bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of the Antisense-to-Latency Transcript Long Noncoding RNA in Kaposi's Sarcoma-Associated Herpesvirus
Authors: Schifano Jason M. , Corcoran Kathleen , Kelkar Hemant , Dittmer Dirk P. 
Published: December 2016

ABSTRACT

The regulation of latency is central to herpesvirus biology. Recent transcriptome-wide surveys have uncovered evidence for promiscuous transcription across the entirety of the Kaposi's sarcoma-associated herpesvirus (KSHV) genome and postulated the existence of multiple viral long noncoding RNAs (lncRNAs). Next-generation sequencing studies are highly dependent on the specific experimental approach and particular algorithms of analysis and therefore benefit from independent confirmation of the results. The antisense-to-latency transcript (ALT) lncRNA was discovered by genome-tiling microarray (Chandriani et al., J Virol 86:7934–7942, 2010,
https://doi.org/10.1128/JVI.00645-10
). To characterize ALT in detail, we physically isolated this lncRNA by a strand-specific hybrid capture assay and then employed transcriptome sequencing and novel reverse transcription-PCR (RT-PCR) assays to distinguish all RNA species in the KSHV latency region. These methods confirm that ALT initiates at positions 120739/121012 and encodes a single splice site, which is shared with the 3′-coterminal K14-vGPCR/ORF74 mRNA, terminating at 130873 (GenBank accession number
GQ994935
), resulting in an ∼10,000-nucleotide transcript. No shorter ALT isoforms were identified. This study also identified a novel intron within the LANA 5′ untranslated region using a splice acceptor at 127888. In summary, ALT joins PAN/nut1/T1.1 as a bona fide lncRNA of KSHV with potentially important roles in viral gene regulation and pathogenesis.

IMPORTANCE
Increasing data support the importance of noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and lncRNAs, which have been shown to exert critical regulatory functions without coding for recognizable proteins. Defining the sequences of these ncRNAs is essential for future studies aiming to functionally characterize a specific ncRNA. Most lncRNA studies are highly dependent on high-throughput sequencing and bioinformatic analyses, few studies follow up on the initial predictions, and analyses are at times discordant. The manuscript characterizes one key viral lncRNA, ALT, by physically isolating ALT and by a sequencing-independent assay. It provides for a simple assay to monitor lncRNA expression in experimental and clinical samples. ALT is expressed antisense to the major viral latency transcripts encoding LANA as well as the viral miRNAs and thus has the potential to regulate this key part of the viral life cycle.
Effect of HIV-1 Env on SERINC5 Antagonism
Authors: Beitari Saina , Ding Shilei , Pan Qinghua , Finzi Andrés , Liang Chen 
Published: December 2016

ABSTRACT
SERINC5 is able to restrict HIV-1 infection by drastically impairing the infectivity of viral particles. Studies have shown that the HIV-1 Nef protein counters SERINC5 through downregulating SERINC5 from the cell surface and preventing the virion incorporation of SERINC5. In addition, the Env proteins of some HIV-1 strains can also overcome SERINC5 inhibition. However, it is unclear how HIV-1 Env does so and why HIV-1 has two mechanisms to resist SERINC5 inhibition. The results of this study show that neither Env nor Nef prevents high levels of ectopic SERINC5 from being incorporated into HIV-1 particles, except that Env, but not Nef, is able to resist inhibition by virion-associated SERINC5. Testing of a panel of HIV-1 Env proteins from different subtypes revealed a high frequency of SERINC5-resistant Envs. Interestingly, although the SERINC5-bearing viruses were not inhibited by SERINC5 itself, they became more sensitive to the CCR5 inhibitor maraviroc and some neutralizing antibodies than the SERINC5-free viruses, which suggests a possible influence of SERINC5 on Env function. We conclude that HIV-1 Env is able to overcome SERINC5 without preventing SERINC5 virion incorporation.

