Temple syndrome as a differential diagnosis to Prader–Willi syndrome: Identifying three new patients

The two imprinting syndromes Temple syndrome (TS14) and Prader–Willi syndrome (PWS) share many features in infancy and childhood. TS14 is an important, yet often neglected, differential diagnosis to PWS. We wanted to assess the frequency of TS14 among patients tested for PWS. In all samples submitted to our lab for genetic PWS testing during 2014 and 2015, we consecutively conducted additional analyses for TS14. A total of 143 samples were included. The most frequent indications for testing were developmental delay, overweight, and hypotonia. For TS14 testing, we performed a methylation-sensitive MLPA-kit detecting deletions and methylation aberrations in chromosomal region 14q32. TS14 was confirmed in 3 out of 143 patients (2.1%). In comparison, PWS was also confirmed in three patients. Brief clinical descriptions of the TS14 patients are presented. Temple syndrome is presumably underdiagnosed, and should be considered when testing children for PWS.

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Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay

Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.

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Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly

Intellectual disability (ID) refers to deficits in mental abilities, social behavior, and motor skills to perform activities of daily living as compared to peers. Numerous genetic and environmental factors may be responsible for ID. We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene. The variant is present in conserved region of ARM domain of ARMC9 protein, which is predicted to form a platform for protein interaction. This domain is likely to be altered in patient due to splicing defect caused by this synonymous variation. Our report of variant in ARMC9 Leading to Joubert syndrome phenotype (JS30), elucidates the genetic heterogeneity of Joubert syndrome, and expands the gene list for ciliopathies.

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Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients

The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies.

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MED13L loss-of-function variants in two patients with syndromic Pierre Robin sequence

We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism. Our findings suggest that MED13L–related disorders are a possible differential diagnosis for syndromic PRS.

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FGFR1 disruption identified by whole genome sequencing in a male with a complex chromosomal rearrangement and hypogonadotropic hypogonadism

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Discordant fetal phenotype of hypophosphatasia in two siblings

Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks' gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.

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Less common underlying genetic diagnoses found in a cohort of 139 individuals surgically corrected for craniosynostosis

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Response to: “In reply to: ‘Mast Cell Disorders in Ehlers–Danlos Syndrome’ (Jaime Vengoechea, Department of Human Genetics, Emory University)”

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Parental education accounts for variability in the IQs of probands with Down syndrome: A longitudinal study

Recent work has demonstrated that variability in probands' phenotypes, including physical features, cognitive abilities, social functioning, and other developmental domains, is influenced by parental traits. Here we examine the role of parental education as a factor contributing to the variability of intelligence quotient (IQ) of offspring with trisomy 21. Participants were 43 probands with trisomy 21, aged 4–21 years of age, and their parents. Data were collected on parental education, and a bi-parental mean education score (BMES) was calculated. Probands' cognitive abilities were assessed by the Stanford-Binet 4th edition at baseline (T1), and again 24 months later (T2). Probands were placed into one of two age groups: 4–12 years and 13–21 years. Results indicated higher parent-proband correlations in Age Group 2 (mean r = .47) relative to Age Group 1 (mean r = .33) and increasing parent-proband correlations across time, with mean correlations of Age Group 1, T1: r = .26, T2: 39; Age Group 2 T1: r = .49, T2: r = 46. Despite the expected IQ deficits observed in trisomy 21 probands, parental education may still contribute to the variability of probands' cognitive abilities. These findings are consistent with the literature noting increasing heritability of IQ with development.

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Tarsal-carpal coalition syndrome: Report of a novel missense mutation in NOG gene and phenotypic delineation

We report a family of Indian origin presenting with Tarsal-carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide. This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum.

