bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural Features of the Glutamate Transporter Family
Authors: Slotboom Dirk Jan , Konings Wil N. , Lolkema Juke S. 
Published: December 2019

SUMMARY

Neuronal and glial glutamate transporters remove the excitatory neurotransmitter glutamate from the synaptic cleft and thus prevent neurotoxicity. The proteins belong to a large and widespread family of secondary transporters, including bacterial glutamate, serine, and C
4
-dicarboxylate transporters; mammalian neutral-amino-acid transporters; and an increasing number of bacterial, archaeal, and eukaryotic proteins that have not yet been functionally characterized. Sixty members of the glutamate transporter family were found in the databases on the basis of sequence homology. The amino acid sequences of the carriers have diverged enormously. Homology between the members of the family is most apparent in a stretch of approximately 150 residues in the C-terminal part of the proteins. This region contains four reasonably well-conserved sequence motifs, all of which have been suggested to be part of the translocation pore or substrate binding site. Phylogenetic analysis of the C-terminal stretch revealed the presence of five subfamilies with characterized members: (i) the eukaryotic glutamate transporters, (ii) the bacterial glutamate transporters, (iii) the eukaryotic neutral-amino-acid transporters, (iv) the bacterial C
4
-dicarboxylate transporters, and (v) the bacterial serine transporters. A number of other subfamilies that do not contain characterized members have been defined. In contrast to their amino acid sequences, the hydropathy profiles of the members of the family are extremely well conserved. Analysis of the hydropathy profiles has suggested that the glutamate transporters have a global structure that is unique among secondary transporters. Experimentally, the unique structure of the transporters was recently confirmed by membrane topology studies. Although there is still controversy about part of the topology, the most likely model predicts the presence of eight membrane-spanning α-helices and a loop-pore structure which is unique among secondary transporters but may resemble loop-pores found in ion channels. A second distinctive structural feature is the presence of a highly amphipathic membrane-spanning helix that provides a hydrophilic path through the membrane. Recent data from analysis of site-directed mutants and studies on the mechanism and pharmacology of the transporters are discussed in relation to the structural model.
Mechanisms of T-Cell Activation by Human T-Cell Lymphotropic Virus Type I
Authors: Höllsberg Per 
Published: December 2019

SUMMARYThe interactions between human T-cell lymphotropic virus type I (HTLV-I) and the cellular immune system can be divided into viral interference with functions of the infected host T cell and the subsequent interactions between the infected T cell and the cellular immune system. HTLV-I-mediated activation of the infected host T cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction pathways, cell cycle control, and apoptosis. These properties of Tax may well explain the ability of HTLV-I to immortalize T cells. It is not clear, though, how HTLV-I induces T-cell transformation (interleukin-2 [IL-2] independence). Recent evidence suggests that Tax may promote the G1- to S-phase transition, although this may involve additional proteins. A role for other viral proteins that may constitutively activate the IL-2 receptor pathway has also been suggested. By virtue of their activated state, HTLV-I-infected T cells can nonspecifically activate resting, uninfected T cells via virus-mediated upregulation of adhesion molecules. This may favor viral dissemination. Moreover, the induction of a remarkably high frequency of antiviral CD8+T cells does not appear to eliminate the infection. Indeed, individuals with a high frequency of virus-specific CD8+T cells have a high viral load, indicating a state of chronic immune system stimulation. Thus, while an activated immune system is needed to eradicate the infection, the spread of the HTLV-I is also accelerated under these conditions. A detailed knowledge of the molecular interactions between virus-specific CD8+T cells and immunodominant viral epitopes holds promise for the development of specific antiviral therapy.
Prions in
Saccharomyces
and
Podospora
spp.: Protein-Based Inheritance
Authors: Wickner Reed B. , Taylor Kimberly L. , Edskes Herman K. , Maddelein Marie-Lise , Moriyama Hiromitsu , Roberts B. Tibor 
Published: December 2019

