bluuebunny/crossref_metadata_2025 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

Multiple 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

Apolipoprotein 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

Diazotrophs 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

The 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

The 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

Co-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

Telomeres 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

The 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.
The role of host cell glycans on virus infectivity: The SARS-CoV-2 case
Authors: Acosta-Gutiérrez Silvia , Buckley Joseph , Battaglia Giuseppe
Published: May 2021

Long and complex chains of sugars, called glycans, often coat both the cell and protein surface. Glycans both modulate specific interactions and protect cells. On the cell surface, these sugars form a cushion known as the glycocalyx. Here, we show that Heparan Sulfate (HS) chains – part of the glycocalyx – and other glycans – expressed on the surface of both host and virus proteins – have a critical role in modulating both attractive and repulsive potentials during viral infection. We analyse the SARS-CoV-2 virus, modelling its spike proteins binding to HS chains and two key entry receptors, ACE2 and TMPRSS2. We include the volume exclusion effect imposed on the HS chains impose during virus insertion into glycocalyx and the steric repulsion caused by changes in the conformation of the ACE2 glycans involved in binding to the spike. We then combine all these interactions, showing that the interplay of all these components is critical to the behaviour of the virus. We show that the virus tropism depends on the combinatorial expression of both HS chains and receptors. Finally, we demonstrate that when both HS chains and entry receptors express at high density, steric effects dominate the interaction, preventing infection.
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

Background

A 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).

Aims

To 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.

Methods

FF 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.

Results

A 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

Sleep 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

Abstract

Bacillus 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 summary

Members 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

For 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.
Chromatin landscape dynamics in development of the plant parasitic nematode Meloidogyne incognita
Authors: Hassanaly-Goulamhoussen Rahim , De Carvalho Augusto Ronaldo , Marteu-Garello Nathalie , Péré Arthur , Favery Bruno , Da Rocha Martine , Danchin Etienne G.J. , Abad Pierre , Grunau Christoph , Perfus-Barbeoch Laetitia
Published: May 2021

In model organisms, epigenome dynamics underlies a plethora of biological processes. The role of epigenetic modifications in development and parasitism in nematode pests remains unknown. The root-knot nematode Meloidogyne incognita adapts rapidly to unfavorable conditions, despite its asexual reproduction. However, the mechanisms underlying this remarkable plasticity and their potential impact on gene expression remain unknown. This study provides the first insight into contribution of epigenetic mechanisms to this plasticity, by studying histone modifications in M. incognita. The distribution of five histone modifications revealed the existence of strong epigenetic signatures, similar to those found in the model nematode Caenorhabditis elegans. We investigated their impact on chromatin structure and their distribution relative to transposable elements (TE) loci. We assessed the influence of the chromatin landscape on gene expression at two developmental stages: eggs, and pre-parasitic juveniles. H3K4me3 histone modification was strongly correlated with high levels of expression for protein-coding genes implicated in stage-specific processes during M. incognita development. We provided new insights in the dynamic regulation of parasitism genes kept under histone modifications silencing. In this pioneering study, we establish a comprehensive framework for the importance of epigenetic mechanisms in the regulation of the genome expression and its stability in plant-parasitic nematodes.

Author summary

The nematode Meloidogyne incognita is one of the most destructive plant parasites worldwide. Its ability to infect a wide range of hosts and its high adaptability contribute to its parasitic success. We investigated the role of epigenetic mechanisms — specifically post-translational histone modifications — in the parasitic life cycle. We showed these modifications are linked to gene expression regulation and likely contribute to nematode development and pathogenicity.
CdrS is a global transcriptional regulator influencing cell division inHaloferax volcanii
Authors: Liao Yan , Vogel Verena , Hauber Sabine , Bartel Jürgen , Alkhnbashi Omer S. , Maaß Sandra , Schwarz Thandi S. , Backofen Rolf , Becher Dörte , Duggin Iain G. , Marchfelder Anita
Published: May 2021

Transcriptional regulators that integrate cellular and environmental signals to control cell division are well known in bacteria and eukaryotes, but their existence is poorly understood in archaea. We identified a conserved gene (cdrS)that encodes a small protein and is highly transcribed in the model archaeonHaloferax volcanii. ThecdrSgene could not be deleted, but CRISPRi-mediated repression of thecdrSgene caused slow growth, cell division defects, and changed the expression of multiple genes and their products associated with cell division, protein degradation and metabolism. Consistent with this complex regulatory network, overexpression ofcdrSinhibited cell division, whereas overexpression of the operon encoding both CdrS and a tubulin-like cell division protein (FtsZ2) stimulated division. ChIP-Seq identified 18 DNA-binding sites of the CdrS protein including one upstream of the promoter for diadenylate cyclase, which is an essential gene involved in c-di-AMP signalling implicated in the regulation of cell division. These findings suggest that CdrS is a transcription factor that plays a central role in a regulatory network coordinating metabolism and cell division.

