bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized clinical trial: a double-blind, placebo-controlled study to assess the clinical efficacy and safety of alginate–antacid (Gaviscon Double Action) chewable tablets in patients with gastro-oesophageal reflux disease
Authors: Wilkinson Joanne , Wade Alan , Thomas S. Jane , Jenner Bartosz , Hodgkinson Victoria , Coyle Cathal 
Published: September 2018

BackgroundThe alginate–antacid Gaviscon Double Action (Gaviscon DA) has a combined acid-neutralizing and reflux-suppressing action. Response to treatment in a symptomatic gastro-oesophageal reflux disease (GERD) population has not yet been tested in a large-scale clinical study.AimThe aim of this study was to assess the efficacy and safety of Gaviscon DA compared with matched placebo tablets in the reduction of upper gastrointestinal symptoms in patients with GERD.Participants and methodsIn this multicentre, randomized, double-blind, placebo-controlled study, adults with GERD symptoms (N=424) received Gaviscon DA or placebo tablets for 7 days. The primary endpoint was a clinically important reduction of at least 1.5 points in the Reflux Disease Questionnaire (RDQ) GERD dimension (combined heartburn/regurgitation) between baseline and the end of the treatment. Secondary endpoints included the change in RDQ score from baseline for individual RDQ dimensions and Overall Treatment Evaluation.ResultsA significantly greater proportion of patients treated with Gaviscon DA met the primary endpoint compared with placebo (47.8 vs. 33.2%, respectively,P=0.0031; odds ratio: 1.85, 95% confidence interval: 1.23–2.78). A significant treatment effect was also observed for heartburn, regurgitation and dyspepsia individually. Patients in the Gaviscon DA group rated their overall treatment response greater than patients in the placebo group [mean Overall Treatment Evaluation (SD): 3.2 (3.08) vs. 2.2 (3.34);P<0.001]. No notable differences in the incidence of adverse events were observed between treatments.ConclusionThe alginate–antacid combination, Gaviscon DA, is an effective and well-tolerated treatment to reduce reflux symptoms and associated dyspepsia in symptomatic GERD patients.
Evaluating the Clinical Practice Model's Strengths and Improvement Opportunities Using the Professional Practice Framework Assessment Survey
Authors: Burke Laura J. , Shaw Christine L. , Schwartz Cathy , Nelson John W. , Edwards Mike , Pfaff Jann , Seitz Verna 
Published: September 2018

OBJECTIVES
The aims of this study are (1) to describe the division, organizational strengths, and improvement opportunities of self-reported behaviors indicative of the multidimensional construct of professional practice and (2) to understand demographic characteristics that contributed to these strengths and improvement opportunities.

BACKGROUND
Prior to implementing a system-wide interdisciplinary shared governance structure, ProHealth Care measured staff attitudes toward the multidimensional construct of professional practice as proposed within the Clinical Practice Model framework using the Professional Practice Framework Assessment Survey (PPFA-S).

METHODS
Clinical and support staff were invited to share their views toward professional practice using the previously validated, reliable tool, the PPFA-S.

RESULTS
Partnering relationships, scope of practice, and shared purpose were strengths. Strategies were initiated to strengthen networking councils, integrated competency, evidence-based practice, transformative capacity, and clinical tools.

CONCLUSIONS
The survey identified professional practice strengths and improvement opportunities across the organization as well as factors contributing to these strengths and opportunities. These findings were useful to help guide system integration.
Physiatry as a Leader for Postacute Care in Integrated Healthcare Systems
Authors: Bartels Matthew N. 
Published: September 2018

Abstract
Because health care is being moved to a higher level of accountability, there has been a focus on improving outcomes through improving postacute care. The issues of cost and readmissions to acute care settings are very important, but the focus on patient function has not been foremost. Because of the fact that most postacute care needs are based on functional limitations and that physiatrists are well versed in transitions of care, rehabilitation of patients back to community settings, team building, and leadership, it is appropriate for rehabilitation medicine to take a leadership role in the planning and development of postacute care services in the new integrated healthcare systems that are becoming prevalent in healthcare. This review discusses some of the issues in postacute care, the growth of the integrated health system model, and how there are opportunities and challenges for physiatric leadership to help develop these new models of care.
Tertiary structural motif sequence statistics enable facile prediction and design of peptides that bind anti-apoptotic Bfl-1 and Mcl-1
Authors: Frappier Vincent , Jenson Justin M. , Zhou Jianfu , Grigoryan Gevorg , Keating Amy E. 
Published: September 2018

