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Abstract Women with pulmonary arterial hypertension (PAH) experience multiple symptoms, including dyspnea, fatigue, and sleep disturbance, that impair their health‐related quality of life (HRQOL). However, we know little about phenotypic subgroups of patients with PAH with similar, concurrent, multiple symptoms. The objectives of this study were to define the “symptome” by symptom cluster phenotypes and compare characteristics such as biomarkers, cardiac structure and function (echocardiography), functional capacity (6‐min walk distance), and HRQOL between the groups. This cross‐sectional study included 60 women with PAH. Subjects completed an assessment battery: Pulmonary Arterial Hypertension Symptom Scale, Pittsburgh Sleep Quality Index, Multidimensional Dyspnea Profile, Patient‐Reported Outcomes Measurement Information System (PROMIS®) Physical Function, PROMIS® Sleep‐Related Impairment, and the emPHasis‐10. Subjects also underwent transthoracic echocardiography, phlebotomy, 6‐min walk distance, and actigraphy. The three symptoms of dyspnea, fatigue, and sleep disturbance were used to define the symptom clusters. Other PAH symptoms, plasma and serum biomarkers, cardiac structure and function (echocardiography), exercise capacity (6‐min walk distance), sleep (actigraphy), and HRQOL were compared across phenotypes. The mean age was 50 ± 18 years, 51% were non‐Hispanic white, 32% were non‐Hispanic Black and 40% had idiopathic PAH. Cluster analysis identified Mild (n = 28, 47%), Moderate (n = 20, 33%), and Severe Symptom Cluster Phenotypes (n = 12, 20%). There were no differences for age, race, or PAH etiology between the phenotypes. WHO functional class (p more...

Arid climates have unpredictable precipitation patterns, and wildlife managers often provide supplemental water to help desert ungulates endure the hottest, driest periods. When surface water is unavailable, the only source of water for ungulates comes from the forage they consume, and they must make resourceful foraging decisions to meet their requirements. We compared two desert bighorn sheep (Ovis canadensis nelsoni) populations in Arizona, USA: a treatment population with supplemental water removed during treatment, and a control population. We examined whether sheep altered their seasonal diets without supplemental water. We calculated water and nutrient intake and metabolic water production from dry matter intake and forage moisture and nitrogen content, to determine whether sheep could meet their seasonal daily water and nutrient requirements solely from forage. Diets of sheep were higher in protein (all seasons) and moisture (autumn and winter) during treatment compared to pretreatment. During treatment, sheep diet composition was similar between the treatment and control populations, which suggests, under the climatic conditions of this study, water removal did not influence sheep diets. We estimated that under drought conditions, without any surface water available (although small ephemeral potholes would contain water after rains), female and male sheep would be unable to meet their daily water requirements in all seasons, except winter, when reproductive females had a nitrogen deficit. We determined that sheep could achieve water and nutrient balances in all seasons by shifting their total diet proportions by 8-55% from lower to higher moisture and nitrogen forage species. We elucidate how seasonal forage quality and foraging decisions by desert ungulates allow them to cope with their xeric and uncertain environment, and suggest that, with the forage conditions observed in our study area during this study period, providing supplemental water during water-stressed periods may not be necessary for desert bighorn sheep. more...

Researchers at the U.S. Department of Veterans Affairs (VA) have used administrative criteria to identify homelessness among U.S. Veterans. Our objective was to explore the use of these codes in VA health care facilities. We examined VA health records (2002-2012) of Veterans recently separated from the military and identified as homeless using VA conventional identification criteria (ICD-9-CM code V60.0, VA specific codes for homeless services), plus closely allied V60 codes indicating housing instability. Logistic regression analyses examined differences between Veterans who received these codes. Health care services and co-morbidities were analyzed in the 90 days post-identification of homelessness. VA conventional criteria identified 21,021 homeless Veterans from Operations Enduring Freedom, Iraqi Freedom, and New Dawn (rate 2.5%). Adding allied V60 codes increased that to 31,260 (rate 3.3%). While certain demographic differences were noted, Veterans identified as homeless using conventional or allied codes were similar with regards to utilization of homeless, mental health, and substance abuse services, as well as co-morbidities. Differences were noted in the pattern of usage of homelessness-related diagnostic codes in VA facilities nation-wide. Creating an official VA case definition for homelessness, which would include additional ICD-9-CM and other administrative codes for VA homeless services, would likely allow improved identification of homeless and at-risk Veterans. This also presents an opportunity for encouraging uniformity in applying these codes in VA facilities nationwide as well as in other large health care organizations. more...