SUMMARY
Genetic evidence showed two non-Mendelian genetic elements of Saccharomyces cerevisiae, called [URE3] and [PSI], to be prions of Ure2p and Sup35p, respectively. [URE3] makes cells derepressed for nitrogen catabolism, while [PSI] elevates the efficiency of weak suppressor tRNAs. The same approach led to identification of the non-Mendelian element [Het-s] of the filamentous fungus Podospora anserina, as a prion of the het-s protein. The prion form of the het-s protein is required for heterokaryon incompatibility, a normal fungal function, suggesting that other normal cellular functions may be controlled by prions. [URE3] and [PSI] involve a self-propagating aggregation of Ure2p and Sup35p, respectively. In vitro, Ure2p and Sup35p form amyloid, a filamentous protein structure, high in β-sheet with a characteristic green birefringent staining by the dye Congo Red. Amyloid deposits are a cardinal feature of Alzheimer’s disease, non-insulin-dependent diabetes mellitus, the transmissible spongiform encephalopathies, and many other diseases. The prion domain of Ure2p consists of Asn-rich residues 1 to 80, but two nonoverlapping fragments of the molecule can, when overproduced, induce the de nova appearance of [URE3]. The prion domain of Sup35 consists of residues 1 to 114, also rich in Asn and Gln residues. While runs of Asn and Gln are important for [URE3] and [PSI], no such structures are found in PrP or the Het-s protein. Either elevated or depressed levels of the chaperone Hsp104 interfere with propagation of [PSI]. Both [URE3] and [PSI] are cured by growth of cells in millimolar guanidine HCl. [URE3] is also cured by overexpression of fragments of Ure2p or fusion proteins including parts of Ure2p.
Adding the Third Dimension to Virus Life Cycles: Three-Dimensional Reconstruction of Icosahedral Viruses from Cryo-Electron Micrographs
Authors: Baker T. S. , Olson N. H. , Fuller S. D. 
Published: December 2019

SUMMARY
Viruses are cellular parasites. The linkage between viral and host functions makes the study of a viral life cycle an important key to cellular functions. A deeper understanding of many aspects of viral life cycles has emerged from coordinated molecular and structural studies carried out with a wide range of viral pathogens. Structural studies of viruses by means of cryo-electron microscopy and three-dimensional image reconstruction methods have grown explosively in the last decade. Here we review the use of cryo-electron microscopy for the determination of the structures of a number of icosahedral viruses. These studies span more than 20 virus families. Representative examples illustrate the use of moderate- to low-resolution (7- to 35-Å) structural analyses to illuminate functional aspects of viral life cycles including host recognition, viral attachment, entry, genome release, viral transcription, translation, proassembly, maturation, release, and transmission, as well as mechanisms of host defense. The success of cryo-electron microscopy in combination with three-dimensional image reconstruction for icosahedral viruses provides a firm foundation for future explorations of more-complex viral pathogens, including the vast number that are nonspherical or nonsymmetrical.
Effectiveness of diabetes self-management education and support via a smartphone application in insulin-treated patients with type 2 diabetes: results of a randomized controlled trial (TRIGGER study)
Authors: Boels Anne Meike , Vos Rimke C , Dijkhorst-Oei Lioe-Ting , Rutten Guy E H M 
Published: December 2019

ObjectiveTo investigate the effect of diabetes self-management education and support via a smartphone app in individuals with type 2 diabetes on insulin therapy.Research design and methodsOpen two-arm multicenter parallel randomized controlled superiority trial. The intervention group (n=115) received theory and evidence-based self-management education and support via a smartphone app (optionally two or six times per week, once daily at different times). The control group (n=115) received care as usual. Primary outcome: HbA1c at 6 months. Other outcomes included HbA1c ≤53 mmol/mol (≤7%) without any hypoglycemic event, body mass index, glycemic variability, dietary habits and quality of life. We performed multiple imputation and regression models adjusted for baseline value, age, sex, diabetes duration and insulin dose.ResultsSixty-six general practices and five hospital outpatient clinics recruited 230 participants. Baseline HbA1c was comparable between groups (8.1% and 8.3%, respectively). At 6 months, the HbA1c was 63.8 mmol/mol (8.0%) in the intervention vs 66.2 mmol/mol (8.2%) in the control group; adjusted difference −0.93 mmol/mol (−0.08%), 95% CI −4.02 to 2.17 mmol/mol (−0.37% to 0.20%), p=0.557. The odds for achieving an HbA1c level ≤7% without any hypoglycemic event was lower in the intervention group: OR 0.87, 95% CI 0.33 to 2.35. There was no effect on secondary outcomes. No adverse events were reported.ConclusionsThis smartphone app providing diabetes self-management education and support had small and clinically not relevant effects. Apps should be more personalized and target individuals who think the app will be useful for them.Trial registration numberNTR5515.
Right-Site Care Programme with a community-based family medicine clinic in Singapore: secondary data analysis of its impact on mortality and healthcare utilisation
Authors: Ang Ian Yi Han , Ng Sheryl Hui-Xian , Rahman Nabilah , Nurjono Milawaty , Tham Tat Yean , Toh Sue-Anne , Wee Hwee Lin 
Published: December 2019