IMPORTANCE
HIV-1 Nef is known to enhance the infectivity of HIV-1 particles and to contribute to the maintenance of high viral loads in patients. However, the underlying molecular mechanism remained elusive until the recent discovery of the antiviral activity of SERINC5. SERINC5 profoundly inhibits HIV-1 but is antagonized by Nef, which prevents the incorporation of SERINC5 into viral particles. Here, we show that HIV-1 Env, but not Nef, is able to resist high levels of SERINC5 without excluding SERINC5 from incorporation into viral particles. However, the virion-associated SERINC5 renders HIV-1 more sensitive to some broadly neutralizing antibodies. It is possible that, under the pressure of some neutralizing antibodies
in vivo
, HIV-1 needs Nef to remove SERINC5 from viral particles, even though viral Env is able to resist virion-associated SERINC5.
Building capacity to use and undertake research in health organisations: a survey of training needs and priorities among staff
Authors: Barratt Helen , Fulop Naomi J 
Published: December 2016

ObjectivesEfforts to improve healthcare and population health depend partly on the ability of health organisations to use research knowledge and participate in its production. We report the findings of a survey conducted to prioritise training needs among healthcare and public health staff, in relation to the production and implementation of research, across an applied health research collaboration.DesignA questionnaire survey using a validated tool, the Hennessy-Hicks Training Needs Assessment Questionnaire. Participants rated 25 tasks on a five-point scale with regard to both their confidence in performing the task, and its importance to their role.SettingA questionnaire weblink was distributed to a convenience sample of 35 healthcare and public health organisations in London and South East England, with a request that they cascade the information to relevant staff.Participants203 individuals responded, from 20 healthcare and public health organisations.InterventionsNone.Outcome measuresTraining needs were identified by comparing median importance and performance scores for each task. Individuals were also invited to describe up to three priority areas in which they require training.ResultsAcross the study sample, evaluation; teaching; making do with limited resources; coping with change and managing competing demands were identified as key tasks. Assessing the relevance of research and learning about new developments were the most relevant research-related tasks. Participants’ training priorities included evaluation; finding, appraising and applying research evidence; and data analysis. Key barriers to involvement included time and resources, as well as a lack of institutional support for undertaking research.ConclusionsWe identify areas in which healthcare and public health professionals may benefit from support to facilitate their involvement in and use of applied health research. We also describe barriers to participation and differing perceptions of research between professional groups.
Life after prostate cancer diagnosis: protocol for a UK-wide patient-reported outcomes study
Authors: Downing Amy , Wright Penny , Wagland Richard , Watson Eila , Kearney Therese , Mottram Rebecca , Allen Majorie , Cairnduff Victoria , McSorley Oonagh , Butcher Hugh , Hounsome Luke , Donnelly Conan , Selby Peter , Kind Paul , Cross William , Catto James W H , Huws Dyfed , Brewster David H , McNair Emma , Matheson Lauren , Rivas Carol , Nayoan Johana , Horton Mike , Corner Jessica , Verne Julia , Gavin Anna , Glaser Adam W 
Published: December 2016

BackgroundProstate cancer and its treatment may impact physically, psychologically and socially; affecting the health-related quality of life of men and their partners/spouses. The Life After Prostate Cancer Diagnosis (LAPCD) study is a UK-wide patient-reported outcomes study which will generate information to improve the health and well-being of men with prostate cancer.Methods and analysisPostal surveys will be sent to prostate cancer survivors (18–42 months postdiagnosis) in all 4 UK countries (n=∼70 000). Eligible men will be identified and/or verified through cancer registration systems. Men will be surveyed twice, 12 months apart, to explore changes in outcomes over time. Second, separate cohorts will be surveyed once and the design will include evaluation of the acceptability of online survey tools. A comprehensive patient-reported outcome measure has been developed using generic and specific instruments with proven psychometric properties and relevance in national and international studies. The outcome data will be linked with administrative health data (eg, treatment information from hospital data). To ensure detailed understanding of issues of importance, qualitative interviews will be undertaken with a sample of men who complete the survey across the UK (n=∼150) along with a small number of partners/spouses (n=∼30).Ethics and disseminationThe study has received the following approvals: Newcastle and North Tyneside 1 Research Ethics Committee (15/NE/0036), Health Research Authority Confidentiality Advisory Group (15/CAG/0110), NHS Scotland Public Benefit and Privacy Panel (0516-0364), Office of Research Ethics Northern Ireland (16/NI/0073) and NHS R&D approval from Wales, Scotland and Northern Ireland. Using traditional and innovative methods, the results will be made available to men and their partners/spouses, the funders, the NHS, social care, voluntary sector organisations and other researchers.
Association of low-density lipoprotein cholesterol within the normal range and NAFLD in the non-obese Chinese population: a cross-sectional and longitudinal study
Authors: Sun Dan-Qin , Wu Sheng-Jie , Liu Wen-Yue , Wang Li-Ren , Chen Yi-Ran , Zhang Dong-Chu , Braddock Martin , Shi Ke-Qing , Song Dan , Zheng Ming-Hua 
Published: December 2016