Abstract Background There are many fewer genes in the human genome than there are expressed transcripts. Alternative splicing is the reason. Alternatively spliced transcripts are often specific to tissue type, developmental stage, environmental condition, or disease state. Accurate analysis of microarray expression data and design of new arrays for alternative splicing require assessment of probes at the sequence and exon levels. Description SpliceMiner is a web interface for querying Evidence Viewer Database (EVDB). EVDB is a comprehensive, non-redundant compendium of splice variant data for human genes. We constructed EVDB as a queryable implementation of the NCBI Evidence Viewer (EV). EVDB is based on data obtained from NCBI Entrez Gene and EV. The automated EVDB build process uses only complete coding sequences, which may or may not include partial or complete 5' and 3' UTRs, and filters redundant splice variants. Unlike EV, which supports only one-at-a-time queries, SpliceMiner supports high-throughput batch queries and provides results in an easily parsable format. SpliceMiner maps probes to splice variants, effectively delineating the variants identified by a probe. Conclusion EVDB can be queried by gene symbol, genomic coordinates, or probe sequence via a user-friendly web-based tool we call SpliceMiner (http://discover.nci.nih.gov/spliceminer). The EVDB/SpliceMiner combination provides an interface with human splice variant information and, going beyond the very valuable NCBI Evidence Viewer, supports fluent, high-throughput analysis. Integration of EVDB information into microarray analysis and design pipelines has the potential to improve the analysis and bioinformatic interpretation of gene expression data, for both batch and interactive processing. For example, whenever a gene expression value is recognized as important or appears anomalous in a microarray experiment, the interactive mode of SpliceMiner can be used quickly and easily to check for possible splice variant issues. more...

Abstract Background As a result of high-throughput genotyping methods, millions of human genetic variants have been reported in recent years. To efficiently identify those with significant biological functions, a practical strategy is to concentrate on variants located in important sequence regions such as gene regulatory regions. Results Analysis of the most common type of variant, single nucleotide polymorphisms (SNPs), shows that in gene promoter regions more SNPs occur in close proximity to transcriptional start sites than in regions further upstream, and a disproportionate number of those SNPs represent nucleotide transversions. Additionally, the number of SNPs found in the predicted transcription factor binding sites is higher than in non-binding site sequences. Conclusion Current information about transcription factor binding site sequence patterns may not be exhaustive, and SNPs may be actively involved in influencing gene expression by affecting the transcription factor binding sites. more...

The purpose of this study was to assess the basic psychometric properties of a progress-monitoring tool designed to measure narrative discourse skills in school-age children with language impairments (LI). A sample of 109 children with LI between the ages of 5 years 7 months and 9 years 9 months completed the "Test of Narrative Language" (TNL). The stories told in response to the alien picture prompt were transcribed and scored according to the TNL manual criteria and the criteria established for scoring the progress-monitoring tool, Monitoring Indicators of Scholarly Language (MISL). The MISL total score demonstrated acceptable levels of internal consistency reliability, inter-rater reliability, and construct validity for use as a progress-monitoring tool for specific aspects of narrative proficiency. The MISL holds promise as a tool for tracking growth in narrative language proficiency that may be taught as part of an intervention program to support the Common Core Standards related to literacy. more...

After overexpression in a suitable host, recombinant protein purification often relies on affinity (e.g., poly‐histidine) and solubility‐enhancing (e.g., small ubiquitin‐like‐modifier [SUMO]) tags. Following purification, these tags are removed to avoid their interference with target protein structure and function. The wide use of N‐terminal His6‐SUMO fusions is partly due to efficient cleavage of the SUMO tag's C‐terminal Gly‐Gly motif by the Ulp1 SUMO protease and generation of the native N‐terminus of the target protein. While adopting this system to purify the Salmonella homodimeric FraB deglycase, we discovered that Shine–Dalgarno (SD) sequences in the eukaryotic SUMO tag resulted in truncated proteins. This finding has precedents for synthesis of partial proteins in Escherichia coli from cryptic ribosome‐binding sites within eukaryotic coding sequences. The SUMO open reading frame has two "GGNGGN" motifs that resemble SD sequences, one of which encodes the Gly‐Gly motif required for Ulp1 cleavage. By mutating these SD sequences, we generated SUMONIT (no internal translation), a variant that eliminated production of the truncated proteins without affecting the levels of full‐length His6‐SUMO‐FraB or Ulp1 cleavage. SUMONIT should be part of the toolkit for enhancing SUMO fusion protein yield, purity, and homogeneity (especially for homo‐oligomers). Moreover, we showcase the value of native mass spectrometry in revealing the complications that arise from generation of truncated proteins, as well as oxidation events and protease inhibitor adducts, which are indiscernible by commonly employed lower resolution methods. [ABSTRACT FROM AUTHOR] more...