ObjectiveStable patients with chronic conditions could be appropriately cared for at family medicine clinics (FMC) and discharged from hospital specialist outpatient clinics (SOCs). The Right-Site Care Programme with Frontier FMC emphasised care organised around patients in community rather than hospital-based providers, with one identifiable primary provider. This study evaluated impact of this programme on mortality and healthcare utilisation.DesignA retrospective study without randomisation using secondary data analysis of patients enrolled in the intervention matched 1:1 with unenrolled patients as controls.SettingProgramme was supported by the Ministry of Health in Singapore, a city-state nation in Southeast Asia with 5.6 million population.ParticipantsIntervention group comprises patients enrolled from January to December 2014 (n=684) and control patients (n=684) with at least one SOC and no FMC attendance during same period.InterventionsFamily physician in Frontier FMC managed patients in consultation with relevant specialist physicians or fully managed patients independently. Care teams in SOCs and FMC used a common electronic medical records system to facilitate care coordination and conducted regular multidisciplinary case conferences.Primary outcome measuresDeidentified linked healthcare administrative data for time period of January 2011 to December 2017 were extracted. Three-year postenrolment mortality rates and utilisation frequencies and charges for SOC, public primary care centres (polyclinic), emergency department attendances and emergency, non-day surgery inpatient and all-cause admissions were compared.ResultsIntervention patients had lower mortality rate (HR=0.37, p<0.01). Among those with potential of postenrolment polyclinic attendance, intervention patients had lower frequencies (incidence rate ratio (IRR)=0.60, p<0.01) and charges (mean ratio (MR)=0.51, p<0.01). Among those with potential of postenrolment SOC attendance, intervention patients had higher frequencies (IRR=2.06, p<0.01) and charges (MR=1.86, p<0.01).ConclusionsIntervention patients had better survival, probably because their chronic conditions were better managed with close monitoring, contributing to higher total outpatient attendance frequencies and charges.
Transitional care quality indicators to assess quality of care following hospitalisation for chronic obstructive pulmonary disease and heart failure: a systematic review protocol
Authors: Michael Faith , Whitelaw Sera , Van Spall Harriette GC 
Published: December 2019

