bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression
Authors: Louis Sam Titus Anto Sam Crosslee , Sharma Dharmendra , Kim Min Soo , D’Mello Santosh R. 
Published: December 2019

Abstract
Background
Histone deacetylase-3 (HDAC3) promotes neurodegeneration in various cell culture and in vivo models of neurodegeneration but the mechanism by which HDAC3 exerts neurotoxicity is not known. HDAC3 is known to be a transcriptional co-repressor. The goal of this study was to identify transcriptional targets of HDAC3 in an attempt to understand how it promotes neurodegeneration.

Results
We used chromatin immunoprecipitation analysis coupled with deep sequencing (ChIP-Seq) to identify potential targets of HDAC3 in cerebellar granule neurons. One of the genes identified was the activity-dependent and neuroprotective transcription factor, Neuronal PAS Domain Protein 4 (Npas4). We confirmed using ChIP that in healthy neurons HDAC3 associates weakly with the Npas4 promoter, however, this association is robustly increased in neurons primed to die. We find that HDAC3 also associates differentially with the brain-derived neurotrophic factor (Bdnf) gene promoter, with higher association in dying neurons. In contrast, association of HDAC3 with the promoters of other neuroprotective genes, including those encoding c-Fos, FoxP1 and Stat3, was barely detectable in both healthy and dying neurons. Overexpression of HDAC3 leads to a suppression of Npas4 and Bdnf expression in cortical neurons and treatment with RGFP966, a chemical inhibitor of HDAC3, resulted in upregulation of their expression. Expression of HDAC3 also repressed Npas4 and Bdnf promoter activity.

Conclusion
Our results suggest that Bdnf and Npas4 are transcriptional targets of Hdac3-mediated repression. HDAC3 inhibitors have been shown to protect against behavioral deficits and neuronal loss in mouse models of neurodegeneration and it is possible that these inhibitors work by upregulating neuroprotective genes like Bdnf and Npas4.
What are emergency ambulance services doing to meet the needs of people who call frequently? A national survey of current practice in the United Kingdom
Authors: Snooks Helen A. , Khanom Ashrafunnesa , Cole Robert , Edwards Adrian , Edwards Bethan Mair , Evans Bridie A. , Foster Theresa , Fothergill Rachael T. , Gripper Carol P. , Hampton Chelsey , John Ann , Petterson Robin , Porter Alison , Rosser Andy , Scott Jason 
Published: December 2019

Abstract
Background
Emergency ambulance services are integral to providing a service for those with unplanned urgent and life-threatening health conditions. However, high use of the service by a small minority of patients is a concern. Our objectives were to describe: service-wide and local policies or pathways for people classified as Frequent Caller; call volume; and results of any audit or evaluation.

Method
We conducted a national survey of current practice in ambulance services in relation to the management of people who call the emergency ambulance service frequently using a structured questionnaire for completion by email and telephone interview. We analysed responses using a descriptive and thematic approach.

Results
Twelve of 13 UK ambulance services responded. Most services used nationally agreed definitions for ‘Frequent Caller’, with 600–900 people meeting this classification each month. Service-wide policies were in place, with local variations. Models of care varied from within-service care where calls are flagged in the call centre; contact made with callers; and their General Practitioner (GP) with an aim of discouraging further calls, to case management through cross-service, multi-disciplinary team meetings aiming to resolve callers’ needs. Although data were available related to volume of calls and number of callers meeting the threshold for definition as Frequent Caller, no formal audits or evaluations were reported.

Conclusions
Ambulance services are under pressure to meet challenging response times for high acuity patients. Tensions are apparent in the provision of care to patients who have complex needs and call frequently. Multi-disciplinary case management approaches may help to provide appropriate care, and reduce demand on emergency services. However, there is currently inadequate evidence to inform commissioning, policy or practice development.
Reporting guideline for priority setting of health research (REPRISE)
Authors: Tong Allison , Synnot Anneliese , Crowe Sally , Hill Sophie , Matus Andrea , Scholes-Robertson Nicole , Oliver Sandy , Cowan Katherine , Nasser Mona , Bhaumik Soumyadeep , Gutman Talia , Baumgart Amanda , Craig Jonathan C. 
Published: December 2019

Abstract
Background
Research priority setting with stakeholders can help direct the limited resources for health research toward priority areas of need. Ensuring transparency of the priority setting process can strengthen legitimacy and credibility for influencing the research agenda. This study aims to develop a reporting guideline for priority setting of health research.