Importance

Cell division is a central mechanism of life, and is essential for growth and development. Bacteria and Eukarya have different mechanisms for cell division, which have been studied in detail. In contrast, cell division in Archaea is still understudied, and its regulation is poorly understood. Interestingly, different cell division machineries appear in the Archaea, with the Euryarchaeota using a cell division apparatus based on the tubulin-like cytoskeletal protein FtsZ, as in bacteria. Here we identify the small protein CdrS as essential for survival and a central regulator of cell division in the EuryarchaeonHaloferax volcanii. CdrS also appears to coordinate other cellular pathways including synthesis of signalling molecules and protein degradation. Our results show that CdrS plays a sophisticated role in cell division, including regulation of numerous associated genes. These findings are expected to initiate investigations into conditional regulation of division in archaea.
Comprehensive profiling of mutations to influenza virus PB2 that confer resistance to the cap-binding inhibitor pimodivir
Authors: Soh Y.Q. Shirleen , Malone Keara D. , Eguia Rachel T. , Bloom Jesse D.
Published: May 2021

Antivirals are used not only in current treatment of influenza, but are also stockpiled as a first line of defense against novel influenza strains for which vaccines have yet to be developed. Identifying drug resistance mutations can guide clinical deployment of the antiviral, and additionally define the mechanisms of drug action and drug resistance. Pimodivir is a first-in-class inhibitor of the polymerase basic protein 2 (PB2) subunit of the influenza A virus polymerase complex. A number of resistance mutations have previously been identified in treated patients or cell culture. Here, we generate a complete map of the effect of all single-amino-acid mutations to an avian PB2 on resistance to pimodivir. We identified both known and novel resistance mutations not only in the previously implicated cap-binding and mid-link domains, but also in the N-terminal domain. Our complete map of pimodivir resistance thus enables the evaluation of whether new viral strains contain mutations that will confer pimodivir resistance.
Non-coding RNAs Associated with Prader-Willi Syndrome Regulate Transcription of Neurodevelopmental Genes in Human Induced Pluripotent Stem Cells
Authors: Sledziowska Monika , Jones Matt , Maghrabi Ruba Al , Hebenstreit Daniel , Garcia Paloma , Grzechnik Pawel
Published: May 2021

Mutations and aberrant gene expression during cellular differentiation lead to neurodevelopmental disorders such as Prader-Willi syndrome (PWS) which results from the deletion of an imprinted locus on chromosome 15. We analysed chromatin-associated RNA in human induced pluripotent cells (iPSCs) upon depletion of hybrid small nucleolar long non-coding RNAs (sno-lncRNAs) and 5’ snoRNA capped and polyadenylated long non-coding RNAs (SPA-lncRNAs) transcribed from the locus deleted in PWS. We found that rapid ablation of these lncRNAs affects transcription of specific gene classes. Downregulated genes contribute to neurodevelopment and neuronal maintenance while genes that are upregulated are predominantly involved in the negative regulation of cellular metabolism and apoptotic processes. Our data revealed the importance of SPA-lncRNAs and sno-lncRNAs in controlling gene expression in iPSCs and provided a platform for synthetic experimental approaches in PWS studies. We conclude that ncRNAs transcribed from the PWS locus are critical regulators of a transcriptional signature important for neuronal differentiation and development.
Molecular basis and functional consequences of the interaction between the Base Excision Repair DNA glycosylase NEIL1 and RPA
Authors: Le Meur Rémy A. , Pecen Turner J. , Le Meur Kateryna V. , Nagel Zachary D. , Chazin Walter J.
Published: May 2021