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Orthopaedic manifestations within the 22q11.2 Deletion syndrome: A systematic review

The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome with an estimated prevalence of 1:4,000 live births. 22q11.2DS is known to have wide phenotypic variability, including orthopaedic manifestations. The purpose of this systematic review is to increase the awareness of orthopaedic manifestations associated with 22q11.2DS. This systematic review was performed according to the PRISMA Guidelines. Original epidemiological studies on the prevalence of orthopaedic manifestations within 22q11.2DS were systematically searched for in PubMed and EMBASE. The included articles were scored according to a risk-of-bias tool, a best-evidence synthesis was performed and the prevalence data was extracted. Sixty-nine published manuscripts described 58 orthopaedic manifestations in a total of 6,055 patients. The prevalence of at least one cervical or occipital anomaly is 90.5–100% (strong evidence). Fourteen studies (n = 2,264) revealed moderate evidence for a wide scoliosis prevalence of 0.6–60%. Two studies demonstrated that 5–6.4% of all 22q11.2DS patients required surgical scoliosis correction. Fifteen studies (n = 2,115) reported a 1.1–13.3% prevalence of clubfoot with moderate evidence. Other reported orthopaedic manifestations are patellar dislocation (10–20%), juvenile rheumatic arthritis (3.75%), impaired growth and skeletal anomalies like polydactyly (1.0–3.7%), syndactyly (11–11.8%), butterfly vertebrae (11.1%) and 13 ribs (2–19%). Orthopaedic findings are important manifestations of the 22q11.2DS, both in bringing patients to diagnostic attention and in requiring surveillance and appropriate intervention. Data on these manifestations are scattered and incomprehensive. Routinely screening for cervical anomalies, scoliosis, and upper and lower limb malformations is recommended in this vulnerable group of patients.

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Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16–18, 2017, Dallas, Texas

Scoliosis represents the most common musculoskeletal disorder in children and affects approximately 3% of the world population. Scoliosis is separated into two major phenotypic classifications: congenital and idiopathic. Idiopathic scoliosis is defined as a curvature of the spine of 10° or greater visualized on plane radiograph and does not have associated vertebral malformations (VM). "Congenital" scoliosis (CS) due to malformations in vertebrae is frequently associated with other birth defects. Recently, significant advances have been made in understanding the genetic basis of both conditions. There is evidence that both conditions are etiologically related. A 2-day conference entitled "Genomic Approaches to Understanding and Treating Scoliosis" was held at Scottish Rite Hospital for Children in Dallas, Texas, to synergize research in this field. This first combined, multidisciplinary conference featured international scoliosis researchers in basic and clinical sciences. A major outcome of the conference advancing scoliosis research was the proposal and subsequent vote in favor of merging the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) and International Consortium for Scoliosis Genetics (ICSG) into a single entity called International Consortium for Spinal Genetics, Development, and Disease (ICSGDD). The ICSGDD is proposed to meet annually as a forum to synergize multidisciplinary spine deformity research.

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Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities

The diagnosis of intellectual disability/developmental delay (ID/DD) benefits from the clinical application of target/exome sequencing. The yield in Mendelian diseases varies from 25% to 68%. The aim of the present study was to identify the genetic causes of 33 ID/DD patients using target/exome sequencing. Recent studies have demonstrated that reanalyzing undiagnosed exomes could yield additional diagnosis. Therefore, in addition to the normal data analysis, in this study, re-evaluation was performed prior to manuscript preparation after updating OMIM annotations, calling copy number variations (CNVs) and reviewing the current literature. Molecular diagnosis was obtained for 19/33 patients in the first round of analysis. Notably, five patients were diagnosed during the re-evaluation of the geno/phenotypic data. This study confirmed the utility of exome sequencing in the diagnosis of ID/DD. Furthermore, re-evaluation leads to a 15% improvement in diagnostic yield. Thus, to maximize the diagnostic yield of next-generation sequencing (NGS), periodical re-evaluation of the geno/phenotypic data of undiagnosed individuals is recommended by updating the OMIM annotation, applying new algorithms, reviewing the literature, sharing pheno/genotypic data, and re-contacting patients.

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Maternal inheritance of BDNF deletion, with phenotype of obesity and developmental delay in mother and child

Childhood obesity is a significant world health problem. Understanding the genetic and environmental factors contributing to the development of obesity in childhood is important for the rational design of strategies for obesity prevention and treatment. Brain-derived neurotrophic factor (BDNF) plays an important role in the growth and development of the central nervous system, there is also an evidence that BDNF plays a role in regulation of appetite. Disruption of the expression of this gene in a child has been previously reported to result in a phenotype of severe obesity, hyperphagia, impaired cognitive function, and hyperactivity. We report a mother and child, both with micro-deletions encompassing the BDNF gene locus, who both have obesity and developmental delay, although without hyperactivity. This report highlights the maternal inheritance of a rare genetic cause of childhood obesity.