Methods
We searched electronic databases and relevant websites for sources (frameworks, guidelines, or models for conducting, appraising, reporting or evaluating health research priority setting, and reviews (including systematic reviews)), and primary studies of research priority setting to July 2019. We inductively developed a list of reporting items and piloted the preliminary guideline with a diverse range of 30 priority setting studies from the records retrieved.

Results
From 21,556 records, we included 26 sources for the candidate REPRISE framework and 455 primary research studies. The REporting guideline for PRIority SEtting of health research (REPRISE) has 31 reporting items that cover 10 domains: context and scope, governance and team, framework for priority setting, stakeholders/participants, identification and collection of priorities, prioritization of research topics, output, evaluation and feedback, translation and implementation, and funding and conflict of interest. Each reporting item includes a descriptor and examples.

Conclusions
The REPRISE guideline can facilitate comprehensive reporting of studies of research priority setting. Improved transparency in research priority setting may strengthen the acceptability and implementation of the research priorities identified, so that efforts and funding are invested in generating evidence that is of importance to all stakeholders.

Trial registration
Not applicable.
Bag-1 stimulates Bad phosphorylation through activation of Akt and Raf kinases to mediate cell survival in breast cancer
Authors: Kizilboga Tugba , Baskale Emine Arzu , Yildiz Jale , Akcay Izzet Mehmet , Zemheri Ebru , Can Nisan Denizce , Ozden Can , Demir Salih , Ezberci Fikret , Dinler-Doganay Gizem 
Published: December 2019

Abstract
Background
Bag-1 (Bcl-2-associated athanogene) is a multifunctional anti-apoptotic protein frequently overexpressed in cancer. Bag-1 interacts with a variety of cellular targets including Hsp70/Hsc70 chaperones, Bcl-2, nuclear hormone receptors, Akt and Raf kinases. In this study, we investigated in detail the effects of Bag-1 on major cell survival pathways associated with breast cancer.

Methods
Using immunoblot analysis, we examined Bag-1 expression profiles in tumor and normal tissues of breast cancer patients with different receptor status. We investigated the effects of Bag-1 on cell proliferation, apoptosis, Akt and Raf kinase pathways, and Bad phosphorylation by implementing ectopic expression or knockdown of Bag-1 in MCF-7, BT-474, MDA-MB-231 and MCF-10A breast cell lines. We also tested these in tumor and normal tissues from breast cancer patients. We investigated the interactions between Bag-1, Akt and Raf kinases in cell lines and tumor tissues by co-immunoprecipitation, and their subcellular localization by immunocytochemistry and immunohistochemistry.

Results
We observed that Bag-1 is overexpressed in breast tumors in all molecular subtypes, i.e., regardless of their ER, PR and Her2 expression profile. Ectopic expression of Bag-1 in breast cancer cell lines results in the activation of B-Raf, C-Raf and Akt kinases, which are also upregulated in breast tumors. Bag-1 forms complexes with B-Raf, C-Raf and Akt in breast cancer cells, enhancing their phosphorylation and activation, and ultimately leading to phosphorylation of the pro-apoptotic Bad protein at Ser112 and Ser136. This causes Bad’s re-localization to the nucleus, and inhibits apoptosis in favor of cell survival.

Conclusions
Overall, Bad inhibition by Bag-1 through activation of Raf and Akt kinases is an effective survival and growth strategy exploited by breast cancer cells. Therefore, targeting the molecular interactions between Bag-1 and these kinases might prove an effective anticancer therapy.
Effectiveness of physical therapy treatment in addition to usual podiatry management of plantar heel pain: a randomized clinical trial
Authors: McClinton Shane M. , Heiderscheit Bryan C. , McPoil Thomas G. , Flynn Timothy W. 
Published: December 2019

Abstract
Background
Many patients will seek care from a podiatrist for plantar heel pain (PHP), while few of these patients will also be seen by a physical therapist. Physical therapists can provide treatment that is not a part of routine podiatric care for PHP and may provide additional improvement. Therefore, the purpose of this study was to examine the effects of interdisciplinary care for PHP that incorporated physical therapy treatment after initiating podiatric treatment.