AbstractUnderstanding the relationship between protein sequence and structure well enough to rationally design novel proteins or protein complexes is a longstanding goal in protein science. The Protein Data Bank (PDB) is a key resource for defining sequence-structure relationships that has supported the development of critical resources such as rotamer libraries and backbone torsional statistics that quantify the probabilities of protein sequences adopting different structures. Here, we show that well-defined, non-contiguous structural motifs (TERMs) in the PDB can also provide rich information useful for protein-peptide interaction prediction and design. Specifically, we show that it is possible to rapidly predict the binding energies of peptides to Bcl-2 family proteins as accurately as can be done with widely used structure-based tools, without explicit atomistic modeling. One benefit of a TERM-based approach is that prediction performance is less sensitive to the details of the input structure than are methods that evaluate energies using precise atomic coordinates. We show that protein design using TERM energies (dTERMen) can generate highly novel and diverse peptides to target anti-apoptotic proteins Bfl-1 and Mcl-1. 15 of 17 peptides designed using dTERMen bound tightly to their intended targets, and these peptides have just 15 - 38% sequence identity to any known native Bcl-2 family protein ligand. High-resolution structures of four designed peptides bound to their targets provided opportunities to analyze strengths and limitations of this approach. Dramatic success designing peptides using dTERMen, which comprised going from input structure to experimental validation of high-affinity binders in approximately one month, provides strong motivation for further developing TERM-based approaches to design.
Xrs2 and Tel1 independently contribute to MR-mediated DNA tethering and replisome stability
Authors: Oh Julyun , Lee So Jung , Rothstein Rodney , Symington Lorraine S. 
Published: September 2018

AbstractThe yeast Mre11-Rad50-Xrs2 (MRX) complex has structural, signaling and catalytic functions in the cellular response to DNA damage. Xrs2, the eukaryotic-specific component of the complex, is required for nuclear import of Mre11 and Rad50, and to recruit the Tel1 kinase to damage sites. We show that nuclear-localized MR complex (Mre11-NLS) catalyzes homology-dependent repair without Xrs2, but MR cannot activate Tel1 and it fails to tether DSBs resulting in sensitivity to genotoxins, replisome instability and increased gross chromosome rearrangements (GCRs). Fusing the Tel1 interaction domain from Xrs2 to Mre11-NLS is sufficient to restore telomere elongation and Tel1 signaling to Xrs2-deficient cells. Furthermore, Tel1 stabilizes Mre11-DNA association, and this stabilization function becomes important for DNA damage resistance in the absence of Xrs2. Enforcing Tel1 recruitment to the nuclear MR complex fully rescues end tethering, stalled replication fork stability and suppresses GCRs, highlighting important roles for Xrs2 and Tel1 to ensure optimal MR activity.HighlightsXrs2 is required for recruitment but not for activation of Tel1 kinaseTel1 and Xrs2 function independently to optimize MR activity at DSBs and stalled replication forksStable association of Mre11 at DSBs is required to maintain end-to-end tetheringMR-mediated DNA tethering promotes replisome stability and genome integrity
Impaired ureagenesis due to arginine-insensitive N-acetylglutamate synthase
Authors: Sonaimuthu Parthasarathy , Senkevitch Emilee , Haskins Nantaporn , Uapinyoying Prech , McNutt Markey , Morizono Hiroki , Tuchman Mendel , Caldovic Ljubica 
Published: September 2018