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Assessment of sedation level prior to neonatal intubation: A systematic review

Summary

Background

Adequate premedication before neonatal endotracheal intubation reduces pain, stress, and adverse physiological responses, diminishes duration and number of attempts at intubation, and prevents traumatic airway injury. Therefore, intubation should not be started until an adequate level of sedation is reached. It is not clear how this should be measured in the clinical situation.

Objectives

The aim of this study is to provide a systematic review of the usability and validity of scoring systems or other objective parameters to evaluate the level of sedation before intubation in neonates. Secondary aims were to describe parameters that are used to determine the level of sedation and criteria on which the decision to proceed with intubation is based.

Methods

Literature was searched (January 2017) in the following electronic databases: Embase, Medline, Web of Science, Cochrane Central Registrar of Controlled Trials, Pubmed Publisher, and Google Scholar.

Results

From 1653 hits, 20 studies were finally included in the systematic review. In 7 studies, intubation was started after a predefined time period; in 1 study, preoxygenation was the criterion to start with intubation; and in 12 studies, intubation was started in case of adequate sedation and/or relaxation. Only 4 studies described the use of 3 different objective scoring system, all in the neonatal intensive care unit, which are not validated.

Conclusion

No validated scoring systems to assess the level of sedation prior to intubation in newborns are available in the literature. Three objective sedation assessment tools seem promising but need further validation before they can be implemented in research and clinical settings.

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Incidence and predictors of 30-day postoperative readmission in children

Summary

Background

Hospital readmissions are being used as a quality metric for hospital reimbursement without a clear understanding of the factors that contribute to readmission.

Objective

The objective of this study was to report the incidence of 30-day postsurgical readmission in children, identify the predictors for readmission, and create an algorithm to identify high-risk children.

Methods

Data from the 2012-2014 Pediatric database of the American College of Surgeons National Surgical Quality Improvement Program were analyzed using univariable and multivariable logistical regression analysis.

Results

Among 182 589 children included in the 2012-2014 American College of Surgeons National Surgical Quality Improvement Program Pediatric database, 4.8% (8815/182 589) experienced a readmission within 30 days. Four significant predictors were retained in the multivariable logistic regression model: American Society of Anesthesiologists physical status ≥ 3 (OR: 1.9, 95% CI: 1.8-2.0), presence of congenital heart disease (OR: 1.66, 95% CI: 1.31-2.11), inpatient status at time of surgery (OR: 3.5, 95% CI: 3.3-3.7), and at least 1 postoperative complication (neurologic, renal, wound, cardiac, bleeding, or pulmonary) (OR: 3.14, 95% CI: 2.92-3.34). The multivariable logistic regression model showed reasonably good discrimination in predicting 30-day readmissions with receiver operating characteristic area under the curve of 0.747 (95% CI: 0.73-0.75) and good calibration (Brier score: 0.044). We created a predictive algorithm of 30-day readmission based on the 4 significant predictors.

Conclusion

Children with congenital heart disease, high American Society of Anesthesiologist physical class, inpatient status, and at least 1 postoperative complication of any kind are at high risk for postsurgical readmissions. We provide an algorithm for quantifying this risk with the goal of reducing the number of readmissions, improving the care of patients with complex chronic illnesses, and reducing hospital costs.

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Severe Fertility Effects of sheepish Sperm Caused by Failure To Enter Female Sperm Storage Organs in Drosophila melanogaster

In Drosophila, mature sperm are transferred from males to females during copulation, stored in the sperm storage organs of females, and then utilized for fertilization. Here, we report a gene named sheepish (shps) of D. melanogaster that is essential for sperm storage in females. shps mutant males, although producing morphologically normal and motile sperm that are effectively transferred to females, produce very few offspring. Direct counts of sperm indicated that the primary defect was correlated to failure of shps sperm to migrate into the female sperm storage organs. Increased sperm motion parameters were seen in the control after transfer to females, whereas sperm from shps males have characteristics of the motion parameters different from the control. The few sperm that occasionally entered the female sperm storage organs showed no obvious defects in fertilization and early embryo development. The female post-mating responses after copulation with shps males appeared normal at least with respect to conformational changes of uterus, mating plug formation and female remating rates. The shps gene encodes a protein with homology to amine oxidases, including as observed in mammals, with a transmembrane region at the C-terminal end. The shps mutation was characterized by a nonsense replacement in the third exon of CG13611 and shps was rescued by transformants of the wild-type copy of CG13611. Thus, shps may define a new class of gene responsible for sperm storage.

