loss (VL) and cognitive deficits (CD) in two cohorts of DM1 patients, and associating them to the large-scale brain transcriptome maps provided by the Allen Human Brain Atlas (AHBA). From a list of preselected hypothesis-driven genes, three of them appear to play a major role in degeneration: dystrophin (DMD), alpha-synuclein (SNCA)and the microtubule-associated protein tau (MAPT). Moreover, a purely data-driven strategy identified gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. Therefore, by combining large-scale transcriptome interactions with brain imaging and cognitive function, we provide a new more comprehensive understanding of DM1 that might help define future therapeutic strategies and research into this condition.
Sequence of aCoxiellaendosymbiont of the tickAmblyomma nuttallisuggests a pattern of convergent genome reduction in theCoxiellagenus
Authors: Nardi Tiago , Olivieri Emanuela , Kariuki Edward , Sassera Davide , Castelli Michele 
Published: July 2020

AbstractTicks require bacterial symbionts for the provision of necessary compounds that are absent in their hematophagous diet. Such symbionts are frequently vertically transmitted and, most commonly, belong to theCoxiellagenus, which also includes the human pathogenCoxiella burnetii. This genus can be divided in four main clades, presenting partial but incomplete co-cladogenesis with the tick hosts. Here we report the genome sequence of a novelCoxiella, endosymbiont of the African tickAmblyomma nuttalli, and the ensuing comparative analyses. Its size (∼1 Mb) is intermediate between symbionts ofRhipicephalusspecies and otherAmblyommaspecies. Phylogenetic analyses show that the novel sequence is the first genome of the B clade, the only one for which no genomes were previously available. Accordingly, it allows to draw an enhanced scenario of the evolution of the genus, one of parallel genome reduction of different endosymbiont lineages, which are now at different stages of reduction from a more versatile ancestor. Gene content comparison allows to infer that the ancestor could be reminiscent ofCoxiella burnetii. Interestingly, the convergent loss of mismatch repair could have been a major driver of such reductive evolution. Predicted metabolic profiles are rather homogenous amongCoxiellaendosymbionts, in particular vitamin biosynthesis, consistently with a host-supportive role. Concurrently, similarities amongCoxiellaendosymbionts according to host genus and despite phylogenetic unrelatedness hint at possible host-dependent effects.Significance statementThe genusCoxiellaincludes the pathogenCoxiella burnetiiand widespread nutritional mutualists in ticks. Current knowledge on their evolution is hampered by the limited genomic resources available.Here we provide the first genome sequence of aCoxiellaendosymbiont of clade B, the only clade for which none was available.These data allow to infer an evolutionary scenario of parallel genome reduction amongCoxiellaendosymbionts, with similar constraints, leading to selective retention of biosynthetic pathways beneficial for the host. The combined predicted functional capabilities of the symbionts appear to be a subset of those ofC. burnetii. Accordingly, this pathogen could be closer to an ancestral state of the endosymbionts, rather than being derived from an endosymbiotic ancestor, as previously hypothesized.
Echis carinatussnake venom metalloprotease-induced toxicities in mice: therapeutic intervention by a repurposed drug, tetraethylthiuram disulfide (disulfiram)
Authors: Rudresha Gotravalli V. , Urs Amog P. , Manjuprasanna Vaddarahally N. , Milan Gowda Mallanayakanakatte D. , Jayachandra Krishnegowda , Rajaiah Rajesh , Vishwanath Bannikuppe S. 
Published: July 2020

AbstractEchis carinatus(EC) is known as saw-scaled viper and it is endemic to the Indian subcontinent. Envenoming by EC represents a major cause of snakebite mortality and morbidity in the Indian subcontinent. Zinc (Zn++)-dependent snake venom metalloproteases (SVMPs) present inEchis carinatusvenom is well known to cause systemic hemorrhage and coagulopathy in experimental animals. An earlier report has shown that ECV activates neutrophils and releases neutrophil extracellular traps (NETs) that blocks blood vessels leading to severe tissue necrosis. However, the direct involvement of SVMPs in the release of NETs is not clear. Here, we investigated the direct involvement of EC SVMPs in observed pathological symptoms in a preclinical setup using zinc (Zn++) metal chelator, Tetraethylthiuram disulfide (TTD)/disulfiram. TTD potently antagonizes the activity of SVMPs-mediated ECM protein degradation in vitro and skin hemorrhage in mice. In addition, TTD protected mice from ECV-induced footpad tissue necrosis by reduced expression of citrullinated H3 (citH3) and myeloperoxidase (MPO) in footpad tissue. TTD also neutralized ECV-induced systemic hemorrhage and conferred protection against lethality in mice. Moreover, TTD inhibited ECV-induced NETosis in human neutrophils and decreased the expression of peptidylarginine deiminase (PAD) 4, citH3, MPO and pERK. Further, we demonstrated that ECV-induced NETosis and tissue necrosis is mediated via PAR-1-ERK axis. Overall, our results provide an insight into SVMPs-induced toxicities and the promising protective efficacy of TTD can be extrapolated to treat severe tissue necrosis complementing ASV.
Leptospiraspp. seroprevalence in humans involved in a cross-sectional study in Garissa and Tana River Counties, Kenya
Authors: Mutembei Arithi , Mutai Festus K. , Mwololo Damaris , Muriuki John , Obonyo Mark , Kairu-Wanyoike S.W. , Wainaina M. , Lindahl J. , Ontiri E. , Bukachi S. , Njeru I. , Karanja J. , sang R. , Grace D. , Bett B. 
Published: July 2020

