bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered structural and effective connectivity in anorexia and bulimia nervosa in circuits that regulate energy and reward homeostasis
Authors: Frank G K W , Shott M E , Riederer J , Pryor T L 
Published: November 2016

AbstractAnorexia and bulimia nervosa are severe eating disorders that share many behaviors. Structural and functional brain circuits could provide biological links that those disorders have in common. We recruited 77 young adult women, 26 healthy controls, 26 women with anorexia and 25 women with bulimia nervosa. Probabilistic tractography was used to map white matter connectivity strength across taste and food intake regulating brain circuits. An independent multisample greedy equivalence search algorithm tested effective connectivity between those regions during sucrose tasting. Anorexia and bulimia nervosa had greater structural connectivity in pathways between insula, orbitofrontal cortex and ventral striatum, but lower connectivity from orbitofrontal cortex and amygdala to the hypothalamus (P<0.05, corrected for comorbidity, medication and multiple comparisons). Functionally, in controls the hypothalamus drove ventral striatal activity, but in anorexia and bulimia nervosa effective connectivity was directed from anterior cingulate via ventral striatum to the hypothalamus. Across all groups, sweetness perception was predicted by connectivity strength in pathways connecting to the middle orbitofrontal cortex. This study provides evidence that white matter structural as well as effective connectivity within the energy-homeostasis and food reward-regulating circuitry is fundamentally different in anorexia and bulimia nervosa compared with that in controls. In eating disorders, anterior cingulate cognitive–emotional top down control could affect food reward and eating drive, override hypothalamic inputs to the ventral striatum and enable prolonged food restriction.
The DPYSL2 gene connects mTOR and schizophrenia
Authors: Pham X , Song G , Lao S , Goff L , Zhu H , Valle D , Avramopoulos D 
Published: November 2016

AbstractWe previously reported a schizophrenia-associated polymorphic CT di-nucleotide repeat (DNR) at the 5′-untranslated repeat (UTR) of DPYSL2, which responds to mammalian target of Rapamycin (mTOR) signaling with allelic differences in reporter assays. Now using microarray analysis, we show that the DNR alleles interact differentially with specific proteins, including the mTOR-related protein HuD/ELAVL4. We confirm the differential binding to HuD and other known mTOR effectors by electrophoretic mobility shift assays. We edit HEK293 cells by CRISPR/Cas9 to carry the schizophrenia risk variant (13DNR) and observe a significant reduction of the corresponding CRMP2 isoform. These edited cells confirm the response to mTOR inhibitors and show a twofold shortening of the cellular projections. Transcriptome analysis of these modified cells by RNA-seq shows changes in 12.7% of expressed transcripts at a false discovery rate of 0.05. These transcripts are enriched in immunity-related genes, overlap significantly with those modified by the schizophrenia-associated gene, ZNF804A, and have a reverse expression signature from that seen with antipsychotic drugs. Our results support the functional importance of the DPYSL2 DNR and a role for mTOR signaling in schizophrenia.
Recognition of the 3′ splice site RNA by the U2AF heterodimer involves a dynamic population shift
Authors: Voith von Voithenberg Lena , Sánchez-Rico Carolina , Kang Hyun-Seo , Madl Tobias , Zanier Katia , Barth Anders , Warner Lisa R. , Sattler Michael , Lamb Don C. 
Published: November 2016

Significance
The splicing of human pre-mRNAs is tightly controlled and regulated during the assembly of the spliceosome onto pre-mRNA introns. Recognition of regulatory RNA sequence motifs by splicing factors is an essential early step during spliceosome assembly. We combine single-pair FRET and NMR to show that the recognition of the 3′ splice site in pre-mRNA introns by the essential heterodimeric splicing factor U2 auxiliary factor (U2AF) involves conformational dynamics and population shifts of its RNA binding domains between open and closed conformations. Unexpectedly, the small subunit U2AF35 facilitates the recognition of weak splice sites by a population shift of the RNA binding domains of U2AF65 toward the open conformation. Notably, disease-linked mutations in U2AF65 do not affect RNA or U2AF35 binding.
Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes
Authors: Lopez-Fabuel Irene , Le Douce Juliette , Logan Angela , James Andrew M. , Bonvento Gilles , Murphy Michael P. , Almeida Angeles , Bolaños Juan P. 
Published: November 2016

