bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel, de novo mutation in the PRKAG2 gene: infantile-onset phenotype and the signaling pathway involved
Authors: Xu Yanchun , Gray A. , Hardie D. Grahame , Uzun Alper , Shaw Sunil , Padbury James , Phornphutkul Chanika , Tseng Yi-Tang 
Published: May 2017

PRKAG2 encodes the γ2-subunit isoform of 5′-AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in the regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload, ventricular preexcitation, and hypertrophy. We identified a novel, de novo PRKAG2 mutation (K475E) in a neonate with prenatal onset of HCM. We aimed to investigate the cellular impact, signaling pathways involved, and therapeutic options for K475E mutation using cells stably expressing human wild-type (WT) or the K475E mutant. In human embryonic kidney-293 cells, the K475E mutation induced a marked increase in the basal phosphorylation of T172 and AMPK activity, reduced sensitivity to AMP in allosteric activation, and a loss of response to phenformin. In H9c2 cardiomyocytes, the K475E mutation induced inhibition of AMPK and reduced the response to phenformin and increases in the phosphorylation of p70S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). Primary fibroblasts from the patient with the K475E mutation also showed marked increases in the phosphorylation of p70S6K and 4E-BP1 compared with those from age-matched, nondiseased controls. Moreover, overexpression of K475E induced hypertrophy in H9c2 cells, which was effectively reversed by treatment with rapamycin. Taken together, we have identified a novel, de novo infantile-onset PRKAG2 mutation causing HCM. Our study suggests the K475E mutation induces alteration in basal AMPK activity and results in a hypertrophy phenotype involving the mechanistic target of rapamycin signaling pathway, which can be reversed with rapamycin. NEW & NOTEWORTHY We identified a novel, de novo PRKAG2 mutation (K475E) in the cystathionine β-synthase 3 repeat, a region critical for AMP binding but with no previous reported mutation. Our data suggest the mutation affects AMP-activated protein kinase activity, activates cell growth pathways, and results in cardiac hypertrophy, which can be reversed with rapamycin.
Keyboard: A Novel Bayesian Toxicity Probability Interval Design for Phase I Clinical Trials
Authors: Yan Fangrong , Mandrekar Sumithra J. , Yuan Ying 
Published: May 2017

Abstract
The primary objective of phase I oncology trials is to find the MTD. The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval. The keyboard design can be implemented in a simple way, similar to the traditional 3+3 design, but provides more flexibility for choosing the target toxicity rate and cohort size. Our simulation studies demonstrate that compared with the 3+3 design, the keyboard design has favorable operating characteristics in terms of identifying the MTD. Compared with the mTPI design, the keyboard design is safer, with a substantially lower risk of treating patients at overly toxic doses, and has the better precision to identify the MTD, thereby providing a useful upgrade to the mTPI design. Software freely available at http://www.trialdesign.org facilitates the application of the keyboard design. Clin Cancer Res; 23(15); 3994–4003. ©2017 AACR.
See related commentary by Paoletti et al., p. 3977
<b>Dna barcoding, population genetics, and phylogenetics of the illegally hunted Philippine Duck <I>Anas luzonica</I> (Aves: Anseriformes: Anatidae)</b>
Authors: Licuanan Ardea Mingoa , Duya Mariano RoyMartin , Ong Perry Sim , Fontanilla Ian Kendrich Carandang 
Published: May 2017