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Genes Integral to the Reproductive Function of Male Reproductive Tissues Drive Heterogeneity in Evolutionary Rates in Japanese Quail

Early comparative genomics studies originally uncovered a non-intuitive pattern - genes involved in reproduction appeared to evolve more rapidly than other classes of genes.  Currently, however, the emerging consensus is that genes encoding reproductive proteins evolve under variable selective pressures, producing more heterogeneous divergence patterns than previously appreciated.  We investigate a facet of that heterogeneity and explore the factors that drive male reproductive tissue-based heterogeneity in evolutionary rates.  In Japanese quail (Coturnix japonica), genes with enriched expression in the testis evolve much more rapidly than those enriched in the foam gland, a novel gland that secretes an airy foam males transfer to females during mating.  We compared molecular evolutionary patterns among 1) genes with induced expression in breeding versus wintering conditions for both tissues and 2) genes that encode foam proteins versus those with varying degrees of expression specificity in the foam gland.  We report two major findings.  First, genes up-regulated in breeding condition testis evolve exceptionally rapidly, while those induced in breeding condition foam glands evolve slowly.  These differences hold even after correcting for horomonally-dependent gene expression and chromosomal location.  Second, genes encoding foam proteins are extremely conserved in terms of gene identity and sequence.  Together, these finding suggest that genes involved in the reproductive function of each tissue drive the marked rate heterogeneity.

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Global Transcriptome Sequencing Reveals Molecular Profiles of Summer Diapause Induction Stage of Onion Maggot, Delia antiqua (Diptera: Anthomyiidae)

The onion maggot, Delia antiqua, is a worldwide subterranean pest and can enter diapause during summer and winter seasons. The molecular regulation of the ontogenesis transition remains largely unknown. Here we used high-throughput RNA-Seq to identify candidate genes and processes linked to summer diapause induction by comparing the transcriptome differences between the most sensitive larval developmental stage of summer-diapause (SD) and non-diapause (ND). Nine pair-wise comparisons were performed and significantly differentially regulated transcripts were identified. Several functional terms related to lipid, carbohydrate and energy metabolism, environmental adaption, immune response and aging were enriched during the most sensitive SD induction period. A subset of genes, including circadian clock genes was expressed differentially under diapause induction conditions, and there was much more variation in the most sensitive period of ND than SD-destined larvae. These expression variations probably resulted in a deep restructuring of metabolic pathways. Potential regulatory elements of summer diapause induction including genes related to lipid, carbohydrate, energy metabolism and environmental adaption. Collectively, our results suggest circadian clock is one of the key drivers for integrating environmental signals into the SD induction. Our transcriptome analysis provides insight into the fundamental role the circadian clock plays in summer diapause induction in this important model insect species, and contributes to the in-depth elucidation of the molecular regulating mechanism of insect diapause induction.

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A Single Residue Mutation in the G{alpha}q Subunit of the G Protein Complex Causes Blindness in Drosophila

Heterotrimeric G proteins play central roles in many signaling pathways, including the phototransduction cascade in animals. However, the degree of involvement of the G protein subunit Gα_q is not clear since animals with strong loss of function mutations previously reported remain responsive to light stimuli. We recovered a new allele of Gα_q in Drosophila that abolishes light response in a conventional ERG assay, and reduces sensitivity in whole-cell recordings of dissociated cells by at least 5 orders of magnitude. In addition, mutant eyes demonstrate a rapid rate of degeneration in the presence of light. Our new allele is likely the strongest hypomorph described to date. Interestingly, the mutant protein is produced in the eyes but carries a single amino acid change of a conserved hydrophobic residue that has been assigned to the interface of interaction between Gα_q and its downstream effector PLC. Our study thus uncovered possibly the first point mutation that specifically affects this interaction in vivo.

