bluuebunny/crossref_metadata_2025_split huggingface dataset:
Field evaluation of a novel, rapid diagnostic assay RLDT, and molecular epidemiology of enterotoxigenicE. coliamong Zambian children presenting with diarrhea
Authors: Silwamba Suwilanji , Chilyabanyama Obvious N. , Liswaniso Fraser , Chisenga Caroline C , Chilengi Roma , Dougan Gordon , Kwenda Geoffrey , Chakraborty Subhra , Simuyandi Michelo 
Published: March 2022

AbstractBackgroundEnterotoxigenicEscherichia coli(ETEC) is one of the top aetiologic agents of diarrhea in children under the age of 5 in low-middle income countries (LMICs). The lack of point of care diagnostic tools for routine ETEC diagnosis results in limited data regarding the actual burden and epidemiology in the endemic areas. We evaluated performance of the novel Rapid LAMP based Diagnostic Test (RLDT) for detection of ETEC in stool as a point of care diagnostic assay in a resource-limited setting.MethodsWe conducted a cross-sectional study of 324 randomly selected stool samples from children under 5 presenting with moderate to severe diarrhea (MSD). The samples were collected between November 2012 to September 2013 at selected health facilities in Zambia. The RLDT was evaluated by targeting three ETEC toxin genes [heat labile toxin (LT) and heat stable toxins (STh, and STp)]. Quantitative PCR was used as the “gold standard” to evaluate the diagnostic sensitivity and specificity of RLDT for detection of ETEC. We additionally described the prevalence and seasonality of ETEC.ResultsThe study included 50.6% of participants that were female. The overall prevalence of ETEC was 19.8% by qPCR and 19.4 % by RLDT. The children between 12 to 59 months had the highest prevalence of 22%. The study determined ETEC toxin distribution was LT (49%), ST (34%) and LT/ST (16%). The sensitivity and specificity of the RLDT compared to qPCR using a Ct 35 as the cutoff, were 90.7% and 97.5% for LT, 85.2% and 99.3% for STh and 100% and 99.7% for STp, respectively.ConclusionThe results of this study suggest that RLDT is sufficiently sensitive and specific and easy to implement in the endemic countries. Being rapid and simple, the RLDT also presents as an attractive tool for point-of-care testing at the health facilities and laboratories in the resource-limited settings.Author SummaryETEC is one of the top causes of diarrheal diseases in low and middle income countries. The advancement of molecular diagnosis has made it possible to accurately detect ETEC in endemic areas. However, the complexity, infrastructure and cost implication of these tests has made it a challenge to routinely incorporate them in health facilities in endemic settings. The ETEC RLDT is a simple and cost-effective molecular tool that can be used to screen for ETEC in resource limited settings. Here, we described the performance of the RLDT against a qPCR as the gold standard. Our findings showed that the ETEC RLDT performs comparable to the qPCR and would be a suitable screening tool in health facilities in recourse limited settings.
EFFECTS OF HIV INFECTION AND FORMER COCAINE DEPENDENCE ON NEUROANATOMICAL MEASURES AND NEUROCOGNITIVE PERFORMANCE
Authors: Wakim Kathryn-Mary , Freedman Edward G. , Tivarus Madalina E. , Christensen Zachary , Molholm Sophie , Foxe John J. 
Published: March 2022

ABSTRACTEvidence from animal research, postmortem analyses, and MRI investigations indicate substantial morphological alteration in brain structure as a function of HIV or cocaine dependence (CD). Although previous research on HIV+ active cocaine users suggests the presence of deleterious morphological effects in excess of either condition alone, a yet unexplored question is whether there is a similar deleterious interaction in HIV+ individuals with CD who are currently abstinent. To this end, the combinatorial effects of HIV and CD history on regional brain volume, cortical thickness, and neurocognitive performance was examined across four groups of participants: healthy controls, HIV-negative individuals with a history of CD, HIV+ individuals with no history of CD, HIV+ individuals with a history of CD. Our analyses revealed no statistical evidence of an interaction between both conditions on brain morphometry and neurocognitive performance. While descriptively, individuals with comorbid HIV and a history of CD exhibited the lowest neurocognitive performance scores, using Principle Component Analysis of neurocognitive testing data, HIV was identified as a primary driver of neurocognitive impairment. Higher caudate volume was evident in CD+ participants relative to CD-participants. Taken together, these data provide evidence of independent effects of HIV and CD history on brain morphometry and neurocognitive performance in cocaine-abstinent individuals.
Circadian rhythm of temporal reproduction as a function of stimulus eccentricity in the visual field
Authors: Wang Wei , Yin Xuanzi , Bao Yan 
Published: March 2022