DNA barcoding is extensively used as a species identification and delineation tool. The aim of this study was to generate a barcode profile for mitochondrial cytochrome c oxidase subunit 1 (COI) in the Philippine Duck Anas luzonica, a dabbling duck species endemic to the Philippines that is classified as ‘Vulnerable’ by the International Union for Conservation of Nature (BirdLife International 2016). COI barcodes were successfully obtained using muscle tissue samples from 46 A. luzonica individuals confiscated from illegal hunters in Pantabangan, Nueva Ecija. Analysis of TrN+Γ+I distances among the Anas luzonica COI sequences and those of 25 other Anas species revealed that COI barcodes cannot generally delineate hybridizing species. While Anas luzonica was differentiated from other species it is known to hybridize with and formed a monophyletic group in the neighbor-joining tree generated, sampling from areas of sympatry is needed since individuals were obtained from only one sampling site. The population structure of the Anas luzonica population was also examined using mitochondrial DNA control region and COI sequences. The population had high haplotype diversity and low nucleotide diversity, an indication that a bottleneck event had occurred, which is likely due to extreme hunting pressures and habitat destruction. The population under study exhibited high genetic diversity. Given that the samples for this study came from a single locality, sampling from other localities is required to determine whether other populations are facing the risk of reduced fitness (inbreeding depression).
<b>New distribution records of some wild crop relatives from India</b>
Authors: Pradheep K. , Rathi R. S. , John K. Joseph , Sultan S. M. , Abraham B. , Pandey Anjula , Nayar E. Roshini , Ahlawat S. P. , Gupta Rita 
Published: May 2017

Field surveys across various parts of the country coupled with an analysis of literature and examination of herbarium specimens revealed the natural distribution of six wild relatives of crop species in various states/union territories of India, viz., Cajanus scarabaeoides (from Lakshadweep), Cucumis javanicus (from Meghalaya), Hystrix duthiei (from Jammu & Kashmir), Luffa echinata (from Haryana) and Trichosanthes pilosa (from Andhra Pradesh), which have not been reported earlier from these states. Their descriptions, phenology, habitat and other field notes have been presented here.
<b>Population dynamics of medium and large mammals in a West African gallery forest area and the potential effects of poaching</b>
Authors: Hema Emmanuel M. , Ouattara Yaya , Karama Mamadou , Petrozzi Fabio , Di Vittorio Massimiliano , Guenda Wendengoudi , Luiselli Luca 
Published: May 2017

Few studies are available on the population dynamics of medium and large mammals in gallery forests of the Sudan and Sahel regions of West Africa. Line-transect studies of the abundance (estimated by KIA) of nine species of ungulates and three species of primates were carried out between 2004 and 2013 in the Comoé-Leraba protected area of Burkina Faso, West Africa. No peer-reviewed study of population sizes of mammals in this protected area has been published, making the data presented of special relevance. Population size trends varied significantly across years in both primates and ungulates, with some species (Papio anubis, Phacochoerus africanus, Alcelaphus busephalus and Tragelaphus scriptus) decreasing consistently. Significant relationships were observed between poaching intensity and population oscillations in Erythrocebus patas, Kobus ellipsiprymnus, Kobus kob, Ourebia ourebi and Cephalophus rufilatus.
Effect of Sodium‐Glucose Cotransport‐2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis of 43 Randomized Control Trials With 22 528 Patients
Authors: Mazidi Mohsen , Rezaie Peyman , Gao Hong‐Kai , Kengne Andre Pascal 
Published: May 2017

Background

The sodium‐glucose cotransporter 2 (
SGLT
2) inhibitors are a class of oral hypoglycemic agents. We undertake a systematic review and meta‐analysis of prospective studies to determine the effect of
SGLT
2 on blood pressure (BP) among individuals with type 2 diabetes mellitus.

Methods and Results

PubMed‐Medline, Web of Science, Cochrane Database, and Google Scholar databases were searched to identify trial registries evaluating the impact of
SGLT
2 on BP. Random‐effects models meta‐analysis was used for quantitative data synthesis. The meta‐analysis indicated a significant reduction in systolic BP following treatment with
SGLT
2 (weighted mean difference −2.46 mm Hg [95%
CI
−2.86 to −2.06]). The weighted mean differences for the effect on diastolic BP was −1.46 mm Hg (95%
CI
−1.82 to −1.09). In these subjects the weighted mean difference effects on serum triglycerides and total cholesterol were −2.08 mg/dL (95%
CI
−2.51 to −1.64) and 0.77 mg/dL (95%
CI
0.33‐1.21), respectively. The weighted mean differences for the effect of
SGLT
2 on body weight was −1.88 kg (95%
CI
−2.11 to −1.66) across all studies. These findings were robust in sensitivity analyses.