Significance
Neurons depend on oxidative phosphorylation for survival, whereas astrocytes do not. Mitochondrial respiratory chain (MRC) complexes can be organized in higher structures called supercomplexes, which dictate MRC electron flux and energy efficiency. Whether the specific metabolic shapes of neurons and astrocytes are determined by the specific organization of MRC complexes is unknown. Here, we found that, in astrocytes, most complex I is free, resulting in poor mitochondrial respiration but high reactive oxygen species (ROS) production. In contrast, neurons show complex I to be mostly embedded into supercomplexes, thus resulting in high mitochondrial respiration and low ROS production. Thus, MRC organization dictates different bioenergetics preferences of neurons and astrocytes impacting on ROS production, possibly playing a role in neurodegenerative diseases.
Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal
Authors: Piochon Claire , Titley Heather K. , Simmons Dana H. , Grasselli Giorgio , Elgersma Ype , Hansel Christian 
Published: November 2016

Significance
Instructive signals play an important role in synaptic plasticity and learning. For example, at cerebellar parallel fiber (PF)-Purkinje cell synapses, climbing fiber (CF) coactivation provides an instructive signal that promotes long-term depression (LTD) by amplifying spine calcium transients above a threshold level that, at these synapses, is higher than for LTP induction. Here, we show that the CF instructive signal maintains its control over PF plasticity regardless of the PF synaptic activation frequency, which, on its own, alters spine calcium signaling. We demonstrate that high-frequency stimulation reduces the calcium sensitivity of LTD, resulting from inhibitory calcium/calmodulin-dependent kinase II autophosphorylation at Thr305/306. We propose that this regulatory mechanism causes a horizontal shift of the long-term potentiation/LTD cross-over point, making plasticity independent from absolute calcium amplitudes.
Evolutionary switches between two serine codon sets are driven by selection
Authors: Rogozin Igor B. , Belinky Frida , Pavlenko Vladimir , Shabalina Svetlana A. , Kristensen David M. , Koonin Eugene V. 
Published: November 2016

Significance
When a rare evolutionary event is observed, such as substitution of two adjacent nucleotides, the question emerges whether such rare changes are caused by mutational bias or by selection. Here we address this question through genome-wide analysis of double substitutions that lead to switch of the codon sets for the amino acid serine, the only one that is encoded by two disjoint sets of codons. We show that selection is the primary factor behind these changes. These findings suggest that short-term evolution of proteins is subject to stronger purifying selection than previously thought and has significant implications for methods of phylogenetic analysis.
Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop
Authors: Wang Haoqing , Cohen Alexander A. , Galimidi Rachel P. , Gristick Harry B. , Jensen Grant J. , Bjorkman Pamela J. 
Published: November 2016

Significance
The HIV-1 envelope (Env) glycoprotein exists in multiple conformations on virion surfaces. Although the closed Env state is well characterized, less is known about open Env conformations stabilized by host receptor (CD4) binding. We solved an 8.9-Å structure of a partially open CD4-bound Env trimer by single particle cryo-EM. In the CD4-bound Env, the gp120 V1V2 loops were displaced by ∼40 Å from their positions at the trimer apex. The displaced V1V2 loops were at the sides of the open trimer in positions adjacent to, and interacting with, the three bound CD4s. These results are relevant to understanding CD4-induced conformational changes leading to coreceptor binding and fusion, and HIV-1 Env conformational dynamics, and describe a target structure relevant to drug design and vaccine efforts.
VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection
Authors: Räsänen Markus , Degerman Joni , Nissinen Tuuli A. , Miinalainen Ilkka , Kerkelä Risto , Siltanen Antti , Backman Janne T. , Mervaala Eero , Hulmi Juha J. , Kivelä Riikka , Alitalo Kari 
Published: November 2016