AbstractThe aim of this study was to elucidate how temporal reproduction changed in a diurnal time course. The overestimated reproduction showed a smaller difference to the standard in the morning and evening and a larger difference in the afternoon, and the underestimated reproduction showed an inverse change. No eccentricity effect in temporal production was observed, which indicates homogenous temporal processing shared in the perifoveal and peripheral visual fields.
A Systematic Strategy for Identifying Causal Single Nucleotide Polymorphisms and Their Target Genes on Juvenile Arthritis Risk Haplotypes
Authors: Jiang Kaiyu , Liu Tao , Kales Susan , Tewhey Ryan , Kim Dongkyeong , Park Yungki , Jarvis James N. 
Published: March 2022

AbstractIntroductionAlthough genome-wide association studies (GWAS) multiple regions conferring genetic risk for juvenile idiopathic arthritis (JIA), we are still faced with the task of identifying the single nucleotide polymorphisms (SNPs) on the disease haplotypes that exert the biological effects that confer risk. Until we identify the risk-driving variants, identifying the genes influenced by these variants, and therefore translating genetic information to improved clinical care, will remain an insurmountable task. We used a function-based approach for identifying causal variant candidates and the target genes on JIA risk haplotypes.MethodsWe used a massively parallel reporter assay (MPRA) in myeloid K562 cells to query the effects of 5,226 SNPs in non-coding regions on JIA risk haplotypes for their ability to alter gene expression when compared to the common allele. The assay relies on 180 bp oligonucleotide reporters (“oligos”) in which the allele of interest is flanked by its cognate genomic sequence. Barcodes were added randomly by PCR to each oligo to achieve >20 barcodes per oligo to provide a quantitative read-out of gene expression for each allele. Assays were performed in both unstimulated K562 cells and cells stimulated overnight with interferon gamma (IFNg). As proof of concept, we then used CRISPRi to demonstrate the feasibility of identifying the genes regulated by enhancers harboring expression-altering SNPs.ResultsWe identified 553 expression-altering SNPs in unstimulated K562 cells and an additional 490 in cells stimulated with IFNg. We further filtered the SNPs to identify those plausibly situated within functional chromatin, using open chromatin and H3K27ac ChIPseq peaks in unstimulated cells and open chromatin plus H3K4me1 in stimulated cells. These procedures yielded 42 unique SNPs (total = 84) for each set. Using CRISPRi, we demonstrated that enhancers harboring MPRA-screened variants in the TRAF1 and LNPEP/ERAP2 loci regulated multiple genes, suggesting complex influences of disease-driving variants.ConclusionUsing MPRA and CRISPRi, JIA risk haplotypes can be queried to identify plausible candidates for disease-driving variants. Once these candidate variants are identified, target genes can be identified using CRISPRi informed by the 3D chromatin structures that encompass the risk haplotypes.
Decreased spliceosome fidelity inhibits mTOR signalling and promotes longevity via an intron retention event
Authors: Huang Wenming , Kew Chun , Fernandes Stephanie A. , Loerhke Anna , Han Lynn , Demetriades Constantinos , Antebi Adam 
Published: March 2022