Conclusions

Treatment with
SGLT
2 glucose cotransporter inhibitors therefore has beneficial off‐target effects on BP in patients with type 2 diabetes mellitus and may also be of value in improving other cardiometabolic parameters including lipid profile and body weight in addition to their expected effects on glycemic control. However, our findings should be interpreted with consideration for the moderate statistical heterogeneity across the included studies.
A National Survey of Canadian Psychiatrists’ Attitudes toward Medical Assistance in Death
Authors: Rousseau Skye , Turner Sarah , Chochinov Harvey Max , Enns Murray W. , Sareen Jitender 
Published: May 2017

Background: Bill C-14 allows for medical assistance in dying (MAID) for patients who have intolerable physical or psychological suffering that occurs in the context of a reasonably foreseeable death. In Canada, psychiatrist support for MAID on the basis of mental illness and beliefs influencing level of support are unknown. The objectives of this research were to 1) determine if psychiatrists are supportive of MAID under certain conditions and on the basis of mental illness and 2) determine what factors are related to psychiatrist support for MAID on the basis of mental illness. Methods: This cross-sectional study was conducted among 528 psychiatrists in Canada using an online survey platform (February 19 to March 11, 2016). Results: The response rate was 20.9% ( n = 528). Most psychiatrists supported the legalisation of MAID in some circumstances (72%); however, only 29.4% supported MAID on the basis of mental illness. Factors correlating with decreased support for MAID for mental illness were the belief that MAID for mental illness would change the psychiatrists’ commitment to their patients through enduring suffering, having a personal faith, and having had past patients who would have received MAID for mental illness were it legal but instead went on to recover. Interpretation: This study found that most psychiatrists do not support the legalisation of MAID for mental illness, despite being quite supportive of MAID in general. Objections seemed to be based upon concern for vulnerable patients, personal moral objections, and concern for the effect it would have on the therapeutic alliance.
Immunotoxicological Effects of Jp-8 Jet Fuel Exposure
Authors: Harris David T. , Sakiestewa Debbie , Robledo Raymond F. , Witten Mark 
Published: May 2017

Chronic exposure to jet fuel has been shown to have adverse effects on human liver function, to cause emotional dysfunction, to cause abnormal electroencephalograms, to cause shortened attention spans, and to decrease sensorimotor speed (3–5). Due to the decision by the United States Air Force to implement the widespread use of JP-8 jet fuel in its operations, a thorough understanding of its potential effects upon exposed personnel is both critical and necessary. Exposure to potential environmental toxicants such as JP-8 may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.); e.g., the immune system. Significant changes in immune consequences, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long-lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed for 1h/day for 7 days to varying concentrations of aerosolized JP-8 jet fuel to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on their immune systems. It was observed that even at exposure concentrations as low as 100 mg/m3 detrimental effects on the immune system occurred. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in losses of different immune cell subpopulations depending upon the immune organ being examined. Further, JP-8 exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low concentration exposure of mice to JP-8 jet fuel caused significant toxicological effects on the immune system. It appears that the immune system may be the most sensitive indicator of toxicological damage due to JP-8 exposure, as effects were seen at concentrations of jet fuel that did not evidence change in other biological systems. Such changes may have significant effects on the health of the exposed individual.
Comparison of intramuscular butorphanol and buprenorphine combined with dexmedetomidine for sedation in cats
Authors: Bhalla Rebecca J , Trimble Toby A , Leece Elizabeth A , Vettorato Enzo 
Published: May 2017