IntroductionThe period following hospitalisation for chronic obstructive pulmonary disease (COPD) or heart failure (HF)—when patients transition between settings and clinicians—is one of high risk. Transitional care services that bridge the gap from hospital to home can improve outcomes, but there are no widely accepted indicators to assess their quality.Methods and analysisIn this systematic review, we will summarise transitional care quality indicators, and describe their associations with clinical, patient-reported and cost outcomes. We will search MEDLINE, Embase, CINAHL and HealthSTAR, as well as grey literature and reference lists of included articles. We will screen all studies published between January 1990 and October 2019 that test an intervention that aims to improve the hospital-to-home transition for patients with COPD and/or HF; and measure at least one process (eg, medication errors), clinical (eg, hospital readmissions) or patient-reported (eg, health-related quality of life) outcome which will serve as a transitional care quality indicator . We will include randomised controlled trials, cohort studies, cross-sectional studies, interrupted time series studies and before–after studies. We will extract data in duplicate and classify transitional care quality indicators as structural, process-related or outcome-related. When possible, we will assess associations between transitional care quality indicators and clinical outcomes. In anticipation of conceptual and statistical heterogeneity, we will provide a qualitative synthesis and narrative review of the results.Ethics and disseminationThis review will provide a list of transitional care quality indicators and their associations with clinical outcomes. These results can be used by hospitals, administrators and clinicians for assessing the quality of transitional care provided to patients with COPD and HF. The findings can also be used by policy-makers to assess and incentivise transitional care quality. We will disseminate results through publications, social media releases and presentations.PROSPERO registration numberThis study is registered on PROSPERO.
Finding/identifying primaries with neck disease (FIND) clinical trial protocol: a study integrating transoral robotic surgery, histopathological localisation and tailored deintensification of radiotherapy for unknown primary and small oropharyngeal head and neck squamous cell carcinoma
Authors: de Almeida John R , Noel Christopher W , Veigas Maria , Martino Rosemary , Chepeha Douglas B , Bratman Scott V , Goldstein David P , Hansen Aaron R , Yu Eugene , Metser Ur , Weinreb Ilan , Perez-Ordonez Bayardo , Xu Wei , Kim John 
Published: December 2019

IntroductionCarcinomas of unknown primary site (CUP) of the head and neck have historically been worked up and managed heterogeneously. Failure to identify a primary site may result in large radiotherapy mucosal volumes. Transoral approaches such as Transoral Robotic Surgery (TORS) may improve the yield of identifying hidden primaries. We aim to assess the oncological and functional outcomes of a combined treatment approach with TORS and tailored radiotherapy.Methods and analysisTwenty-five patients with metastatic squamous cell carcinoma to the neck without clinical or radiographic evidence of a primary site will be enrolled in a phase II trial. Patients will undergo a diagnostic or therapeutic approach with TORS based on specific algorithms incorporating tailored radiotherapy according to the location and laterality of the primary tumour. The primary outcome is to evaluate the out-of-field failure rate over a 2-year period. Secondary outcomes include identification rates, survival outcomes, patient reported outcomes and functional swallowing outcomes.Ethics and disseminationThe University Health Network Research Ethics Board approved this study (ID 15–9767). The results will be published in an open access journal.Trial registration numberNCT03281499.
Enhanced Risk of Traumatic Brain Injury in Patients with Chronic Obstructive Pulmonary Disease
Authors: Huang Tang-Hsiu , Chen Chiung-Zuei , Kuo Hung-I , Er Hong-Ping , Lin Sheng-Hsiang 
Published: December 2019

This study tests our hypothesis that patients with chronic obstructive pulmonary disease (COPD) have an increased risk of traumatic brain injury (TBI). In this nationwide retrospective cohort study, we used a subset of Taiwan's National Health Insurance Research Database, involving 1 million randomly selected beneficiaries. Patients with newly diagnosed COPD between 2000 and 2008 were identified. They were subgrouped as ‘COPDAE+’ (if they had severe acute exacerbation of COPD during the follow-ups) or ‘COPDAE−’ (if they had no acute exacerbation), and were frequency matched with randomly selected subjects without COPD (the ‘non-COPD’ group). Baseline differences were balanced by the inverse probability of treatment weighting based on the propensity score. For each patient, the risk of TBI during the subsequent 5 years was determined. The competing risk of death was controlled. We identified 3734 patients in ‘COPDAE+’, and frequency matched them with 11,202 patients in ‘COPDAE−’ and 11,202 subjects in ‘non-COPD’. Compared with those in ‘non-COPD’, patients in ‘COPDAE+’ and ‘COPDAE−’ had an increased risk of TBI: the adjusted HR for ‘COPDAE+’ was 1.50, 95% CI 1.31 to 1.73, and that for ‘COPDAE−’ was 1.21, 95% CI 1.09 to 1.34. The highest risk was observed in the ‘COPDAE+’ group that aged <65 (the adjusted HR was 1.92; 95% CI 1.39 to 2.64). COPD has been linked to complications beyond the respiratory system. In this study we showed that COPD is associated with an increased risk of TBI.
A Reformist, a Diplomat, and a Benevolent Merchant: Hājī Mīrzā Sayyīd Muhammad-Taqī Shīrāzī (Afnān), the Shīrāzī Trading House and the Propagation of the Babi-Baha⁠ʾi Faith
Authors: Shahvar Soli 
Published: December 2019