NEIL1 is a DNA glycosylase that recognizes and initiates base excision repair of oxidized bases. The ubiquitous ssDNA binding scaffolding protein replication protein A (RPA) modulates NEIL1 activity in a manner that depends on DNA structure. Interaction between NEIL1 and RPA has been reported, but the molecular basis of this interaction has yet to be investigated. Using a combination of NMR spectroscopy and isothermal titration calorimetry (ITC), we show that NEIL1 interacts with RPA through two contact points. An interaction with the RPA32C protein recruitment domain was mapped to a motif in the common interaction domain (CID) of NEIL1 and a dissociation constant (Kd) of 200 nM was measured. A substantially weaker secondary interaction with the tandem RPA70AB ssDNA binding domains was also mapped to the CID. Together these two contact points reveal NEIL1 has a high overall affinity (Kd ∼ 20 nM) for RPA. A homology model of the complex of RPA32C with the NEIL1 RPA binding motif in the CID was generated and used to design a set of mutations in NEIL1 to disrupt the interaction, which was confirmed by ITC. The mutant NEIL1 remains catalytically active against ionizing radiation-induced DNA lesions in duplex DNA in vitro. Testing the functional effect of disrupting the NEIL1-RPA interaction in vivo using a Fluorescence Multiplex-Host Cell Reactivation (FM-HCR) reporter assay revealed that RPA interaction is not required for NEIL1 activity against oxidative damage in duplex DNA, and furthermore revealed an unexpected role for NEIL1 in nucleotide excision repair. These findings are discussed in the context of the role of NEIL1 in replication-associated repair.
Brainstem cholinergic modulation of the thalamocortical activity in urethane anesthetized mice
Authors: Hay Y Audrey
Published: May 2021

In mammals, sleep consists in the recurrence of two main stages the rapid eye movement (REM) sleep and the slow wave sleep (SWS). The full expression of sleep rhythms requires an intact thalamocortical loop, and its modulation by neuromodulators such as acetylcholine. A high tone of acetylcholine is observed during REM sleep while a low tone of acetylcholine modulates the cortical slow waves during SWS. Brainstem Cholinergic neurons activity correlates with cortical sleep stages but these neurons do not project directly to the cortex. Instead, they could contribute to cortically-recorded sleep stage modulation via a thalamic relay, in particular via the midline thalamic nuclei. Focusing on the brainstem LDTg cholinergic neurons, I investigated how midline thalamic single unit activity and cortical sleep-like stages are modulated during optogenetic-induced activation or silencing of LDTg cholinergic neurons in urethane anesthetized mice. Thalamic neurons were more active during REM-like than SWS-like stages. Bursting activity predominated during SWS-like while tonic firing was prominent during REM-like stage. Optogenetic silencing of the brainstem LDTg cholinergic neurons abolished REM-like stages and reduced tonic spiking of thalamic neurons. Moreover, during SWS-like, silent Down states were prolonged and thalamic tonic spiking during Up states was reduced. Stimulation of the brainstem LDTg cholinergic neurons had a mild effect on thalamic activity even though tonic discharge was increased. Surprisingly, optogenetic stimulation abolished as well REM-like stages maybe through compensatory mechanisms.
FDI inflows and bank deposits: evidence from 18 MENA economies
Authors: Saif-Alyousfi Abdulazeez Y.H.
Published: May 2021

Purpose

This paper aims to examine and compare the impact of foreign direct investment (FDI) inflows on bank deposits in aggregate as well as at the level of conventional and Islamic banks in Middle East and North Africa (MENA) countries. The study also tests hypotheses of direct and indirect impacts of FDI flow and FDI stock on bank deposits.

Design/methodology/approach

Static and dynamic panel generalized methods of moments (GMM) estimation techniques are applied to analyze a large data set of 491 commercial banks (422 conventional banks and 69 Islamic banks) across 18 MENA countries between 1993 and 2017 (12,275 year observations).

Findings

Empirical results indicate that inflowing FDI flow and FDI stock have a significant negative direct impact on deposits of MENA banks. The results lend support for the direct channel hypothesis for the effect of FDI on bank deposits and find no evidence in support of the indirect channel hypothesis. FDI inflows affect bank deposits directly via increased FDI-related excessive competition in the banking market. Deposits from conventional banks appear to be more affected than those from Islamic banks. The variation may due to the fact that Islamic banks have fewer multinational corporations (MNC) customers than conventional banks and therefore are less sensitive to fluctuations in FDI.