ObjectivesThe relationship between normal low-density lipoprotein cholesterol (LDL-c) levels and non-alcoholic fatty liver disease (NAFLD) in non-obese individuals remains unclear. We aimed to investigate the precise prevalence and incidence of NAFLD within the normal LDL-c range in non-obese individuals.DesignCross-sectional and longitudinal study.SettingWenzhou Medical Center of Wenzhou People's Hospital from 2010 to 2014.Participants183 903 non-obese individuals were enrolled from a cross-sectional population, and a total of 16 173 initially NAFLD-free non-obese individuals were included who completed a 5-year follow-up examination in the longitudinal population.ResultsIn our study, NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver disease. The cross-sectional study showed that at baseline, the prevalence of NAFLD was 13.9% in non-obese individuals with normal LDL-c levels. The prospective study demonstrated that NAFLD-free participants developed NAFLD during the 5-year follow-up period, with a cumulative incidence of 14.4%. In addition, the ORs for NAFLD in the cross-sectional population were 1.11 (95% CI 1.04 to 1.18), 1.37 (95% CI 1.27 to 1.47) and 1.56 (95% CI 1.43 to 1.69), respectively, after adjusting for known confounding variables. The HRs for NAFLD in the longitudinal population were 1.15 (95% CI 0.98 to 1.36), 1.32 (95% CI 1.10 to 1.58) and 1.82 (95% CI 1.47 to 2.52), compared with Q1. Individuals with higher LDL-c level within the normal range had an increased cumulative incidence rate of NAFLD in non-obese individuals.ConclusionsNAFLD is prevalent in the non-obese Chinese population. Furthermore, this is the first study to demonstrate that increased normal LDL-c levels are independently associated with an elevated risk of NAFLD in non-obese individuals.
Bedside cerebral microdialysis monitoring of delayed cerebral hypoperfusion in comatose patients with poor grade aneurysmal subarachnoid haemorrhage
Authors: Patet Camille , Quintard Hervé , Zerlauth Jean-Baptiste , Maibach Thomas , Carteron Laurent , Suys Tamarah , Bouzat Pierre , Bervini David , Levivier Marc , Daniel Roy T , Eckert Philippe , Meuli Reto , Oddo Mauro 
Published: December 2016

BackgroundDelayed cerebral ischaemia (DCI) is frequent after poor grade aneurysmal subarachnoid haemorrhage (SAH). Owing to the limited accuracy of clinical examination, DCI diagnosis is often based on multimodal monitoring. We examined the value of cerebral microdialysis (CMD) in this setting.Methods20 comatose SAH participants underwent CMD monitoring—for hourly sampling of cerebral extracellular lactate/pyruvate ratio (LPR) and glucose—and brain perfusion CT (PCT). Patients were categorised as DCI when PCT (8±3 days after SAH) showed cerebral hypoperfusion, defined as cerebral blood flow <32.5 mL/100 g/min with a mean transit time >5.7 s. Clinicians were blinded to CMD data; for the purpose of the study, only patients who developed cerebral hypoperfusion in anterior and/or middle cerebral arteries were analysed.ResultsDCI (n=9/20 patients) was associated with higher CMD LPR (51±36 vs 31±10 in patients without DCI, p=0.0007) and lower CMD glucose (0.64±0.34 vs 1.22±1.05, p=0.0005). In patients with DCI, CMD changes over the 18 hours preceding PCT diagnosis revealed a pattern of CMD LPR increase (coefficient +2.96 (95% CI 0.13 to 5.79), p=0.04) with simultaneous CMD glucose decrease (coefficient −0.06 (95% CI −0.08 to −0.01), p=0.03, mixed-effects multilevel regression model). No significant CMD changes were noted in patients without DCI.ConclusionsIn comatose patients with SAH, delayed cerebral hypoperfusion correlates with a CMD pattern of lactate increase and simultaneous glucose decrease. CMD abnormalities became apparent in the hours preceding PCT, thereby suggesting that CMD monitoring may anticipate targeted therapeutic interventions.
NOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus
Authors: Demitrack Elise S. , Gifford Gail B. , Keeley Theresa M. , Horita Nobukatsu , Todisco Andrea , Turgeon D. Kim , Siebel Christian W. , Samuelson Linda C. 
Published: December 2016