AbstractThe urea cycle protects the central nervous system from ammonia toxicity by converting ammonia to non-toxic urea. N-acetylglutamate synthase (NAGS) is an enzyme that catalyzes the formation of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1), the rate limiting enzyme of the urea cycle. Enzymatic activity of mammalian NAGS doubles in the presence of L-arginine but the physiological significance of NAGS activation by L-arginine is unknown. Previously, we have described the creation of a NAGS knockout (Nags−/−) mouse, which develops hyperammonemia without N-carbamylglutamate and L-citrulline supplementation (NCG+Cit). In order to investigate the effect of L-arginine on ureagenesisin vivo, we used adeno associated virus (AAV) mediated gene transfer to deliver either wild-type or E354A mutant mouse NAGS (mNAGS), which is not activated by L-arginine, toNags−/−mice. The ability of the E354A mNAGS mutant protein to rescueNags−/−mice was determined by measuring their activity on the voluntary wheel following NCG+Cit withdrawal. TheNags−/−mice that received E354A mNAGS remained apparently healthy and active but had elevated plasma ammonia concentration despite similar expression levels of the E354A mNAGS and control wild-type NAGS proteins. The corresponding mutation in human NAGS (NP 694551.1:p.E360D) that abolishes binding and activation by L-arginine was also identified in a patient with hyperammonemia due toNAGSdeficiency. Taken together, our results suggest that L-arginine binding to the NAGS enzyme is essential for normal ureagenesis.
Novel 5-Hydroxymethylcytosine Markers for Pancreatic Cancer
Authors: Zeng Chang , Zhang Zhou , Wang Jun , Chiu Brian C-H. , Hou Lifang , Zhang Wei 
Published: September 2018

AbstractOBJECTIVESRobust biomarkers for pancreatic cancer (PaC) early detection/prognosis are critical for improved patient survival. Our goal was to explore the biomarker potential of 5-hydroxymethylcytosines (5hmC), an epigenetic marker with a distinct role in cancer pathobiology, yet under-investigated due largely to technical constraints.METHODSWe used the TAB-Array assay, a state-of-the-art technology to directly profile 5hmC at single base resolution with the Illumina EPIC array (>850,000 CpG sites) in 17 pairs of tumor/adjacent tissue samples from US patients.RESULTSWe demonstrated distinctive distributions of 5hmC in tissues, and substantial differences between tumor and adjacent tissues, suggesting their diagnostic/prognostic value of for PaC.CONCLUSIONThis study established the potential of 5hmC as a novel epigenetic biomarker for PaC.
Empirical patterns of environmental variation favor the evolution of adaptive transgenerational plasticity
Authors: Colicchio Jack M. , Herman Jacob 
Published: September 2018

AbstractEffects of parental environment on offspring traits have been well known for decades. Interest in this transgenerational form of phenotypic plasticity has recently surged due to advances in our understanding of its mechanistic basis. Theoretical research has simultaneously advanced by predicting the environmental conditions that should favor the adaptive evolution of transgenerational plasticity. Yet whether such conditions actually exist in nature remains largely unexplored. Here, using long-term climate data, we modeled optimal levels of transgenerational plasticity for an organism with a one-year life cycle at a spatial resolution of 4km2 across the continental US. Both annual temperature and precipitation levels were often autocorrelated, but the strength and direction of these autocorrelations varied considerably across the continental US and even among nearby sites. When present, such environmental autocorrelations render offspring environments statistically predictable based on the parental environment, a key condition for the adaptive evolution of transgenerational plasticity. Results of our optimality models were consistent with this prediction: high levels of transgenerational plasticity were favored at sites with strong environmental autocorrelations, and little-to-no transgenerational plasticity was favored at sites with weak or non-existent autocorrelations. These results are among the first to show that natural patterns of environmental variation favor the evolution of adaptive transgenerational plasticity. Furthermore, these findings suggest that transgenerational plasticity is highly variable in nature, depending on site-specific patterns of environmental variation.
Sexual selection, environmental robustness and evolutionary demography of maladapted populations: a test using experimental evolution in seed beetles
Authors: Martinossi-Allibert Ivain , Thilliez Emma , Arnqvist Göran , Berger David 
Published: September 2018