Practical implications

From this analysis, this study concludes that foreign investments have a higher productivity than local investments in MENA region. Attracting more FDI is aimed at increasing overall national productivity through competition. However, governments would be wise to enact such a policy to maximize benefits and minimize potential harm to local industry. Furthermore, FDI policy should encourage small to medium-size banks and firms (SMEs)’ participation and linkage with multinational banks and MNCs, while upgrading research and development institutions and innovation activities to help SMEs to benefit from potential spillovers from foreign presence in the industry. In addition, the linkage and connection between SMEs and foreign firms should be strengthened and promoted by government policy.

Originality/value

This study is the first of its kind to examine the effect of FDI inflows on bank deposits. It also provides an in-depth quantitative analysis of the impact of FDI flow and FDI stock, separately, on bank deposits for both conventional and Islamic banks. It distinguishes between direct and indirect channels through which FDI inflows may affect bank deposits. The study analyzes 25 years of panel data for 491 banks (12,275 year observations) and uses both static and dynamic panel GMM estimation techniques to analyze the data.
An investigation of factors influencing intercultural communication competence of the international students from a higher education institute in Malaysia
Authors: Nadeem Muhammad Umar , Mohammed Rosli , Dalib Syarizan , Mumtaz Samavia
Published: May 2021

Purpose

The purpose of this study is to highlight the importance of intercultural communication competence (ICC) of international students living in Malaysia. This study considered the culture-general factors of integrated model of ICC (IMICC) established from the West with an addition of empathy and further addressed these influencers on the international students from a Malaysian university. It is proposed that empathy, sensation seeking, ethnocentrism, attitude and motivation have a direct influence on ICC.

Design/methodology/approach

A quantitative research methodology was considered to address the relationship between the variables of this study. Data were collected through a survey by visiting different parts of the university campus. A total of 388 international students took part in the study voluntarily. Data were analysed using statistical package for social sciences (SPSS) and structural equation modeling-analysis of a moment structures (SEM-AMOS).

Findings

The findings revealed that empathy, sensation seeking and attitude are the antecedents of ICC. However, ethnocentrism and motivation do not influence ICC significantly.

Originality/value

Through the findings of this study, a series of training sessions can be conducted by Malaysia (host country training) and sender countries (home country training) to educate international students regarding ICC. Furthermore, ministry of higher education (MoHE) Malaysia and higher education institutes (HEIs) can improve their infrastructure and services in terms of hosting and accommodating more international students by considering the findings of this study. These approaches could help international students to adjust in a new cultural setting of Malaysia.
Cross-border banking and foreign branch regulation in Europe
Authors: Gibilaro Lucia , Mattarocci Gianluca
Published: May 2021

Purpose

This paper aims to examine the relevance of cross-border activity in the European banking sector, evaluating the role of differences in regulation to explain the level of interest in entering foreign markets.

Design/methodology/approach

The sample considers all banks in the European Union (EU 28) existing at year-end 2017, and information about the ultimate owners’ nationality to classify local and foreign banks is collected. The analysis provides a mapping of regulatory restrictions for foreign banks and evaluates how they impact the role of foreign players in the deposit and lending markets.

Findings

Results show that the lower are the capital adequacy requirements, the higher are the amounts of loans and deposits offered by non-European Economic Area banks and, additionally, the higher the probability of having a foreign bank operating in the country.

Originality/value

This paper provides new evidence on regulatory arbitrage opportunities in the EU and outlines differences among EU countries not previously studied.
Polypharmacy as maintenance treatment in bipolar illness: A systematic review
Authors: Amerio Andrea , Russo Daniel , Miletto Norberto , Aguglia Andrea , Costanza Alessandra , Benatti Beatrice , Odone Anna , Barroilhet Sergio A. , Brakoulias Vlasios , Dell’Osso Bernardo , Serafini Gianluca , Amore Mario , Ghaemi S. Nassir
Published: May 2021

Objectives

Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research.

Method

A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library.

Results

Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone.