Purpose: The storage-only deficit and joint mechanism deficit hypotheses are 2 possible explanations of the verbal working memory (vWM) storage capacity limitation of school-age children with developmental language disorder (DLD). We assessed the merits of each hypothesis in a large group of children with DLD and a group of same-age typically developing (TD) children. Method: Participants were 117 children with DLD and 117 propensity-matched TD children 7--11 years of age. Children completed tasks indexing vWM capacity, verbal short-term storage, sustained attention, attention switching, and lexical long-term memory (LTM). Results: For the DLD group, all of the mechanisms jointly explained 26.5% of total variance. Storage accounted for the greatest portion (13.7%), followed by controlled attention (primarily sustained attention; 6.5%) and then lexical LTM (5.6%). For the TD group, all 3 mechanisms together explained 43.9% of total variance. Storage accounted for the most variance (19.6%), followed by lexical LTM (16.0%), sustained attention (5.4%), and attention switching (3.0%). There was a significant LTM × Group interaction, in which stronger LTM scores were associated with significantly higher vWM capacity scores for the TD group as compared to the DLD group. Conclusions: Results support a joint mechanism deficit account of the vWM capacity limitation of children with DLD. Results provide substantively new insights into the underlying factors of the vWM capacity limitation in DLD. more...

Protein footprinting is a useful method for studying protein higher order structure and conformational changes induced by interactions with various ligands via addition of covalent modifications onto the protein. Compared to other methods that provide single amino acid-level structural resolution, such as cryo-EM, X-ray diffraction, and NMR, mass spectrometry (MS)-based methods can be advantageous as they require lower protein amounts and purity. As with other MS-based proteomic methods, such as post-translational modification analysis, enrichment techniques have proven necessary for both optimal sensitivity and sequence coverage when analyzing highly complex proteomes. Currently used reagents for footprinting via covalent labeling, such as hydroxyl radicals and carbodiimide-based methods, do not yet have a suitable enrichment method, limiting their applicability to whole proteome analysis. Here, we report a method for enrichable covalent labeling built upon the GEE/EDC system commonly used to covalently label aspartic acid and glutamic acid residues. Novel labeling reagents containing alkynyl functionality can be "clicked" to any azido-containing molecule with copper-catalyzed azide–alkyne cycloaddition (CuAAC), allowing for enrichment or further labeling. Multiple azide- and alkyne-containing GEE-like molecules were tested, and the most efficient method was determined to be the EDC-facilitated coupling of glycine propargyl amide (GPA) to proteins. The pipeline we report includes clicking via CuAAC to a commercially available biotin-azide containing a photocleavable linker, followed by enrichment using a streptavidin resin and subsequent cleavage under ultraviolet light. The enrichment process was optimized through the screening of clickable amines, coupling reagents, and enrichment scaffolds and methods with pure model proteins and has also been applied to complex mixtures of proteins isolated from the model plant, Arabidopsis thaliana, suggesting that our method may ultimately be used to measure protein conformation on a proteomic scale. [ABSTRACT FROM AUTHOR] more...

Purpose: We assessed the potential direct and indirect (mediated) influences of 4 cognitive mechanisms we believe are theoretically relevant to canonical and noncanonical sentence comprehension of school-age children with and without developmental language disorder (DLD). Method: One hundred seventeen children with DLD and 117 propensity-matched typically developing (TD) children participated. Comprehension was indexed by children identifying the agent in implausible sentences. Children completed cognitive tasks indexing the latent predictors of fluid reasoning (FLD-R), controlled attention (CATT), complex working memory (cWM), and long-term memory language knowledge (LTM-LK). Results: Structural equation modeling revealed that the best model fit was an indirect model in which cWM mediated the relationship among FLD-R, CATT, LTM-LK, and sentence comprehension. For TD children, comprehension of both sentence types was indirectly influenced by FLD-R (pattern recognition) and LTM-LK (linguistic chunking). For children with DLD, canonical sentence comprehension was indirectly influenced by LTM-LK and CATT, and noncanonical comprehension was indirectly influenced just by CATT. Conclusions: cWM mediates sentence comprehension in children with DLD and TD children. For TD children, comprehension occurs automatically through pattern recognition and linguistic chunking. For children with DLD, comprehension is cognitively effortful. Whereas canonical comprehension occurs through chunking, noncanonical comprehension develops on a word-by-word basis. more...

This paper reports the findings of a study of the impact of the transformative professional development (TPD) model on student achievement on state-mandated assessments of science in elementary school. Two schools (one intervention and one control) participated in the case study where teachers from one school received the TPD intervention across a 2-year period while teachers at the other school received no program and continued business as usual. The TPD program includes a focus on the core conceptual framework for effective professional development (Desimone in "Educ Res" 38:181-199, 2009) as well as an emphasis on culturally relevant pedagogy (CRP) and other effective science instructional strategies. Findings revealed that participation in TPD had a significant impact on student achievement for Burns Elementary with the percentage of proficient students growing from 25% at baseline to 67% at the end of the 2-year program, while the comparison school did not experience similar growth. Implications for future research and implementation of professional development programs to meet the needs of teachers in the realm of CRP in science are discussed. more...