Significance
The cardiotoxicity of anthracyclines is a major problem in cancer chemotherapy, and its alleviation would improve the life expectancy of cancer patients. This study shows that vascular endothelial growth factor-B (VEGF-B) gene therapy can be used to prevent the cardiotoxicity of doxorubicin (DOX). VEGF-B inhibited DOX-induced cardiac atrophy, protected endothelial cells from apoptosis, and preserved the myocardial capillary network. Importantly, DOX-induced whole body wasting (cachexia), which both impairs the quality of life and increases drug toxicity in patients as well as decreases their survival, was inhibited by VEGF-B treatment in the DOX-treated mice. Additional preclinical studies are needed for development of the VEGF-B gene therapy for cardiac protection in patients.
Phonological awareness in reading acquisition
Authors: Özata Hatice , Babür Nalan , Haznedar Belma 
Published: November 2016

Abstract
This study investigates phonological awareness skills of Turkish-English successive bilingual children in order to determine the predictors of success in word reading in English and Turkish. Fifty Turkish-English successive bilingual and sixteen monolingual English-speaking children participated in the study. The data were collected through multiple instruments, examining phonological awareness (PA) and word recognition in both languages. The results indicated that phonological awareness was a strong predictor of word level reading success in both Turkish and English. These data also revealed that PA followed a developmental pattern from syllables to phonemes. Additionally, both qualitative and quantitative analyses demonstrated that Turkish PA exerted an impact on English word recognition in bilingual children, suggesting cross-language transfer of PA between the two languages.
Second language exposure in the preschool
Authors: Aktan-Erciyes Aslı , Aksu-Koç Ayhan 
Published: November 2016

Abstract
An emerging situation in Turkey involves the acquisition of a second language (L2; English) in a context where the first language (L1; Turkish) is the majority language by children from advantaged social backgrounds. The present study explores the consequences of exposure to L2 in preschool on L1 and on executive functioning. One-hundred-four preschool children, attending Turkish-instruction preschools with one hour of English per day and English-instruction preschools with full-time English were assessed for their L1 and L2 competence and for executive functioning. An SEM model showed no difference in L1 competence between the two groups. Contrary to expectations, L2 competence did not have an effect on executive functioning in L2 preschools whereas an effect was observed in L1 preschools with fewer hours of exposure.
Natural History of Cryptosporidiosis in a Birth Cohort in Southern India
Authors: Kattula Deepthi , Jeyavelu Nithya , Prabhakaran Ashok D , Premkumar Prasanna S , Velusamy Vasanthakumar , Venugopal Srinivasan , Geetha Jayanthi C , Lazarus Robin P , Das Princey , Nithyanandhan Karthick , Gunasekaran Chandrabose , Muliyil Jayaprakash , Sarkar Rajiv , Wanke Christine , Ajjampur Sitara Swarna Rao , Babji Sudhir , Naumova Elena N , Ward Honorine D , Kang Gagandeep 
Published: November 2016

Abstract

Background
Cryptosporidium is a leading cause of moderate to severe childhood diarrhea in resource-poor settings. Understanding the natural history of cryptosporidiosis and the correlates of protection are essential to develop effective and sustainable approaches to disease control and prevention.

Methods
Children (N = 497) were recruited at birth in semiurban slums in Vellore, India, and followed for 3 years with twice-weekly home visits. Stool samples were collected every 2 weeks and during diarrheal episodes were tested for Cryptosporidium species by polymerase chain reaction (PCR). Serum samples obtained every 6 months were evaluated for seroconversion, defined as a 4-fold increase in immunoglobulin G directed against Cryptosporidium gp15 and/or Cp23 antigens between consecutive sera.

Results
Of 410 children completing follow-up, 397 (97%) acquired cryptosporidiosis by 3 years of age. PCR identified 1053 episodes of cryptosporidiosis, with an overall incidence of 0.86 infections per child-year by stool and serology. The median age for the first infection was 9 (interquartile range, 4–17) months, indicating early exposure. Although infections were mainly asymptomatic (693 [66%]), Cryptosporidium was identified in 9.4% of diarrheal episodes. The proportion of reinfected children was high (81%) and there was clustering of asymptomatic and symptomatic infections (P &lt; .0001 for both). Protection against infection increased with the order of infection but was only 69% after 4 infections. Cryptosporidium hominis (73.3%) was the predominant Cryptosporidium species, and there was no species-specific protection.