AbstractThe aim of this paper is to offer a glimpse into the Baha⁠ʾi mercantile community in Iran during the second half of the nineteenth century and its reformist and modernist attitudes through the accounts of one of its leading merchants, Hājī Mīrzā Sayyīd Muhammad-Taqī Shīrāzī (Afnān).
Involvement of phosphatase and tensin homolog-induced putative kinase 1/Parkin-mediated autophagy in angiotensin II-induced cardiac hypertrophy in C57BL/6 mice
Authors: Fan Gang , Chen Meng-Jie , Wei Jin 
Published: December 2019

Objective To study the role of autophagy in angiotensin II-induced cardiac hypertrophy in C57BL/6 mice. Methods We randomly assigned 10 C57BL/6 mice into the control and angiotensin II (Ang II) groups (n = 5 in each group). Ang II group mice were injected with Ang II (3 mg/kg/day). Cardiac structure, myocardial pathological changes, mitochondrial structure, autophagosomes, mitochondrial membrane potential (MMP), and myocardial apoptosis were examined. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), Parkin, and microtubule-associated protein1A/1B-light chain 3 (LC3) II protein expression levels and mRNA expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were examined. Results The heart weight/body weight ratio, posterior wall of the left ventricle, myocardial apoptosis (%), relative number of autophagosomes, ANP and BNP mRNA levels, and PINK1, Parkin, and LC3 II protein levels were significantly higher in the Ang II group than in the control group. The MMP and left ventricular ejection fraction were significantly lower in the Ang II group than in the control group. There was disordered arrangement of cardiomyocytes and mitochondria, and obvious mitochondrial swelling, cardiomyocyte hypertrophy, and fibrosis in the Ang II group. Conclusion PINK1/PARKIN-mediated autophagy is involved in Ang II-induced cardiac hypertrophy by affecting myocardial apoptosis and mitochondrial function.
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins
Authors: Valdés-Sánchez Lourdes , Calado Sofia M. , de la Cerda Berta , Aramburu Ana , García-Delgado Ana Belén , Massalini Simone , Montero-Sánchez Adoración , Bhatia Vaibhav , Rodríguez-Bocanegra Eduardo , Diez-Lloret Andrea , Rodríguez-Martínez Daniel , Chakarova Christina , Bhattacharya Shom S. , Díaz-Corrales Francisco J. 
Published: December 2019

AbstractBackgroundMutations in pre-mRNA splicing factorPRPF31can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease.MethodsIn this study, we have analyzed a mouse model containing the p.A216P mutation inPrpf31gene.ResultsWe found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation,Hspa4lis overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus.ConclusionsOur data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations inPRPF31.HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due toPRPF31mutations.
Role of 5-HT7 receptors in the immune system in health and disease
Authors: Quintero-Villegas Alejandro , Valdés-Ferrer Sergio Iván 
Published: December 2019

AbstractIn mammalians, serotonin (5-HT) has critical roles in the central nervous system (CNS), including mood stability, pain tolerance, or sleep patterns. However, the vast majority of serotonin is produced by intestinal enterochromaffin cells of the gastrointestinal tract and circulating blood platelets, also acting outside of the CNS. Serotonin effects are mediated through its interaction with 5-HT receptors (5-HTRs), a superfamily with a repertoire of at least fourteen well-characterized members. 5-HT7receptors are the last 5-HTR member to be identified, with well-defined functions in the nervous, gastrointestinal, and vascular systems. The effects of serotonin on the immune response are less well understood. Mast cells are known to produce serotonin, while T cells, dendritic cells, monocytes, macrophages and microglia express 5-HT7receptor. Here, we review the known roles of 5-HT7receptors in the immune system, as well as their potential therapeutic implication in inflammatory and immune-mediated disorders.