AbstractWhether sexual selection impedes or aids adaptation has become a pressing question in times of rapid environmental change and parallels the debate about how the evolution of individual traits impacts on population dynamics and viability. The net effect of sexual selection on population viability results from a balance between genetic benefits of “good genes” effects and costs of sexual conflict. Depending on how these facets of sexual selection are affected under environmental change, extinction of maladapted populations could either be avoided or accelerated. Here, we evolved seed beetles under three alternative mating regimes (polygamy, monogamy and male-limited selection) to disentangle the contributions of sexual selection, fecundity selection and male-female coevolution to individual reproductive success and population fitness. We compared these contributions between the ancestral environment and two new stressful environments (temperature and host plant shift). Evolution under polygamy resulted in the highest individual reproductive success in competitive context for both sexes. Moreover, females evolving only via sexual selection on their male siblings in the male-limited regime had similar reproductive success and higher fertility than females evolving under monogamy, suggesting that sexual selection on males had positive effects on female fitness components. Interestingly, male-limited sexual selection resulted in males that were robust to stress, compared to males from the two evolution regimes applying fecundity selection. We quantified the population-level consequences of this sex-specific adaptation and found evidence that costs of socio-sexual interactions were higher in male-limited lines compared to polygamous lines, and that this difference was particularly pronounced at elevated temperature to which males from the male-limited regime were more robust compared to their conspecific females. These results illustrate the tension between individual-level adaptation and population-level viability in sexually reproducing species and suggest that sex-specific selection can cause differences in environmental robustness that may impact population demography under environmental change.
Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop
Authors: Chen Zhen-Hua , Zeng Zhan-Cheng , Chen Tian-Qi , Han Cai , Sun Yu-Meng , Huang Wei , Sun Lin-Yu , Fang Ke , Luo Xue-Qun , Wang Wen-Tao , Chen Yue-Qin 
Published: September 2018

AbstractAberrant chromosomal translocations leading to tumorigenesis have been ascribed to the heterogeneously oncogenic functions. However, how fusion transcripts exporting remains to be declared. Here, we showed that the nuclear speckle-specific long non coding RNA MALAT1 controls chimeric mRNA export processes and regulates myeloid progenitor cell differentiation in malignant hematopoiesis. We demonstrated that MALAT1 regulates chimeric mRNAs export in an m6A-dependent manner and thus controls hematopoietic cell differentiation. Specifically, reducing MALAT1 or m6A methyltransferases and the ‘reader’ YTHDC1 result in the universal retention of distinct oncogenic gene mRNAs in nucleus. Mechanically, MALAT1 hijacks both the chimeric mRNAs and fusion proteins in nuclear speckles during chromosomal translocations and mediates the colocalization of oncogenic fusion proteins with METTL14. MALAT1 and fusion protein complexes serve as a functional loading bridge for the interaction of chimeric mRNA and METTL14. This study demonstrated a universal mechanism of chimeric mRNA transport that involves lncRNA-fusion protein-m6A autoregulatory loop for controlling myeloid cell differentiation. Targeting the lncRNA-triggered autoregulatory loop to disrupt chimeric mRNA transport might represent a new common paradigm for treating blood malignancies.
Twenty-four hour face mask sampling in pulmonary tuberculosis reveals three distinct patterns of bacterial aerosol production dissociated from conventional markers of transmission risk
Authors: Williams CML , Abdulwhhab M , Birring SS , De Kock E , Garton NJ , Stoltz A , Haldar P , Barer MR 
Published: September 2018

Rationale:Although tuberculosis (TB) is transmitted byMycobacterium tuberculosis(Mtb) in aerosols, little is known of the dynamic characteristics of spontaneous output of bacilli in this form. We have developed and implemented a mask aerosol sampling system (MASS) for longitudinal capture and study of spontaneous aerosol.Objective:To determine patterns of Mtb output in aerosols, captured using the MASS over 24 hours and their association with existing criteria used to assess transmission risk in patients with pulmonary TB.Methods:Twenty-four hospitalised patients with newly diagnosed pulmonary TB recruited in Pretoria, South Africa, wore FFP1 masks for one hour out of every three for 24 hours. Aerosol was captured in a gelatine filter processed for Mtb quantitation by PCR. Serial sputum was collected and objective cough frequency monitoring performed over the same period.Measurements and Main Results:Mtb was detected in 86.5% of 192 mask samples and 20.7% of 38 assessable sputum samples obtained from the cohort. Mtb was detected by MASS in all but two patients. Three dynamic patterns of expression were identifiable in Mtb aerosol producers: i. variable high; ii. consistent; and iii. variable low. No diurnal variation was apparent and there was no correlation between mask Mtb and either sputum Mtb levels or cough frequency. Sputum smear status, culture time to positivity and chest radiographic characteristics also failed to associate with MASS bacillary output.Conclusions:Conventional markers of tuberculosis case infectivity do not predict bacillary aerosols detected by the MASS. The MASS provides a novel, non-invasive tool for tuberculosis diagnosis and control.
WNT1 Inducible Signaling Pathway Protein 1 (WISP1) stimulates melanoma cell invasion and metastasis by promoting epithelial – mesenchymal transition
Authors: Deng Wentao , Fernandez Audry , McLaughlin Sarah L. , Klinke David J. 
Published: September 2018