The Notch signaling pathway is known to regulate stem cells and epithelial cell homeostasis in gastrointestinal tissues; however, Notch function in the corpus region of the stomach is poorly understood. In this study we examined the consequences of Notch inhibition and activation on cellular proliferation and differentiation and defined the specific Notch receptors functioning in the mouse and human corpus. Notch pathway activity was observed in the mouse corpus epithelium, and gene expression analysis revealed NOTCH1 and NOTCH2 to be the predominant Notch receptors in both mouse and human. Global Notch inhibition for 5 days reduced progenitor cell proliferation in the mouse corpus, as well as in organoids derived from mouse and human corpus tissue. Proliferation effects were mediated through both NOTCH1 and NOTCH2 receptors, as demonstrated by targeting each receptor alone or in combination with Notch receptor inhibitory antibodies. Analysis of differentiation by marker expression showed no change to the major cell lineages; however, there was a modest increase in the number of transitional cells coexpressing markers of mucous neck and chief cells. In contrast to reduced proliferation after pathway inhibition, Notch activation in the adult stomach resulted in increased proliferation coupled with reduced differentiation. These findings suggest that NOTCH1 and NOTCH2 signaling promotes progenitor cell proliferation in the mouse and human gastric corpus, which is consistent with previously defined roles for Notch in promoting stem and progenitor cell proliferation in the intestine and antral stomach. NEW & NOTEWORTHY Here we demonstrate that the Notch signaling pathway is essential for proliferation of stem cells in the mouse and human gastric corpus. We identify NOTCH1 and NOTCH2 as the predominant Notch receptors expressed in both mouse and human corpus and show that both receptors are required for corpus stem cell proliferation. We show that chronic Notch activation in corpus stem cells induces hyperproliferation and tissue hypertrophy, suggesting that Notch may drive gastric tumorigenesis.
Are there sex differences in the capillary blood volume and diffusing capacity response to exercise?
Authors: Bouwsema Melissa M. , Tedjasaputra Vincent , Stickland Michael K. 
Published: December 2016

Previous work suggests that women may exhibit a greater respiratory limitation in exercise compared with height-matched men. Diffusion capacity (DlCO) increases with incremental exercise, and the smaller lungs of women may limit membrane diffusing capacity (Dm) and pulmonary capillary blood volume (Vc) in response to the increased oxygen demand. We hypothesized that women would have lower DlCO, DlCO relative to cardiac output (DlCO/Q̇), Dm, Vc, and pulmonary transit time, secondary to lower Vc at peak exercise. Sixteen women (112 ± 12% predicted relative V̇o2peak) and sixteen men (118 ± 22% predicted relative V̇o2peak) were matched for height and weight. Hemoglobin-corrected diffusing capacity (DlCO), Vc, and Dm were determined via the multiple-[Formula: see text] DlCO technique at rest and during incremental exercise up to 90% of V̇o2peak. Both groups increased DlCO, Vc, and Dm with exercise intensity, but women had 20% lower DlCO ( P < 0.001), 18% lower Vc ( P = 0.002), and 22% lower Dm ( P < 0.001) compared with men across all workloads, and neither group exhibited a plateau in Vc. When expressed relative to alveolar volume (Va), the between-sex difference was eliminated. The drop in DlCO/Q̇ was proportionally less in women than men, and mean pulmonary transit time did not drop below 0.3 s in either group. Women demonstrate consistently lower DlCO, Vc, and Dm compared with height-matched men during exercise; however, these differences disappear with correction for lung size. These results suggest that after differences in lung volume are accounted for there is no intrinsic sex difference in the DlCO, Vc, or Dm response to exercise. NEW & NOTEWORTHY Women demonstrate lower diffusing capacity-to-cardiac output ratio (DlCO/Q̇), pulmonary capillary blood volume (Vc), and membrane diffusing capacity (Dm) compared with height-matched men during exercise. However, these differences disappear after correction for lung size. The drop in DlCO/Q̇ was proportionally less in women, and pulmonary transit time did not drop below 0.3 s in either group. After differences in lung volume are accounted for, there is no intrinsic sex difference in DlCO, Vc, or Dm response to exercise.
The effects of voluntary exercise and prazosin on capillary rarefaction and metabolism in streptozotocin-induced diabetic male rats
Authors: Dunford Emily C. , Leclair Erwan , Aiken Julian , Mandel Erin R. , Haas Tara L. , Birot Olivier , Riddell Michael C. 
Published: December 2016

