bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study protocol: Strengthening understanding of effective adherence strategies for first-line and second-line antiretroviral therapy (ART) in selected rural and urban communities in South Africa
Authors: Gumede Siphamandla Bonga , de Wit John Benjamin Frank , Venter Willem Daniel Francois , Lalla-Edward Samanta Tresha 
Published: May 2021

AbstractMultiple factors make adherence to antiretroviral therapy (ART) a complex process. This study aims to describe the barriers and facilitators to adherence for patients receiving first-line and second-line ART, identify different adherence strategies utilized and make recommendations for an improved adherence strategy.This mixed method parallel convergent study will be conducted in seven high volume public health facilities in Gauteng and one in Limpopo province in South Africa. The study consists of four phases; a retrospective secondary data analysis of a large cohort of patients on ART (using TIER.Net, an ART patient and data management system for recording and monitoring patients on ART and tuberculosis (TB) from seven Johannesburg inner-city public health facilities (Gauteng province); a secondary data analysis of the Intensified Treatment Monitoring Accumulation (ITREMA) trial (a randomized control trial which ran from June 2015 to January 2019) conducted at the Ndlovu Medical Center (Limpopo province); in-depth interviews with HIV infected patients on ART (in both urban and rural settings); and a systematic review of the impact of treatment adherence interventions for chronic conditions in sub-Saharan Africa. Data will be collected on demographics, socio-economic status, treatment support, retention in care status, disclosure, stigma, clinical markers (CD4 count and viral load), self-reported adherence information, intrapersonal, and interpersonal factors, community networks, and policy level factors. The systematic review will follow the PRISMA reporting and PICO criteria. Analyses will involve tests of association (Chi-square and t-test), thematic analysis (deductive and inductive approaches) and network meta-analysis.Using an integrated multilevel socio-ecological framework this study will describe the factors associated with adherence for HIV infected patients who are taking first-line or second-line ART. Implementing evidence-based adherence approaches, when taken up, will improve patient’s overall health outcomes. Our study results will provide guidance regarding context-specific intervention strategies to improve ART adherence.
Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes
Authors: Zhang Zhongyang , Sun Zeguo , Lin Qisheng , Banu Khadija , Chauhan Kinsuk , Planoutene Marina , Wei Chengguo , Salem Fadi , Yi Zhengzi , Fu Jia , Liu Ruijie , Cheng Haoxiang , Hao Ke , O’Connell Philip , Ishibe Shuta , Zhang Weijia , Coca Steven G. , Gibson Ian W. , Colvin Robert B. , He John Cijiang , Heeger Peter S. , Murphy Barbara , Menon Madhav C. 
Published: May 2021

ABSTRACTApolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss but whether recipient risk allele expression impacts kidney transplant outcomes is unclear. To test whether recipient APOL1 allelic variants independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of genetic ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. Analysis of the CTOT cohort validated these associations. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4+/CD8+ T cells and natural killer cells. We detected enriched immune response gene pathways in G1/G2 allele carriers vs. non-carriers among patients on the kidney waitlist and healthy controls. Together our findings highlight a previously unrecognized contribution of recipient APOL1 risk alleles to renal allograft outcomes. This immunomodulatory role has broader implications for immune mediated injury to native kidneys.
Massive export of diazotrophs across the South Pacific tropical Ocean
Authors: Bonnet Sophie , Benavides Mar , Le Moigne Frédéric A.C. , Camps Mercedes , Torremocha Antoine , Grosso Olivier , Dimier Céline , Spungin Dina , Berman-Frank Ilana , Garczarek Laurence , Cornejo-Castillo Francisco M. 
Published: May 2021