Objectives The objective of this study was to compare the sedative effect of butorphanol–dexmedetomidine with buprenorphine–dexmedetomidine following intramuscular (IM) administration in cats. Methods Using a prospective, randomised, blinded design, 40 client-owned adult cats were assigned to receive IM dexmedetomidine (10 µg/kg) combined with either butorphanol (0.4 mg/kg) (‘BUT’ group) or buprenorphine (20 µg/kg) (‘BUP’ group). Sedation was scored using a previously published multidimensional composite scale before administration (T0) and 5, 10, 15 and 20 mins afterwards (T5, T10, T15 and T20, respectively). Alfaxalone (1.5 mg/kg) was administered IM at T20 if the cat was not deemed adequately sedated to place an intravenous catheter. Adverse events were recorded. Friedman two-way ANOVA analysed sedation scores within groups. Mann–Whitney Rank Sum test compared sedation scores between groups; Fisher’s exact test analysed the frequency of alfaxalone administration and adverse events. P <0.05 was considered statistically significant. Results Sedation scores between groups were similar at baseline, but at T5, T10, T15 and T20 scores were higher in the BUT group ( P <0.01). Within both groups, sedation scores changed over time and the highest sedation scores were reached at T10. Requirement for additional sedation was similar between groups: two cats in the BUT group and five cats in the BUP group. One cat and 11 cats vomited ( P = 0.002) in the BUT and BUP groups, respectively. No other adverse events were recorded. Conclusions and relevance At these doses, IM buprenorphine–dexmedetomidine provides inferior sedation and a higher incidence of vomiting than butorphanol–dexmedetomidine in cats. Butorphanol–dexmedetomidine may be preferred for feline sedation, especially where vomiting is contraindicated.
Felis catus papillomavirus type 2 DNA loads on kittens are transient and do not reflect their susceptibility to infection
Authors: Thomson Neroli A , Thomas David G , Weidgraaf Karin , Munday John S 
Published: May 2017

Objectives Felis catus papillomavirus type 2 (FcaPV-2) commonly infects the skin of domestic cats, and mounting evidence suggests that the virus could be involved in a subset of feline skin cancers. The reason why some cats develop FcaPV-2-induced disease and others do not is currently unknown. However, it has been shown that kittens in different litters have markedly different FcaPV-2 DNA loads and the aim of this study was to determine whether these differences could be due to inherent differences in susceptibility to infection. Such differences could potentially explain why only a small proportion of cats develop FcaPV-2-associated skin disease. Methods Repeated skin swabs were taken to measure FcaPV-2 DNA loads in queens and kittens in a research colony. The kittens either stayed in their original litters or were moved between litters; eventually, all of the kittens were housed together. A subset of samples was also analysed for FcaPV-2 mRNA. Results While there were initially large differences in FcaPV-2 DNA loads between litters of kittens, these differences disappeared when the kittens were moved between litters or housed together. Importantly, the viral DNA loads changed too rapidly to be due to the acquisition or clearance of infection. In contrast, the differences in viral DNA loads between the different queens were sustained throughout the experiment. FcaPV-2 mRNA was also detected in samples from 1- to 8-day-old kittens. Conclusions and relevance The results suggest that the FcaPV-2 DNA load in a swab sample from an individual kitten largely reflects the overall level of FcaPV-2 shedding in the group of in-contact cats, rather than the infection status of the individual kitten. Therefore, there was no evidence for inherent differences in susceptibility to infection. However, the finding of FcaPV-2 mRNA suggests that at least some kittens do become infected with FcaPV-2 early in life.
Ultrasonic roll bite measurements in cold rolling: Contact length and strip thickness
Authors: Carretta Yves , Hunter Andrew , Boman Romain , Ponthot Jean-Philippe , Legrand Nicolas , Laugier Maxime , Dwyer-Joyce Rob 
Published: May 2017