Type-1 diabetes mellitus (T1D) causes impairments within the skeletal muscle microvasculature. Both regular exercise and prazosin have been shown to improve skeletal muscle capillarization and metabolism in healthy rats through distinct angiogenic mechanisms. The aim of this study was to evaluate the independent and additive effects of voluntary exercise and prazosin treatment on capillary-to-fiber ratio (C:F) in streptozotocin (STZ)-treated diabetic rats. STZ (65 mg/kg) was intraperitoneally administered to male Sprague-Dawley rats ( n = 36) to induce diabetes, with healthy, nondiabetic, sedentary rats ( n = 10) as controls. The STZ-treated rats were then divided into sedentary (SED) or exercising (EX; 24-h access to running wheels) groups and then further subdivided into prazosin (Praz) or water (H2O) treatment groups: nondiabetic-SED-H2O, STZ-SED-H2O, STZ-EX-H2O, STZ-SED-Praz, and STZ-EX-Praz. After 3 wk, untreated diabetes significantly reduced the C:F in tibialis anterior (TA) and soleus muscles in the STZ-SED-H2O animals (both P < 0.05). Voluntary exercise and prazosin treatment independently resulted in a normalization of C:F within the TA (1.86 ± 0.12 and 2.04 ± 0.03 vs 1.71 ± 0.09, P < 0.05) and the soleus (2.36 ± 0.07 and 2.68 ± 0.14 vs 2.13 ± 0.12, P < 0.05). The combined STZ-EX-Praz group resulted in the highest C:F within the TA (2.26 ± 0.07, P < 0.05). Voluntary exercise volume was negatively correlated with fed blood glucose levels ( r2 = −0.7015, P < 0.01) and, when combined with prazosin, caused further enhanced nonfasted glucose ( P < 0.01). Exercise and prazosin reduced circulating nonesterified fatty acids more than either stimulus alone ( P < 0.05). These results suggest that the distinct stimulation of angiogenesis, with both regular exercise and prazosin treatment, causes a cooperative improvement in the microvascular complications associated with T1D. NEW & NOTEWORTHY It is currently well established that poorly controlled diabetes reduces both skeletal muscle mass and muscle capillarization. These muscle-specific features of diabetes may, in turn, compromise insulin sensitivity and glucose control. Using a model of streptozotocin-induced diabetes, we show the vascular complications linked with disease and how chronic exposure to exercise and prazosin (an α1-adrenergic antagonist) can reduce these complications and improve glycemic control.
Suite of clinically relevant functional assays to address therapeutic efficacy and disease mechanism in the dystrophic mdx mouse
Authors: Song Yafeng , Rosenblum Shira T. , Morales Leon , Petrov Mihail , Greer Christopher , Globerman Samantha , Stedman Hansell H. 
Published: December 2016

Duchenne muscular dystrophy (DMD) is a progressive primary myodegenerative disease caused by a genetic deficiency of the 427-kDa cytoskeletal protein dystrophin. Despite its single-gene etiology, DMD’s complex pathogenesis remains poorly understood, complicating the extrapolation from results of preclinical studies in genetic homologs to the design of informative clinical trials. Here we describe novel phenotypic assays which when applied to the mdx mouse resemble recently used primary end points for DMD clinical trials. By coupling force transduction, high-precision motion tracking, and respiratory measurements, we have achieved a suite of integrative physiological tests that provide novel insights regarding normal and pathological responses to muscular exertion. A common feature of these physiological assays is the precise tracking and analysis of volitional movement, thereby optimizing the relevance to clinical tests. Unexpectedly, the measurable biological distinction between dystrophic and control mice at early time points in the disease process is better resolved with these tests than with the majority of previously used, labor-intensive studies of individual muscle function performed ex vivo. For example, the dramatic loss of volitional movement following a novel, standardized grip test distinguishes control mice from mdx mice by a 17.4-fold difference of the means (3.5 ± 2.2 vs. 60.9 ± 12.1 units of activity, respectively; effect size 1.99). The findings have both mechanistic and translational implications of potential significance to the fields of basic myology and neuromuscular therapeutics. NEW & NOTEWORTHY This study uses novel phenotypic assays which when applied to the mdx mouse resemble recently used primary end points for DMD clinical trials. A measurable distinction between dystrophic and control mice was seen at early time points in vivo compared with invasive muscle studies performed ex vivo. These assays shed light on normal and pathological responses to muscular exertion and have significant mechanistic and translational implications for the fields of basic myology and neuromuscular therapeutics.