AbstractIntroductionLeptospirosis is a neglected bacterial zoonotic infection caused by spirochetes ofLeptospira genus.Humans get infected through direct or indirect contact with urine of infected animals or environment. It accounts for more than 300,000 severe cases annually worldwide with case fatality rates of over 30%. Costs of diagnosis and treatment for human and animals, disruption of international trade of animals and products, reduced productivity and reproductivity in animals constitute economic importance. In Kenya, leptospirosis burden is significant but under-diagnosis and under-reporting affects the awareness of the disease. This study aimed to determine and compare the sero-prevalence and factors associated withLeptospiraspp. in the two counties.MethodsWe conducted a cross-sectional study that involved apparently healthy people of at least 5 years of age in randomly selected households in Garissa and Tana River Counties. Blood samples were collected and tested forLeptospiraspp antibodies using IgM ELISA. Standardized structured questionnaires were administered to collect socio-demographic and exposure information. We calculated frequencies and proportions for categorical variables and odds ratios (OR) and 95% confidence interval (CI) to evaluate association between sero-positivity and exposure factors. We used Wilcoxon test to evaluate statistical difference in sero-positivity for continuous variables and calculated test statistic (H) and p-value.ResultsA total of 952 subjects were recruited into the study – these included 482 persons from Garissa and 470 from Tana River. The overall sero-prevalence was 26% [(244/952); (CI: 23% to 29%)]. Garissa County had significantly higherLeptospiraspp. seroprevalence (31%, n = 147; CI: 27% to 35%) compared to Tana River County (21 %, n = 97; CI: 17% to 25%). Being a female (OR=1.6, CI: 1.2-2.2) and engaging in pastoralism (OR=2.7, CI: 1.8-3.9) were significantly associated with higher odds ofLeptospiraspp. seropositivity compared to being a male or working in irrigated areas. The mean altitude of residence of sero-positive patients was 73m ± 21 SD (standard deviation) above sea level and that for sero-negative was 80m ± 22 SD (H=35, p-value = 0.00).ConclusionThis study determined the seroprevalence and risk factors forLeptospiraspp. exposure in Garissa and Tana River Counties, Kenya. Females in pastoral communities experience high burden of the disease. Enhanced surveillance in humans and animals and further research is required to understand the complex and multifactorial drivers of leptospirosis transmission in the two Counties.
Modeling the Impact of Lock-down on COVID-19 Spread in Malaysia
Authors: Altahir Altahir A. , Mathur Nirbhay , Thiruchelvam Loshini , Mustafa Abro Ghulam E. , Radzi Syaimaa’ S. M. , Dass Sarat C. , Gill Balvinder Singh , Sebastian P. , Zulkifli Saiful A.M. , Asirvadam Vijanth S. 
Published: July 2020

AbstractAfter a breakdown notified in Wuhan, China in December 2019, COVID-19 is declared as pandemic diseases. To the date more than 13 million confirmed cases and more than half a million are dead around the world. This virus also attached Malaysia in its immature stage where 8718 cases were confirmed and 122 were declared as death. Malaysia responsibly controlled the spread by enforcing MCO. Hence, it is required to visualize the pattern of Covid-19 spread. Also, it is necessary to estimate the impact of the enforced prevention measures. In this paper, an infectious disease dynamic modeling (SEIR) is used to estimate the epidemic spread in Malaysia. The main assumption is to update the reproduction number Rt with respect to the implemented prevention measures. For a time-frame of five month, the Rt was assumed to vary between 2.9 and 0.3. Moreover, the manuscript includes two possible scenarios: the first will be the extension of the stricter measures all over the country, and the second will be the gradual lift of the lock-down. After implementing several stages of lock-down we have found that the estimated values of theRtwith respect to the strictness degree varies between 0.2 to 1.1. A continuous strict lock-down may reduce theRtto 0.2 and accordingly the estimated active cases will be reduced to 20 by the beginning of September 2020. In contrast, the second scenario considers a gradual lift of the enforced prevention measures by the end of June 2020, here we have considered three possible outcomes according to the MCO relaxation. Thus, the estimated values ofRt= 0.7, 0.9, 1.1, which shows a rapid increase in the number of active cases. The implemented SEIR model shows a close resemblance with the actual data recorded from 10, March till 7, July 2020.Author summaryConceptualization, A.A.A; methodology, A.A.A, N.M; validation, A.A.A, N.M; formal analysis, A.A.A; investigation, N.M, A.A.A; resources, G.E.M.A, L.T; data collection, L.T, N.M; writing—original draft preparation, A.A.A, L.T, G.E.M.A, N.M; writing—review and editing, V.S.A, S.C.D, B.S.G, P.S, S.A.B.M.Z, N.M; visualization, N.M; supervision, V.S.A; project administration, V.S.A. All authors have read and agreed to the published version of the manuscript
Integrated aqueous humor ceRNA and miRNA-TF-mRNA network analysis reveals potential molecular mechanisms governing primary open-angle glaucoma pathogenesis
Authors: Wang Xiaoqin , Chen Ming , Zeng Liuzhi , Liu Longqian 
Published: July 2020