AbstractDiazotrophs are widespread microorganisms that alleviate nitrogen limitation in 60% of our oceans, regulating marine productivity. Yet, their contribution to organic matter export has not been quantified, making an assessment of their impact on the biological carbon pump impossible. Here, we demonstrate that cyanobacterial and non-cyanobacterial diazotrophs are massively exported down to 1000 m-depth in the western subtropical South Pacific Ocean (WTSP), accounting for up to 52-100% of the total particulate nitrogen export fluxes. We further demonstrate that small size unicellular diazotrophs (UCYN, 1-8 µm) are exported more efficiently than filamentous diazotrophs (>100-1000 µm) under the form of large (>50 µm) aggregates linked by an extracellular organic matrix. Beyond the WTSP, our data are supported by analysis of the Tara Oceans metagenomes collected in other ocean basins, showing that diazotrophs are systematically detected in mesopelagic waters when present at the surface. We thus conclude that diazotrophs are key players in carbon sequestration in the ocean and need to be considered in future studies to improve the accuracy of current regional and global estimates of export.
T-type Ca2+and persistent Na+currents synergistically elevate ventral, not dorsal, entorhinal cortical stellate cell excitability
Authors: Topczewska Aleksandra , Giacalone Elisabetta , Pratt Wendy S. , Migliore Michele , Dolphin Annette C. , Shah Mala M. 
Published: May 2021

SummaryThe medial entorhinal cortex (mEC) plays a salient role in physiological processes such as spatial cognition and spatial coding. mEC layer II stellate neurons, in particular, influence these processes. Interestingly, ventral and dorsal stellate neurons diversely affect these processes and have distinct intrinsic membrane properties and action potential firing patterns. Little, though, is known about how ventral stellate neuron intrinsic excitability is regulated. We show that ventral stellate neurons predominantly possess T-type Ca2+currents encoded by CaV3.2 subunits, with dorsal stellate neurons having small or no currents. Further, twice as much CaV3.2 mRNA was present in ventral than dorsal mEC. In line with T-type, CaV3.2 Ca2+current biophysical properties, depolarising stimuli activated these currents in ventral, but not dorsal, neurons. Here, these currents acted in concert with persistent Na+currents to elevate input resistance and tonic action potential firing. CaV3.2 currents also enhanced excitatory post-synaptic potential decay and integration solely in ventral neurons. These results reveal that CaV3.2 currents, together with persistent Na+currents, impart the characteristic intrinsic membrane and firing properties of ventral stellate neurons. This signifies that specific voltage-gated conductances distinctly affect ventral and dorsal mEC stellate neuron activity and functions such as spatial memory and spatial navigation.
SwrA as global modulator of the two-component system DegS/U inB. subtilis
Authors: Ermoli Francesca , Vitali Giulia , Calvio Cinzia 
Published: May 2021

ABSTRACTThe two-component system DegS/U ofBacillus subtiliscontrols more than one hundred genes involved in several different cellular behaviours. Since the consensus sequence recognized by the response regulator DegU has not been clearly defined yet, mutations in either component have been crucial in the identification of the cellular targets of this regulatory system. Over the years, thedegU32Hymutant allele, that was supposed to mimic the activated regulator, has been commonly used to define the impact of this TCS on its regulated genes in domestic strains.SwrA encodes a small protein essential for swarming motility and for poly-γ-glutamate biosynthesis and is only present in wild strains. Previous work indicated that SwrA is partnering with DegU~P in exerting its role on both phenotypes.In this work, inserting adegS200Hymutation inswrA+andswrA-isogenic strains we demonstrate that SwrA modulates the action of DegU~P on two new phenotypes, subtilisin expression and competence for DNA uptake, with a remarkable effect on transformation. These effects cannot not be appreciated with the DegU32Hymutant as it does not mirror the wild-type DegU protein in its ability to interact with SwrA.
Phosphatidylserine binding regulates TIM-3 effects on T cell receptor signaling
Authors: Smith Courtney M. , Li Alice , Krishnamurthy Nithya , Lemmon Mark A. 
Published: May 2021

SUMMARYCo-signaling receptors for the T cell receptor are important therapeutic targets, with blocking co-inhibitory receptors such as PD-1 now central in immuno-oncology. Advancing additional therapeutic immune modulation approaches requires understanding ligand regulation of other co-signaling receptors. One poorly understood therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which ligands are relevant for TIM-3 signaling is unclear, and different studies have reported it as co-inhibitory or co-stimulatory. Here, we show that TIM-3 promotes NF-κB signaling and IL-2 secretion following T cell receptor stimulation in Jurkat cells, and is regulated by phosphatidylserine (PS) binding. TIM-3 signaling is stimulated by PS exposed constitutively in cultured Jurkat cells, and can be blocked by mutating the PS-binding site or by occluding this site with an antibody. We also find that TIM-3 signaling alters CD28 phosphorylation. Our findings help clarify conflicting literature results with TIM-3, and inform its exploitation as a therapeutic target.
Trypanosoma bruceiPolIE suppresses telomere recombination
Authors: Tonini Maiko , Rabbani M. A. G. , Afrin Marjia , Li Bibo 
Published: May 2021