Conclusions

The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.
Aquaporin 4 differentially modulates osmotic effects on vasopressin neurons in rat supraoptic nucleus
Authors: Wang Xiaoran , Li Tong , Liu Yang , Jia Shuwei , Liu Xiaoyu , Jiang Yunhao , Wang Ping , Parpura Vladimir , Wang Yu‐Feng
Published: May 2021

Aim

Glial fibrillary acidic protein (GFAP) molecularly associates with aquaporin 4 (AQP4) in astrocytic plasticity. Here, we further examined how AQP4 modulates osmotic effects on vasopressin (VP) neurons in rat supraoptic nucleus (SON) through interactions with GFAP in astrocytes.

Methods

Brain slices from adult male rats were kept under osmotic stimulation. Western blot, co‐immunoprecipitation, immunohistochemistry and patch‐clamp recordings were used for analysis of expressions and interactions between GFAP and AQP4, astrocyte‐specific proteins in the SON, as well as their influence on VP neuronal activity. Data were analysed using SPSS software.

Results

Hyposmotic challenge (HOC) of acute SON slices caused an early (within 5 minutes) and transient increase in the colocalization of AQP4 with GFAP filaments. This effect was prominent at astrocytic processes surrounding VP neuron somata and was accompanied by inhibition of VP neuronal activity. Similar HOC effect was seen in the SON isolated from rats subjected to in vivo HOC, wherein a transiently increased molecular association between GFAP and AQP4 was detected using co‐immunoprecipitation. The late stage rebound excitation (10 minutes) of VP neurons in brain slices subjected to HOC and the associated astrocytic GFAP’s ‘return to normal’ were both hampered by 2‐(nicotinamide)‐1,3,4‐thiadiazole, a specific AQP4 channel blocker that itself did not influence VP neuronal activity. Moreover, this agent prevented hyperosmotic stress‐evoked excitation of VP neurons and associated reduction in GFAP filaments.

Conclusion

These findings indicate that osmotically driven increase in VP neuronal activity requires the activation of AQP4, which determines a retraction of GFAP filaments.
Effect of CES1 genetic variation on enalapril steady‐state pharmacokinetics and pharmacodynamics in healthy subjects
Authors: Her Lucy H. , Wang Xinwen , Shi Jian , Choi Hee Jae , Jung Sun Min , Smith Logan S. , Wu Audrey H. , Bleske Barry E. , Zhu Hao‐Jie
Published: May 2021

Aims

Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single‐dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi‐dose, pharmacokinetics and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady‐state PK and PD in healthy volunteers.

Methods

Study participants were stratified to G143E non‐carriers (n = 15) and G143E carriers (n = 6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72 hour PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established liquid chromatography–tandem mass spectrometry (LC–MS/MS) method.

Results

The CES1 G143E carriers had 30.9% lower enalaprilat Cmax (P =  0.03) compared to the non‐carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC0–∞ (P =  0.02) of plasma enalaprilat compared to the non‐carriers (374.29 vs. 515.91 ng*h/mL). The carriers also had a 32.3% lower enalaprilat‐to‐enalapril AUC0–∞ ratio (P =  0.003) relative to the non‐carriers. The average maximum reduction of systolic blood pressure in the non‐carrier group was approximately 12.4% at the end of the study compared to the baseline (P =  0.001). No statistically significant blood pressure reduction was observed in the G143E carriers.

Conclusions

The CES1 loss‐of‐function G143E variant significantly impaired enalapril activation and its systolic blood pressure‐lowering effect in healthy volunteers.
An ethical defense of cryptocurrencies
Authors: Bagus Philipp , de la Horra Luis P.
Published: May 2021

The growing importance of the cryptocurrency phenomenon has raised concerns about the ethical implications of a hypothetical widespread use of these new forms of digital money. In this paper, we undertake an ethical assessment of cryptocurrencies drawing upon two specific ethical theories: private property ethics and utilitarianism. Particularly, we focus on three distinctive aspects. First, we examine the advantages and disadvantages of cryptocurrencies vis‐à‐vis central bank fiat money. Second, we analyze cryptocurrencies as facilitators of tax evasion and the ethical implications arising therefrom. Finally, we explore the use of cryptocurrencies for nefarious consumption. We conclude that, were cryptocurrencies to become widespread media of exchange, governments capacity to undertake monetary, fiscal, and drug policy would be undermined. We argue that this would be an ethically desirable outcome from both a private‐property‐rights and a utilitarian perspective since it would force governments to reduce their size and scope in these three areas.