Methods
Eligible individuals with PHP that presented to a podiatrist were randomized to receive usual podiatric care (uPOD) or usual podiatric care plus physical therapy treatment (uPOD+PT). The primary outcome was change in foot and ankle ability measure (FAAM) at 6-months. Secondary outcomes included change in numeric pain rating scale (NPRS), patient-reported success, and 6-week and 1-year endpoints. Patient-reported success was defined as the top two global rating of change scale rankings. Primary analysis was intention-to-treat (ITT) using analysis by covariance adjusted to baseline scores, and a secondary per-protocol (PP) analysis was performed analyzing only those who completed treatment.

Results
Ninety-five individuals participated and were included in the ITT analysis, and 79 were included in the PP analysis. For the primary outcome of FAAM change from baseline to 6-months, both groups improved significantly (uPOD+PT: 26.8 [95% CI 21.6, 31.9]; uPOD: (20 [15.6, 24.4]), but there was no between-group difference (4.3 [− 1, 9.6]). For secondary outcomes, the uPOD+PT group demonstrated greater improvement in NPRS at 6 weeks (0.9 [0.3, 1.4]) and 1 year (1.5 [0.6, 2.5]) in the ITT analysis. In the PP analysis, the uPOD+PT group demonstrated greater improvement in FAAM at 6 months (7.7 [2.1, 13.3]) and 1 year (5.5 [0.1, 10.8]), NPRS at 6 weeks (0.9 [0.2, 1.6]), 6 months (1.3 [0.6, 2.1]) and 1 year (1.3 [0.6, 2.1]), and in patient-reported success (relative risk [95% CI]) at 6 weeks (2.8 [1.1, 7.1]), 6 months (1.5 [1.1, 2.1]), and 1 year (1.5 [1.1, 1.9]).

Conclusions
There was no significant benefit of uPOD+PT in the primary outcome of FAAM change at 6 months. Secondary outcomes and PP analysis indicated additional benefit of uPOD+PT, mostly observed in individuals who completed treatment.

Trial registration
Prospectively registered May 24, 2013 at www.clinicaltrials.gov (NCT01865734).
Optimising clinical effectiveness and quality along the atrial fibrillation anticoagulation pathway: an economic analysis
Authors: Moloney Eoin , Craig Dawn , Holdsworth Nikki , Smithson Joanne 
Published: December 2019

Abstract
Background
Atrial fibrillation (AF) represents the most common sustained cardiac arrhythmia. A service evaluation was carried out at an anticoagulation clinic in Newcastle upon-Tyne to explore the efficacy of introducing self-testing of anticoagulation status for AF patients on warfarin. The analysis presented aims to assess the potential cost savings and clinical outcomes associated with introducing self-testing at a clinic in the Northeast of England, and to determine the cost-effectiveness of a redesigned treatment pathway including genetic testing and self-testing components.

Methods
Questionnaires were administered to individuals participating in the service evaluation to understand the patient costs associated with clinical monitoring (139 patients), and quality-of-life before and after the introduction of self-testing (varying numbers). Additionally, data on time in therapeutic range (TTR) were captured at multiple time points to identify any change in outcome. Finally, an economic model was developed to assess the cost-effectiveness of introducing a redesigned treatment pathway, including genetic testing and self-testing, for AF patients.

Results
The average cost per patient of attending the anticoagulation clinic was £16.24 per visit (including carer costs). Costs were higher amongst patients tested at the hospital clinic than those tested at the community clinic. Improvements in quality-of-life across all psychological topics, and improved TTR, were seen following the introduction of self-testing. Results of the cost-effectiveness analysis showed that the redesigned treatment pathway was less costly and more effective than current practice.

Conclusions
Allowing AF patients on warfarin to self-test, rather than attend clinic to have their anticoagulation status assessed, has the potential to reduce patient costs. Additionally, self-testing may result in improved quality-of-life and TTR. Introducing genetic testing to guide patient treatment based on sensitivity to warfarin, and applying this in combination with self-testing, may also result in improved patient outcomes and reduced costs to the health service in the long-term.
Oleic acid influences the adipogenesis of 3T3-L1 cells via DNA Methylation and may predispose to obesity and obesity-related disorders
Authors: Malodobra-Mazur Malgorzata , Cierzniak Aneta , Dobosz Tadeusz 
Published: December 2019

Abstract
Background
Adipogenesis is the process of adipocytes formation from unspecialized progenitor cells called mesenchymal stromal cells. Numerous mechanisms including epigenetic regulation modulate the correct progress of this process. Dietary exposures occurring over a specific period of time might cause long-lasting and even permanent changes in gene expression regulated by epigenetic mechanisms. For that reason, we investigated the adipogenesis of 3 T3-L1 cells with the excess of saturated and monounsaturated fatty acids and their influence on global and site-specific DNA methylation in these cells.