In cold rolling of thin metal strip, contact conditions between the work rolls and the strip are of great importance: roll deformations and their effect on strip thickness variation may lead to strip flatness defects and thickness inhomogeneity. To control the process, online process measurements are usually carried out; such as the rolling load, forward slip and strip tensions at each stand. Shape defects of the strip are usually evaluated after the last stand of a rolling mill thanks to a flatness measuring roll. However, none of these measurements is made within the roll bite itself due to the harsh conditions taking place in that area. This paper presents a sensor capable of monitoring strip thickness variations as well as roll bite length in situ and in real time. The sensor emits ultrasonic pulses that reflect from the interface between the roll and the strip. Both the time-of-flight of the pulses and the reflection coefficient (the ratio of the amplitude of the reflected signal to that of the incident signal) are recorded. The sensor system was incorporated into a work roll and tested on a pilot rolling mill. Measurements were taken as steel strips were rolled under several lubrication conditions. Strip thickness variation and roll-bite length obtained from the experimental data agree well with numerical results computed with a cold rolling model in the mixed lubrication regime.
Multiple sclerosis: Serum anti-CNS autoantibodies
Authors: Prineas John W , Parratt John D.E 
Published: May 2017

Background: It is uncertain whether there are autoantibodies detectable by indirect immunofluorescence in the serum of patients with multiple sclerosis (MS). Objective: To determine whether there are anti-central nervous system (CNS) autoantibodies detectable by indirect immunofluorescence in the serum of MS patients. Methods: Sera and in some cases cerebrospinal fluid from 106 patients with multiple sclerosis, 156 patients with other neurological diseases, and 70 healthy control subjects were examined by indirect immunofluorescence using cryostat sections of rat cerebrum fixed by perfusion with paraformaldehyde. Results: Autoantibodies were detected that recognized more than 30 neuronal, glial, and mesodermal structures in 28 of 106 MS cases. Most were also detected in patients with other related and unrelated neurological diseases and several were also found in healthy controls. Novel anti-CNS autoantibodies recognizing particular sets of interneurons were detected in both normal controls and in subjects with CNS diseases. Interpretation: Serum anti-CNS autoantibodies of diverse specificities are common in MS patients. The same anti-CNS autoantibodies are not uncommon in patients with other neurological diseases. The findings provide no support for the proposition that myelin breakdown in MS is caused by exposure of intact myelin sheaths or oligodendrocytes to a pathogenic serum anti-myelin or anti-oligodendrocyte autoantibody.
Low reliability of anti-KIR4.183–120 peptide auto-antibodies in multiple sclerosis patients
Authors: Marino Mariapaola , Frisullo Giovanni , Di Sante Gabriele , Samengo Daniela Maria , Provenzano Carlo , Mirabella Massimiliano , Pani Giovambattista , Ria Francesco , Bartoccioni Emanuela 
Published: May 2017

Background: Multiple sclerosis (MS) is an autoimmune disease for which auto-antibodies fully validated as diagnostic and prognostic biomarkers are widely desired. Recently, an immunoreactivity against the inward rectifying potassium channel 4.1 (KIR4.1) has been reported in a large proportion of a group of MS patients, with amino acids 83–120 being the major epitope. Moreover, a strong correlation between anti-KIR4.183–120 and anti-full-length-protein auto-antibodies titer was reported. However, this finding received limited confirmation. Objective: Validation of the diagnostic potential of anti-KIR4.183–120 antibodies in 78 MS patients, 64 healthy blood donors, and 42 individuals with other neurological diseases. Methods: Analysis of anti-KIR4.183–120 antibodies by enzyme-linked immunosorbent assay (ELISA) using a mouse antiserum we produced as a new ELISA reliability control. Additionally, evaluation of reactivity against 293-T cells transiently transfected with full-length KIR4.1 by flow cytometry. Results: We found antibodies to KIR4.183–120 only in 13 out of 78 (16.6%) MS patients; among these, only 2 were positive for anti-full-length KIR4.1 antibodies. Conclusion: Employing a new reliability control and a new cytofluorometric assay, we cannot support anti-KIR4.183–120 auto-antibodies as a reliable biomarker in MS.