AbstractPrimary open-angle glaucoma (POAG) is the leading cause of blindness globally, which develops through complex and poorly understood biological mechanisms. Herein, we conducted an integrated bioinformatics analysis of extant aqueous humor (AH) gene expression datasets in order to identify key genes and regulatory mechanisms governing POAG progression. We downloaded AH gene expression datasets (GSE101727 and GSE105269) corresponding to healthy controls and POAG patients from the Gene Expression Omnibus. We then identified mRNAs, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) that were differentially expressed (DE) between control and POAG patients. DEmRNAs and DElncRNAs were then subjected to pathway enrichment analyses, after which a protein-protein interaction (PPI) network was generated. This network was then expanded to establish lncRNA-miRNA-mRNA and miRNA-transcription factor(TF)-mRNA networks. In total, the GSE101727 dataset was used to identify 2746 DElncRNAs and 2208 DEmRNAs, while the GSE105269 dataset was used to identify 45 DEmiRNAs. We ultimately constructed a competing endogenous RNA (ceRNA) network incorporating 37, 5, and 14 of these lncRNAs, miRNAs and mRNAs, respectively. The proteins encoded by these 14 hub mRNAs were found to be significantly enriched for activities that may be linked to POAG pathogenesis. In addition, we generated a miRNA-TF-mRNA regulatory network containing 2 miRNAs (miR-135a-5p and miR-139-5p), 5 TFs (TGIF2, TBX5, HNF1A, TCF3, and FOS) and 5 mRNAs (SHISA7, ST6GAC2, TXNIP, FOS, and DCBLD2). The SHISA7, ST6GAC2, TXNIP, FOS, and DCBLD2 genes that may be viable therapeutic targets for the prevention or treatment of POAG, and regulated by the TFs (TGIF2, HNF1A, TCF3, and FOS).
Diversified agroforestry systems improve carbon foot printand farmer’s livelihood under limited irrigation conditions
Authors: Rathore Sanjay Singh , Shekhawat Kapila , Singh VK , Babu Subhash , Singh RK , Upadhyay PK , Bhattacharyya Ranjan 
Published: July 2020

AbstractIncreasing weather aberrations cause frequent crop failure in monoculture cropping system. Specialized crop production systems, where few seasonal crops occupy vast arable lands, resulting in more biotic and abiotic stresses in agri-ecosystem. Therefore a diversified agroforestry systemwas evaluated to ensure resilience underlimited water conditions, with an aim to augment carbon footprint with enhanced productivity and profitability. The study hypothesised that integration of perennial fruits trees with seasonal crops will have benign effect for sequestering more carbon and improving livelihood of the farmers. This is one of the first timesthat arid fruits tress along with leguminous,and other low water requiring crops were studied for improved carbon sequestration, livelihood of the farmers andfor better resilience in production system. The experimental findings showed that arid fruit trees along with leguminous, oilseeds and cash crops resulted in higher profitability and thus improved livelihood of the farmersin arid and semi-arid areas of South Asia. Diversified phalsa-mung bean-potato and moringa-mung bean-potato were the most productive agroforestry system (36.7t/ha and 36.2 t/ha respectively. Under limited irrigation conditions, Karonda (Carisa spp.)-mung bean potato system was found best in improving livelihood with maximum net return of $ 3529.1/ha with higher profitability/day ($ 19.9/day). Phalsa -MB-potato system was also recorded maximum water use efficiency (33.0 kg/ha-mm), whereas density of SOC was in Phalsa-cowpea-mustard (9.10 Mg/ha) andmoringa-mung bean -potato AFS (9.16 Mg/ha). Carbon footprint analysis revealed that maximum net C gain was in Phalsa-mung bean -potato system (7030 Carbon equivalent kg CE/ha/year).
Coffee consumption and risk of breast cancer: a Mendelian Randomization study
Authors: Ellingjord-Dale Merete , Papadimitriou Nikos , Katsoulis Michalis , Yee Chew , Dimou Niki , Gill Dipender , Aune Dagfinn , Ong Jue-Sheng , MacGregor Stuart , Elsworth Benjamin , Lewis Sarah J , Martin Richard M , Riboli Elio , Tsilidis Konstantinos K 
Published: July 2020

AbstractBackgroundObservational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.MethodsWe conducted a two-sample Mendelian randomization randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations.ResultsOne cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR=0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07).ConclusionsThe results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak inverse association.