Materials and methods
3T3-L1 cells were cultured in vitro to obtain 100% of confluence, then the adipogenesis was induced by a differentiation cocktail with the addition of the excess of 0.25 mM and 0.5 mM of palmitic (16:0), stearic (18:0) and oleic (18:1n-9) acids. DNA and RNA were extracted at five-time points to assess the adipogenesis process. The phenotype of mature adipocytes (insulin sensitivity, adipokines secretion, fat content) was estimated in fully mature adipocytes. DNA methylation was investigated both during adipogenesis and in mature adipocytes.

Results
Oleic acids stimulated expression of C/ebpα and Pparγ, which was correlated with lower methylation levels at promoters sites. Furthermore, cells cultured with an excess of oleic acid were characterized by higher lipid accumulation rate, higher leptin, and lower adiponectin secretion. Moreover, in all experimental cells, insulin signaling and glucose utilization were impaired.

Conclusion
Oleic acid affected the methylation of Pparγ and C/ebpα promoters, what correlated with higher expression. Furthermore, examined free fatty acids influenced the phenotype of mature adipocytes, especially insulin signaling pathway and adipokine secretion.
Evaluation of eight formulas for LDL-C estimation in Iranian subjects with different metabolic health statuses
Authors: Karkhaneh Azam , Bagherieh Molood , Sadeghi Solmaz , Kheirollahi Asma 
Published: December 2019

Abstract
Background
Considering the crucial role of low-density lipoprotein-cholesterol (LDL-C) concentration in determining cardiovascular risk, the accuracy of LDL-C estimation is essential. To date, various types of formulae have been introduced, albeit their accuracy has not been assessed in varied populations. In this study, the accuracy of eight formulae for LDL-C estimation was evaluated in an Iranian population.

Methods
A data set of 2752 individuals was included in the study and all samples were analyzed in term of lipid profiles using direct homogeneous assay. The population was divided into various subgroups based on the triglyceride (TG), high-density lipoprotein- cholesterol (HDL-C), total cholesterol (TC), fasting blood sugar (FBS) and age values and estimated LDL-C values by Friedewald, Chen, de Cordova, Vujovic, Anandaraja, Hattori, Ahmadi, and Puavillai equations were compared to the directly measured LDL-C in each subgroup.

Results
Estimated LDL-C values by Puavillai formulae showed an insignificant difference compared to the directly measured LDL-C in subjects with high level of TG. However, for TG range < 3.38 mmol/L and high levels of HDL-C, the difference between the means of estimated LDL-C by Hattori and de Cordova formulas, and directly measured LDL-C was relatively lower than other equations. In addition, estimated LDL-C by Hattori and de Cordova formulae had insignificant differences as compared to the direct LDL-C at some levels of cholesterol, the normal level of FBS and some age ranges.

Conclusions
Therefore, it seems that Hattori and de Cordova formulas can be considered as the best alternatives for LDL-C direct measurement in the Iranian population, especially for healthy subjects.
A novel mutation of ABHD5 gene in a Chanarin Dorfman patient with unusual dermatological findings
Authors: Eskiocak Ali Haydar , Missaglia Sara , Moro Laura , Durdu Murat , Tavian Daniela 
Published: December 2019

Abstract
Background
Chanarin Dorfman Syndrome (CDS) is a rare autosomal recessive disorder characterized by the multisytemic accumulation of neutral lipids inside the cytoplasmic lipid droplets. This condition is caused by mutations in the abhydrolase domain containing 5 gene (ABHD5). In CDS the skin involvement is the prevalent and always observed clinical feature, consisting of a non-bullous congenital ichthyosiform erythroderma (NCIE). Moreover, a variable involvement of the liver and neuromuscular system can be also observed. In this report, we aimed to perform the clinical and genetic characterization of a patient affected by CDS with atypical dermatological findings, considering this rare inborn error of neutral lipid metabolism.

Methods
Genomic DNA samples obtained from patient and his parents were used to perform the sequencing of the ABHD5 exons and their intron/exon boundaries. Bioinformatic analyses were performed to investigate the possible effect of the identified mutation on protein structure.