AbstractTelomeres are essential for genome integrity and stability. InT. bruceithat causes human African trypanosomiasis, the telomere structure and telomere proteins also influence the virulence of the parasite, as its major surface antigen involved in the host immune evasion is expressed exclusively from loci immediately upstream of the telomere repeats. However, telomere maintenance mechanisms are still unclear except that telomerase-mediated telomere synthesis is a major player. We now identify PolIE as an intrinsic telomere complex component. We find that depletion of PolIE leads to an increased amount of telomere/subtelomere DNA damage, an elevated rate of antigenic variation, and an increased amount of telomere T-circles and C-circles, indicating that PolIE suppresses telomere recombination and helps maintain telomere integrity. In addition, we observe much longer telomere G-rich 3’ overhangs in PolIE-depleted cells, which is not dependent on telomerase. Furthermore, the level of telomere DNA synthesis is slightly increased in PolIE-depleted cells, which is dependent on telomerase. Therefore, we identify PolIE as a major player for telomere maintenance inT. brucei.
Suppression of Global Protein Translation in SARS-CoV-2 Infection
Authors: Parthasarathy Haripriya , Gupta Divya , Suresh Abhirami P , Tandel Dixit , Sah Vishal , Harshan Krishnan Harinivas 
Published: May 2021

ABSTRACTThe relationship of SARS-CoV-2 with the host translation remains largely unexplored. Using polysome profiling of SARS-CoV-2 infected Caco2 cells, we here demonstrate that the virus induces a strong suppression of global translation by 48 hours of infection. Heavy polysome fractions displayed substantial depletion in the infected cells, indicating the loss of major translational activities in them. Further assessment of the major pathways regulating translation in multiple permissive cell lines revealed strong eIF4E dephosphorylation accompanied by Mnk1 depletion and ERK1/2 dephosphorylations. p38MAPK showed consistent activation and its inhibition lowered viral titers, indicating its importance in viral survival. mTORC1 pathway showed the most profound inhibition, indicating its potential contribution to the suppression of global translation associated with the infection. Pharmacological activation of mTORC1 caused a drop in viral titers while inhibition resulted in higher viral RNA levels, confirming a critical role of mTORC1 in regulating viral replication. Surprisingly, the infection did not cause a general suppression of 5’-TOP translation, as evident from the continued expression of ribosomal proteins. Our results collectively indicate that the differential suppression of mTORC1 might allow SARS-CoV-2 to hijack translational machinery in its favor and specifically target a set of host mRNAs.
In schizophrenia, chronic fatigue syndrome- and fibromyalgia-like symptoms are driven by breakdown of the paracellular pathway with increased zonulin and immune activation-associated neurotoxicity
Authors: Maes Michael , Andrés-Rodríguez Laura , Vojdani Aristo , Sirivichayakul Sunee , Barbosa Decio S. , Kanchanatawan Buranee 
Published: May 2021

AbstractBackgroundA meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic) which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs).AimsTo examine whether FF symptoms in schizophrenia are associated with breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial-(BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome.MethodsFF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods.ResultsA large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively) and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome. Discussion: The physio-somatic symptoms of schizophrenia are driven by various pathways including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.
Tonic endocannabinoid signaling supports sleep through development in both sexes
Authors: Martin Sheneé C. , Gay Sean M. , Armstrong Michael L. , Pazhayam Nila M. , Reisdorph Nichole , Diering Graham H. 
Published: May 2021

AbstractSleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in developing and adult mice. We find that eCBs are downregulated in response to acute sleep deprivation in juvenile mice, while in young adults eCBs are upregulated during the sleep phase in a circadian manner. Next we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a non-invasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.
Unraveling protein interactions between the temperate virus Bam35 and its Bacillus host using an integrative Yeast two hybrid-High throughput sequencing approach
Authors: Lechuga Ana , Lood Cédric , Berjón-Otero Mónica , Prado Alicia del , Wagemans Jeroen , van Noort Vera , Lavigne Rob , Salas Margarita , Redrejo-Rodríguez Modesto 
Published: May 2021