AbstractChanges in splicing fidelity are associated with loss of homeostasis and ageing1–3, yet only a handful of splicing factors have been shown to be causally required to promote longevity 1–3, and the underlying mechanisms and downstream targets in these paradigms remain elusive. Surprisingly, we found a hypomorphic mutation within RNP-6/PUF60, a spliceosome component promoting weak 3’ splice site recognition, which causes aberrant splicing, elevated stress responses, and enhances longevity in Caenorhabditis elegans. Through genetic suppressor screens, we identify a gain-of-function mutation within rbm-39, an RNP-6 interacting splicing factor, which increases nuclear speckle formation, alleviates splicing defects and curtails longevity caused by rnp-6 mutation. By leveraging the splicing changes induced by RNP-6/RBM-39 activities, we uncover a single intron retention event in egl-8/phospholipase C B4 as a key splicing target prolonging life. Genetic and biochemical evidence show that neuronal RNP-6/EGL-8 downregulate mTORC1 signaling to control organismal life span. In mammalian cells, PUF60 downregulation also potently and specifically inhibits mTORC1 signaling. Altogether, our results reveal that splicing fidelity modulates mTOR signaling and suggest a potential therapeutic strategy to delay ageing.
Diverse regulatory pathways modulate “bet hedging” of competence induction in epigenetically-differentiated phase variants ofStreptococcus pneumoniae
Authors: Kwun Min Jung , Ion Alexandru V. , Oggioni Marco R. , Bentley Stephen D. , Croucher Nicholas J. 
Published: March 2022

AbstractDespite enablingStreptococcus pneumoniaeto acquire antibiotic resistance and evade vaccine-induced immunity, transformation occurs at variable rates across pneumococci. Phase variants of isolate RMV7, distinguished by altered methylation patterns driven by the translocating variable restriction-modification (tvr) locus, differed significantly in their transformation efficiencies and biofilm thicknesses. These differences were replicated when the correspondingtvralleles were introduced into an RMV7 derivative lacking the locus. RNA-seq identified differential expression of the type 1 pilus, causing the variation in biofilm formation, and inhibition of competence induction in the less transformable variant, RMV7domi. This was partly attributable to lower expression of ManLMN in RMV7domi, which promoted competence induction through importingN-acetylglucosamine. This effect was potentiated by orthologues of the gram-negative competence regulatory machinery. Furthermore, a phage-related chromosomal island was more active in RMV7domi, which inhibited transformation by increasing expression of the stress response proteins ClpP and HrcA. However, HrcA increased competence induction in the other variant, with its effects depending on Ca2+supplementation or heat shock. Hence the heterogeneity in transformation efficiency likely reflects the diverse signalling pathways by which it is affected. This regulatory complexity will modulate population-wide responses to synchronising quorum sensing signals to produce co-ordinated yet stochastic “bet hedging” behaviour.
Zoonotic Tick Borne Pathogens in Ticks at Human-Wildlife-Livestock interfaces in Kwale County, Kenya
Authors: Godani Salim Kobo , Menza C. Nelson , Muturi W. Margaret 
Published: March 2022

ABSTRACTBackgroundTicks are vectors that can harbor pathogens like viruses, protozoa and bacteria that can cause zoonotic diseases in human. Human gets infected through tick bites where the pathogens are passed to the human blood. One tick bite can lead to transmission of more than one disease. Ticks are obligate hematophagous, infest most vertebrates globally. Lack of surveillance information about the tick-borne pathogens and diseases has made it impossible to assess its impact to the community.Materials and MethodsWe morphologically identified ticks collected from two game reserves in Kenya, locations near the Shimba Hills National Reserve (SHNR) and Tsavo National Reserve (TNR). We identified tick-borne pathogens by HRM analysis and sequencing of specific RT-PCR products of Anaplasma, Ehrlichia, and Rickettsia.ResultsA total of 317 (281 adult ticks and 36 nymphs) was collected at near Tsavo National Reserve in Taita Taveta County, which includes seven species. Amblyomma was the most sampled genus with Amblyomma gemma being the most sampled species (n=135, 42.6%). Other Amblyomma species sampled was Amblyomma Variegatum (n= 40, 12.62%). Greatest species diversity was identified in Rhipicephalus genus with four species identified that includes; Rhipicephalus appendiculatus (n=44, 13.9%), Rhipicephalus Averts (n=1, 0.31%), Rhipicephalus Decoloratus (n=5, 1.6%), Rhipicephalus Pulchellus (n= 91, 28.7%). A single species of Hyalomma sp. was sampled. From near Shimba Hill game reserve (SHNR), a total of 240 adult’s ticks were sampled that comprises of eight species. Amblyomma was the most sampled genus and again Amblyomma gemma being the most sampled species (n=156, 65 %). Other Amblyomma species sampled includes; Amblyomma Lepidum (n= 5, 2.1 %), Amblyomma Variegatum (n= 15, 6.3 %). Greatest species diversity was also identified in Rhipicephalus genus with four species identified that includes; Rhipicephalus appendiculatus (n=18, 7.5 %), Rhipicephalus Averts (n=6, 2.5 %), Rhipicephalus Decoloratus (n=4, 1.7 %), Rhipicephalus Pulchellus (n= 34, 14.2 %). The least sampled species was a single species of Hyalomma Scupense (n=2, 0.83 %). At near Tsavo National Reserve (TNR) in Taita Taveta County, a total of three pools of Rhipicephaline appendiculatus were positive for Theileria parva, two pools of Rhipicephaline evertsi for Anaplasma platys and one pool of Amblyomma variegatum nymphs for Rickettsia africae. From near Shimba Hill game reserve (SHNR), Kwale County, Rickettsia africae pathogen was detected in two pools of Am. variegatum and one pool of Am. Gemma. Rickettsia sp. and Anaplasma sp. were detected in Am. Gemma and Rh. evertsi respective. R. aeschlimannii was detected in a pool of Am. Gemma. These findings highlight the risk of transmission of zoonotic R. africae and unclassified Rickettsia spp. to humans causing African tick-bite fever and other spotted-fever group rickettsioses.
Alterations of the axon initial segment in multiple sclerosis
Authors: Senol Aysegul Dilsizoglu , Pinto Giulia , Beau Maxime , Guillemot Vincent , Dupree Jeff L. , Stadelmann Christine , Ranft Jonas , Lubetzki Catherine , Davenne Marc 
Published: March 2022