Results
Here we present the case of a 29-year-old male patient with CDS, who, for long time, has been misdiagnosed as pityriasis rubra pilaris (PRP). He has a history of increasing hyperlipidemia; hepatomegaly associated with hepatosteatosis was also detected. ABHD5 molecular analysis revealed a novel missense mutation, the c.811G > A (p.G271R). Bioinformatic investigations showed that the variant has a deleterious effect on ABHD5 function, probably causing an incorrect folding of the mutant protein.

Conclusions
These results highlihts the importance of genetic testing for ABHD5 in unresolved cases of patients presenting unusual skin lesions, that resemble PRP, associated with a history of hyperlipidemia and nonalcoholic fatty liver.
Ovulatory signals alter granulosa cell behavior through YAP1 signaling
Authors: Sun Tianyanxin , Diaz Francisco J. 
Published: December 2019

Abstract
Background
The Hippo pathway plays critical roles in regulating cell proliferation, differentiation and survival among species. Hippo pathway proteins are expressed in the ovary and are involved in ovarian function. Deletion of Lats1 causes germ cell loss, ovarian stromal tumors and reduced fertility. Ovarian fragmentation induces nuclear YAP1 accumulation and increased follicular development. At ovulation, follicular cells stop proliferating and terminally differentiate, but the mechanisms controlling this transition are not completely known. Here we explore the role of Hippo signaling in mouse granulosa cells before and during ovulation.

Methods
To assess the effect of oocytes on Hippo transcripts in cumulus cells, cumulus granulosa cells were cultured with oocytes and cumulus oocyte complexes (COCs) were cultured with a pSMAD2/3 inhibitor. Secondly, to evaluate the criticality of YAP1 on granulosa cell proliferation, mural granulosa cells were cultured with oocytes, YAP1-TEAD inhibitor verteporfin or both, followed by cell viability assay. Next, COCs were cultured with verteporfin to reveal its role during cumulus expansion. Media progesterone levels were measured using ELISA assay and Hippo transcripts and expansion signatures from COCs were assessed. Lastly, the effects of ovulatory signals (EGF in vitro and hCG in vivo) on Hippo protein levels and phosphorylation were examined. Throughout, transcripts were quantified by qRT-PCR and proteins were quantified by immunoblotting. Data were analyzed by student’s t-test or one-way ANOVA followed by Tukey’s post-hoc test or Dunnett’s post-hoc test.

Results
Our data show that before ovulation oocytes inhibit expression of Hippo transcripts and promote granulosa cell survival likely through YAP1. Moreover, the YAP1 inhibitor verteporfin, triggers premature differentiation as indicated by upregulation of expansion transcripts and increased progesterone production from COCs in vitro. In vivo, ovulatory signals cause an increase in abundance of Hippo transcripts and stimulate Hippo pathway activity as indicated by increased phosphorylation of the Hippo targets YAP1 and WWTR1 in the ovary. In vitro, EGF causes a transient increase in YAP1 phosphorylation followed by decreased YAP1 protein with only modest effects on WWTR1 in COCs.

Conclusions
Our results support a YAP1-mediated mechanism that controls cell survival and differentiation of granulosa cells during ovulation.
The history of neuromyelitis optica. Part 2: ‘Spinal amaurosis’, or how it all began
Authors: Jarius S. , Wildemann B. 
Published: December 2019

AbstractNeuromyelitis optica (NMO) was long considered a clinical variant of multiple sclerosis (MS). However, the discovery of a novel and pathogenic anti-astrocytic serum autoantibody targeting aquaporin-4 (termed NMO-IgG or AQP4-Ab), the most abundant water channel protein in the central nervous system, led to the recognition of NMO as a distinct disease entity in its own right and generated strong and persisting interest in the condition. NMO is now studied as a prototypic autoimmune disorder, which differs from MS in terms of immunopathogenesis, clinicoradiological presentation, optimum treatment, and prognosis. While the history of classic MS has been extensively studied, relatively little is known about the history of NMO. In Part 1 of this series we focused on the late 19th century, when the term ‘neuromyelitis optica’ was first coined, traced the term’s origins and followed its meandering evolution throughout the 20th and into the 21st century. Here, in Part 2, we demonstrate that the peculiar concurrence of acute optic nerve and spinal cord affliction characteristic for NMO caught the attention of physicians much earlier than previously thought by re-presenting a number of very early cases of possible NMO that date back to the late 18th and early 19th century. In addition, we comprehensively discuss the pioneering concept of ‘spinal amaurosis’, which was introduced into the medical literature by ophthalmologists in the first half of the 19th century.