AbstractBacillus virus Bam35 is the model Betatectivirus and member of the Tectiviridae family, which is composed of tailless, icosahedral, and membrane-containing bacteriophages. The interest in these viruses has greatly increased in recent years as they are thought to be an evolutionary link between diverse groups of prokaryotic and eukaryotic viruses. Additionally, betatectiviruses infect bacteria of the Bacillus cereus group, known for their applications in industry and notorious since it contains many pathogens. Here, we present the first protein-protein interactions network for a tectivirus-host system by studying the Bam35-Bacillus thuringiensis model using a novel approach that integrates the traditional yeast two-hybrid system and Illumina high-throughput sequencing. We generated and thoroughly analyzed a genomic library of Bam35’s host B. thuringiensis HER1410 and screened interactions with all the viral proteins using different combinations of bait-prey couples. In total, this screen resulted in the detection of over 4,000 potential interactions, of which 183 high-confidence interactions were defined as part of the core virus-host interactome. Overall, host metabolism proteins and peptidases are particularly enriched within the detected interactions, distinguishing this host-phage system from the other reported host-phage protein-protein interaction networks (PPIs). Our approach also suggests biological roles for several Bam35 proteins of unknown function, resulting in a better understanding of the Bam35-B. thuringiensis interaction at the molecular level.Author summaryMembers of the family Tectiviridae, composed of non-tailed icosahedral, membrane-containing bacteriophages, have been increasingly scrutinized in recent years for their possible role in the origin of dsDNA viruses. In particular, the genus Betatectivirus receives increased attention as these phages can infect clinical strains as well as industrially relevant members of the B. cereus group. However, little is known about the interactions between these temperate viruses and their hosts. Here, we present the first high-throughput study of tectivirus-host protein-protein interactions focusing on Bam35, model virus of betatectiviruses, and its host B. thuringiensis, an important entomopathogenic bacterium. We adapted the well-known technique yeast-two-hybrid and integrated high-throughput sequencing and bioinformatics for the downstream analysis of the results which enables large-scale analysis of protein-protein interactions. In total, 182 detected interactions show an enrichment in host metabolic proteins and peptidases, in contrast with the current knowledge on host-phage PPIs. Specific host-viral protein-protein interactions were also detected enabling us to propose functions for uncharacterized proteins.
Efflux only impacts drug accumulation in actively growing cells
Authors: Whittle Emily E , McNeil Helen E , Trampari Eleftheria , Webber Mark , Overton Tim W , Blair Jessica M A 
Published: May 2021

AbstractFor antibiotics with intracellular targets, effective treatment of bacterial infections requires the drug to accumulate to a high concentration inside cells. Bacteria produce a complex cell envelope and possess drug-export efflux pumps to limit drug accumulation inside cells. Decreasing cell envelope permeability and increasing efflux pump activity can reduce intracellular accumulation of antibiotics, and are commonly seen in antibiotic resistant strains. Here, we show that the balance between influx and efflux differs depending on bacterial growth phase in Gramnegative bacteria. Accumulation of the model fluorescent drug, ethidium bromide (EtBr) was measured in S. Typhimurium SL1344 (wild-type) and efflux deficient (ΔacrB) strains during growth. In SL1344, EtBr accumulation remained low, regardless of growth phase and did not correlate with acrAB transcription. EtBr accumulation in ΔacrB was high in exponential phase but dropped sharply later in growth, with no significant difference to SL1344 in stationary phase. Low EtBr accumulation in stationary phase was not due to the upregulation of other efflux pumps, but instead, due to decreased permeability of the envelope in stationary phase. RNAseq identified changes in expression of several pathways that remodel the envelope in stationary phase, leading to lower permeability. This study shows that efflux is only important for maintaining low drug accumulation in actively growing cells, and that envelope permeability is the predominant factor dictating the rate of drug entry in stationary phase cells. This conclusion means that (i) antibiotics with intracellular targets may be less effective in complex non-growing or slow-growing bacterial infections where intracellular accumulation may be low, (ii) efflux inhibitors may be successful in potentiating the activity of existing antibiotics, but potentially only for bacterial infections where cells are actively growing and (iii) the remodelling of the cell envelope prior to stationary phase could provide novel drug targets.