Conclusions
There is a high burden of endemic cryptosporidiosis in southern India. Clustering of infection is suggestive of host susceptibility. Multiple reinfections conferred some protection against subsequent infection.
Automatic health record review to help prioritize gravely ill Social Security disability applicants
Authors: Abbott Kenneth , Ho Yen-Yi , Erickson Jennifer 
Published: November 2016

AbstractObjective: Every year, thousands of patients die waiting for disability benefits from the Social Security Administration. Some qualify for expedited service under the Compassionate Allowance (CAL) initiative, but CAL software focuses exclusively on information from a single form field. This paper describes the development of a supplemental process for identifying some overlooked but gravely ill applicants, through automatic annotation of health records accompanying new claims. We explore improved prioritization instead of fully autonomous claims approval.Materials and Methods: We developed a sample of claims containing medical records at the moment of arrival in a single office. A series of tools annotated both patient records and public Web page descriptions of CAL medical conditions. We trained random forests to identify CAL patients and validated each model with 10-fold cross validation.Results: Our main model, a general CAL classifier, had an area under the receiver operating characteristic curve of 0.915. Combining this classifier with existing software improved sensitivity from 0.960 to 0.994, detecting every deceased patient, but reducing positive predictive value to 0.216.Discussion: True positive CAL identification is a priority, given CAL patient mortality. Mere prioritization of the false positives would not create a meaningful burden in terms of manual review. Death certificate data suggest the presence of truly ill patients among putative false positives.Conclusion: To a limited extent, it is possible to identify gravely ill Social Security disability applicants by analyzing annotations of unstructured electronic health records, and the level of identification is sufficient to be useful in prioritizing case reviews.
Benign Glandular Schwannoma With Ancient Change
Authors: Holliday Alex C. , Mazloom Sean E. , Coman Garrett C. , Kolodney Michael S. , Chavan Rahul N. , Grider Douglas J. 
Published: November 2016

Abstract:
Benign glandular schwannomas are rare and should be distinguished from malignant peripheral nerve sheath tumors with similar divergent tissue differentiation. The authors present a benign glandular schwannoma with ancient change that developed in the subcutis of a 46-year-old man's posterior calf. He lacked stigmata of neurofibromatosis type 1 (NF1). The glandular elements stained positively for epithelial membrane antigen and pancytokeratin. The spindled cells stained positively for SOX10 and S100 protein, supporting schwannian (neural crest) differentiation. The tumor's location and histopathology suggest that the pathogenesis stems from entrapment of sweat glands. Finally, it must be recognized that ancient change may mimic malignancy in these neoplasms as the malignant counterparts have a greater association with NF1 and a poorer prognosis.
Developmental Behavioral Pediatrician Support of the Medical Home for Children with Autism Spectrum Disorders
Authors: Nolan Robyn , Walker Tarik , Hanson Janice L. , Friedman Sandra 
Published: November 2016

ABSTRACT:

Objective:
To identify challenges primary care providers (PCPs) experience providing a Medical Home for children with autism spectrum disorders (ASDs) and to describe the role developmental behavioral pediatricians (DBPs) play in the Medical Home Neighborhood.

Methods:
The authors used purposeful sampling to recruit 25 PCPs from around Colorado to participate in 4 focus groups. Member checking was performed at the end of each group. Sampling continued until themes repeated and saturation was achieved. Focus groups were transcribed verbatim, and transcripts were analyzed using content analysis; an outside reviewer audited the data.

Results:
Qualitative analysis yielded 30 codes that fell into 7 themes: provider education, shared model of care, initial diagnostic evaluation by the DBP, communication, office factors, cost and coverage, and access. PCPs identified knowledge gaps that led to decreased comfort and desired ongoing education and a centralized resource for providers. They envisioned a shared care model with ongoing specialist collaboration and improved communication within the care team. A specific role desired of the DBP was to provide the initial diagnostic evaluation and treatment plan with specific resources. Office factors, high cost and variable coverage, and poor access to services were barriers to providing a Medical Home for children with ASD.