AbstractGrey matter damage has been established as a key contributor to disability progression in multiple sclerosis. Aside from neuronal loss and axonal transections, which predominate in cortical demyelinated lesions, synaptic alterations have been detected in both demyelinated plaques and normal-appearing grey matter, resulting in functional neuronal damage. The axon initial segment is a key element of neuronal function, responsible for action potential initiation and maintenance of neuronal polarity. Despite several reports of profound axon initial segment alterations in different pathological models, among which experimental auto-immune encephalomyelitis, whether the axon initial segment is affected in multiple sclerosis is still unknown. Using immunohistochemistry, we analyzed axon initial segments from control and multiple sclerosis tissue, focusing on layer 5/6 pyramidal neurons in the neocortex and Purkinje cells in the cerebellum and performed analysis on the parameters known to control neuronal excitability, i.e., axon initial segment length and position. We found that the axon initial segment length was unchanged among the different multiple sclerosis samples, and not different from controls. In contrast, in both cell types, the axon initial segment position was altered, with an increased soma-axon initial segment gap, in both active and inactive demyelinated lesions. In addition, using a computational model, we show that this increased gap between soma and axon initial segment might increase neuronal excitability. Taken together, these results show for the first time changes of axon initial segments in multiple sclerosis, in active as well as inactive grey matter lesions in both neocortex and cerebellum, which might alter neuronal function.
CF-Seq, An Accessible Web Application for Rapid Re-Analysis of Cystic Fibrosis Pathogen RNA Sequencing Studies
Authors: Neff Samuel L. , Hampton Thomas H. , Puerner Charles , Cengher Liviu , Doing Georgia , Lee Alexandra J. , Koeppen Katja , Cheung Ambrose L. , Hogan Deborah A. , Cramer Robert A. , Stanton Bruce A. 
Published: March 2022

AbstractResearchers studying cystic fibrosis (CF) pathogens have produced numerous RNA-seq datasets which are available in the gene expression omnibus (GEO). Although these studies are publicly available, substantial computational expertise and manual effort are required to compare similar studies, visualize gene expression patterns within studies, and use published data to generate new experimental hypotheses. Furthermore, it is difficult to filter available studies by domain-relevant attributes such as strain, treatment, or media, or for a researcher to assess how a specific gene responds to various experimental conditions across studies. To reduce these barriers to data re-analysis, we have developed an R Shiny application called CF-Seq, which works with a compendium of 147 studies and 1,446 individual samples from 13 clinically relevant CF pathogens. The application allows users to filter studies by experimental factors and to view complex differential gene expression analyses at the click of a button. Here we present a series of use cases that demonstrate the application is a useful and efficient tool for new hypothesis generation. (CFSeq: http://scangeo.dartmouth.edu/CFSeq/)
Co-targeting B-RAF and PTEN enables sensory axons to regenerate across and beyond the spinal cord injury
Authors: Noristani Harun N. , Kim Hyukmin , Pang Shuhuan , Zhong Jian , Son Young-Jin 
Published: March 2022