ABSTRACTBesides intrinsic changes, malignant cells release soluble signals to reshape their microenvironment. Among the signaling factors is WNT1 inducible signaling pathway protein 1 (WISP1), a secreted matricellular protein that is elevated in a variety of cancers including melanoma and is associated with reduced overall survival of patients diagnosed with primary melanoma. In this work, we found thatWISP1knockout both increased cell proliferation and repressed wound healing, migration and invasion of mouse and human melanoma cells in an ensemble ofin vitroassays.In vivometastasis assays showed that WISP1 knockout repressed tumor metastasis in both C57BL/6Ncrl and NOD-scid IL2Rgammanull (NSG) mice with B16F10 and YUMM1.7 melanoma cells. Mechanistically, B16F10 cells that invaded in a transwell assay possessed a gene expression signature similar to Epithelial - Mesenchymal Transition (EMT), including coincident repression of E-cadherin and induction of fibronectin and N-cadherin. Upon WISP1 knockout, these EMT signature genes went in opposite directions in both mouse and human cell lines and were rescued by media containing WISP1 or recombinant WISP1 protein.In vivo,metastasis repression by WISP1 knockout was reversed by the reintroduction of either WISP1 or SNAI1. A set of EMT gene activation and inhibition experiments using recombinant WISP1 or kinase inhibitors in B16F10 and YUMM1.7 cells suggested that WISP1 activates Akt and MAP kinase signaling pathways to shift melanoma cells from a proliferative to invasive phenotype. Collectively, the results supported a model that WISP1 within the tumor microenvironment stimulates melanoma invasion and metastasis by promoting an EMT-like process.
Naproxen impairs load-induced bone formation, reduces bone toughness, and delays stress fracture repair in mice
Authors: Park Jino , Fertala Andrzej , Tomlinson Ryan E. 
Published: September 2018

SUMMARYDebilitating stress fractures are surprisingly common in physically active individuals, including athletes, military recruits, and dancers. These individuals are overrepresented in the 30 million daily users of non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesized that regular use of NSAIDs would predispose habitually loaded bones to stress fracture and delay the repair of these injuries. To test this hypothesis, adult mice were subjected to six bouts of axial forelimb compression over two weeks. Aspirin, naproxen, or vehicle was administered 24 hours before loading. Naproxen-treated mice had diminished load-induced bone formation as well as a significant loss in toughness in non-loaded bone, which were not observed in aspirin-treated mice. Furthermore, there were no differences in RANKL/OPG ratio or cortical bone parameters. Picrosirius red staining and second harmonic generation imaging revealed that alterations in bone collagen fibril size and organization were driving the loss of toughness in naproxen-treated mice. Separately, adult mice were subjected to an ulnar stress fracture generated by a single bout of fatigue loading, with NSAIDs provided 24 hours before injury. Both aspirin-treated and naproxen-treated mice had normal forelimb use in the week after injury, whereas control mice favored the injured forelimb until day 7. However, woven bone volume was only significantly impaired by naproxen. Both NSAIDs were found to significantly inhibitCox2andNgfexpression following stress fracture, but only naproxen significantly affected serum PGE2 concentration. Overall, our results suggest that naproxen, but not aspirin, may increase the risk of stress fracture and extend the healing time of these injuries, warranting further clinical evaluation for patients at risk for fatigue injuries.