Conclusion:
Working to remove barriers to shared care as well as providing continued educational opportunities will help improve access to a Medical Home Neighborhood for children with ASD. Advocacy is needed to help remove barriers related to cost, coverage, and access to services.
Development of a Simple and Rapid Method to Measure the Free Fraction of Tacrolimus in Plasma Using Ultrafiltration and LC-MS/MS
Authors: Stienstra Nicolaas A. , Sikma Maaike A. , van Dapperen Anouk L. , de Lange Dylan W. , van Maarseveen Erik M. 
Published: November 2016

Background:
Tacrolimus is an immunosuppressant mainly used in the prophylaxis of solid organ transplant rejection. Therapeutic drug monitoring of tacrolimus is essential for avoiding toxicity related to overexposure and transplant rejection from underexposure. Previous studies suggest that unbound tacrolimus concentrations in the plasma may serve as a better predictor of tacrolimus-associated nephrotoxicity and neurotoxicity compared to tacrolimus concentration in whole blood. Monitoring the plasma concentrations of unbound tacrolimus might be of interest in preventing tacrolimus-related toxicity. Therefore, the aim was to develop a method for the measurement of total and unbound tacrolimus concentrations in plasma.

Methods:
The sample preparation for the determination of the plasma concentrations of unbound tacrolimus consisted of an easy-to-use ultrafiltration method followed by solid-phase extraction. To determine the total concentration of tacrolimus in plasma, a simple method based on protein precipitation was developed. The extracts were injected into a Thermo Scientific HyPurity C18 column using gradient elution. The analytes were detected by liquid chromatography-tandem mass spectrometry with positive ionization.

Results:
The method was validated over a linear range of 1.00–200 ng/L for unbound tacrolimus concentrations in plasma and 100–3200 ng/L for total plasma concentrations. The lower limit of quantification was 1.00 ng/L in ultrafiltrate and 100 ng/L in plasma. The inaccuracy and imprecision for the determination of unbound tacrolimus concentrations in ultrafiltrate and plasma showed a maximum coefficients of variation (CV) of 11.7% and a maximum bias of 3.8%.

Conclusions:
A rapid and easy method based on ultrafiltration and liquid chromatography-tandem mass spectrometry was established to measure the total and unbound tacrolimus concentrations in plasma. This method can facilitate further investigations on the relationship between plasma concentrations of unbound tacrolimus and clinical outcomes in transplant recipients.
Vertical sleeve gastrectomy improves indices of metabolic disease in rodent model of surgical menopause
Authors: Lawson William J. , Shirey Kristin , Spann Redin A. , Zamarripa Carlos A. , Hosler Jonathan P. , Grayson Bernadette E. 
Published: November 2016

Abstract

Objective:
Although women are the most common recipients of weight loss surgeries for the amelioration of the comorbidities of obesity, few studies have addressed the efficacy of these procedures with specific attention to reproductive stage. Here we ask in a rodent model of vertical sleeve gastrectomy (VSG) whether improvements to metabolic health are realized in women having received surgical menopause. Specifically we were interested in knowing whether rats made menopausal through surgical means would exhibit persistent hepatic steatosis as reported in previously pregnant, freely cycling female VSG rats or if it is resolved as reported in male VSG rats.

Methods:
All the rats first received ovariectomy (OVX) and then were placed on high-fat diet before either sham or VSG surgery (N = 12, 9) and then were monitored for resolution of obesity-related comorbidities.

Results:
VSG was sufficient to reduce weight and adiposity in OVX females in comparison to obese rats (P < 0.001). Glucose tolerance (P < 0.05) was improved in OVX-VSG females with no change in insulin sensitivity. Both circulating (P < 0.01) and hepatic triglyceride (P < 0.01) levels were also reduced after VSG. Liver integrity was improved in OVX-VSG in comparison to OVX-obese as reflected by reduced aspartate aminotransferase levels (P < 0.05). The ability of mitochondria to generate adenosine triphosphate was maintained, and an increase in complex IV may decrease the production of mitochondrial reactive oxygen species.

Conclusions:
Taken together, VSG in OVX rats experience many positive benefits including the resolution of hepatic steatosis that persists in reproductively intact female rats after VSG.