ABSTRACTPrimary sensory axons in adult mammals fail to regenerate after spinal cord injury (SCI), in part due to insufficient intrinsic growth potential. Robustly boosting their growth potential continues to be a challenge. Previously, we showed that constitutive activation of B-RAF (rapidly accelerated fibrosarcoma kinase) markedly promotes axon regeneration after dorsal root and optic nerve injuries. The regrowth is further augmented by supplemental deletion of PTEN (phosphatase and tensin homolog). Here, we examined whether concurrent B-RAF activation and PTEN deletion promotes dorsal column axon regeneration after SCI. Remarkably, genetically targeting B-RAF and PTEN selectively in DRG neurons of adult mice enables many DC axons to enter, cross, and grow beyond the lesion site after SCI; some axons reach ~2 mm rostral to the lesion by 3 weeks post-injury. Co-targeting B-RAF and PTEN promotes more robust DC regeneration than a pre-conditioning lesion, which additively enhances the regeneration triggered by B-RAF/PTEN. We also found that post-injury targeting of B-RAF and PTEN enhances DC axon regeneration. These results demonstrate that co-targeting B-RAF and PTEN effectively enhances the intrinsic growth potential of DC axons after SCI and therefore may help to develop a novel strategy to promote robust long-distance regeneration of primary sensory axons.
E. coli Leucine-responsive regulatory protein bridges DNA in vivo and tunably dissociates in the presence of exogenous leucine
Authors: Ziegler Christine A. , Freddolino Peter L. 
Published: March 2022

AbstractFeast-Famine Response Proteins are a widely conserved class of global regulators in prokaryotes, the most highly studied of which is the E. coli leucine-responsive regulatory protein (Lrp). Lrp senses environmental nutrition status and subsequently regulates up to one-third of the genes in E. coli, either directly or indirectly. Lrp exists predominantly as octamers and hexadecamers (16mers), where leucine is believed to shift the equilibrium towards the octameric state. In this study, we analyzed the effects of three oligomerization state mutants of Lrp in terms of their ability to bind to DNA and regulate gene expression in response to exogenous leucine. We find that oligomerization beyond dimers is required for Lrp’s regulatory activity, and that contrary to prior speculation, exogenous leucine modulates Lrp activity at its target promoters exclusively by inhibiting Lrp binding to DNA. We also find evidence that Lrp binding bridges DNA over length scales of multiple kilobases, revealing a new range of mechanisms for Lrp-mediated transcriptional regulation.
What drives bank lending? A closer look at bank lending types in Africa
Authors: Ayagre Philip , Dzeha Gloria , Kriese Maryam , Kusi Baah 
Published: March 2022

PurposeIn this study, the authors present unique evidence on bank lending types by paying particular attention to the factors that drive the different types of bank lending in Africa using bank level data.Design/methodology/approachIn presenting such evidence, the study employs a robust fixed effect panel data with year and technological controls comprising 57 banks from 29 African economies between 2006 and 2015.FindingsThe results show that different factors affect different bank lending types differently in Africa. Specifically, while the authors find that total or aggregate bank lending is positively driven by bank capitalization and spread but negatively driven by bank size, corporate and commercial bank lending is positively driven by bank size, spread, inflation, elections and extent of business disclosure but negatively driven by bank capitalization, loan loss reserves, operational cost and gross domestic product per capita. Moreover, interbank lending is both negatively and positively driven by bank capitalization and size, respectively, while other bank lending type is driven positively by financial crisis but negatively driven by bank size, inflation and extent of business disclosure. Finally, retail and consumer lending is positively driven by bank capitalization, loan loss reserves and spread while negatively driven by bank size and inflation.Practical implicationsThese imply that bank managers, regulators, policymakers and researchers must begin to see each bank lending category separately and independently since varying factors influence the different categories of bank lending differently.Originality/valueThe study presents new insights into how different factors determine different lending types in Africa for the first time to the best of the authors’ knowledge.