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Genome-Wide Mapping of Decay Factor-mRNA Interactions in Yeast Identifies Nutrient Responsive Transcripts as Targets of the Deadenylase Ccr4

The Ccr4-Not complex is a major regulator of stress responses that controls gene expression at multiple levels, from transcription to mRNA decay. Ccr4, a core subunit of the complex, is the main cytoplasmic deadenylase in Saccharomyces cerevisiae, however its mRNA targets have not been mapped on a genome-wide scale. Here we describe a genome-wide approach, RNA immunoprecipitation-high throughput sequencing (RIP-seq), to identify the RNAs bound to Ccr4, and two proteins that associate with it, Dhh1 and Puf5. All three proteins were preferentially bound to lowly abundant mRNAs, most often at the 3' end of the transcript. Furthermore, Ccr4, Dhh1 and Puf5 are recruited to mRNAs that are targeted by other RNA-binding proteins that promote decay, mRNA transport and inhibit translation.  Although Ccr4-Not regulates mRNA transcription and decay, Ccr4 recruitment to mRNAs correlates better with decay rates, suggesting it imparts greater control over transcript abundance through decay.  Ccr4-enriched mRNAs are refractory to control by the other deadenylase complex in yeast, Pan2/3, suggesting a division of labor between these deadenylation complexes. Finally, Ccr4 and Dhh1 associate with mRNAs whose abundance increases during nutrient starvation and those that fluctuate during metabolic and oxygen consumption cycles, which explains the known genetic connections between these factors and nutrient utilization and stress pathways.

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A Deconvolution Protocol for ChIP-Seq Reveals Analogous Enhancer Structures on the Mouse and Human Ribosomal RNA Genes

The combination of Chromatin Immunoprecipitation and Massively Parallel Sequencing, or ChIP-Seq, has greatly advanced our genome-wide understanding of chromatin and enhancer structures. However, its resolution at any given genetic locus is limited by several factors. In applying ChIP-Seq to the study of the ribosomal RNA genes, we found that a major limitation to resolution was imposed by the underlying variability in sequence coverage that very often dominates the protein-DNA interaction profiles. Here we describe a simple numerical deconvolution approach that in large part corrects for this variability and significantly improves both the resolution and quantitation of protein-DNA interaction maps deduced from ChIP-Seq data. This approach has allowed us to determine the in vivo organization of the RNA Polymerase I preinitiation complexes that form at the promoters and enhancers of the mouse (Mus musculus) and human (Homo sapiens) ribosomal RNA genes, and to reveal a phased binding of the HMG-box factor UBF across the rDNA. The data identify and map a "Spacer Promoter" and associated stalled polymerase in the Intergenic Spacer of the human ribosomal RNA genes, and reveal a very similar Enhancer structure to that found in rodents and lower vertebrates.

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A randomized phase II study of S-1 versus capecitabine as first-line chemotherapy in elderly metastatic gastric cancer patients with or without poor performance status: clinical and pharmacogenetic results.

Objective: This study investigated the efficacy and safety of S-1 versus capecitabine in elderly patients with metastatic gastric cancer (MGC), and examined the association between cytochrome P450 2A6 (CYP2A6) polymorphisms and treatment outcomes. Materials and methods: MGC patients 70-85 years old with Eastern Cooperative Oncology Group performance status 0-2 or 65-70 years old with Eastern Cooperative Oncology Group performance status 2 were randomized to receive S-1 40 mg/m2, twice daily, or capecitabine 1250 mg/m2, twice daily, on days 1-14 every 3 weeks. Results: From May 2007 up to July 2010, 107 patients were enrolled. G3/4 neutropenia developed in 3.8% of each arm, and the most common G3/4 nonhematological toxicities were anorexia and fatigue. Vomiting and tearing were more frequent with S-1 and hand-foot syndrome with capecitabine. The primary endpoint, the overall response rate, was 26.4% (14/53, 95% confidence interval: 14.5-38.3%) in S-1 and 24.1% (13/54, 95% confidence interval: 12.7-35.5%) in capecitabine, both of which exceeded the null hypothesis response rate of 10%. The median time to progression (TTP; 3.2 vs. 3.4 months, P=0.813) and overall survival (OS; 8.5 vs. 10.3 months, P=0.691) were similar in both arms. CYP2A6 polymorphisms were associated with S-1 efficacy. In the S-1 arm only, patients with CYP2A6 variant/variant alleles had worse TTP and OS than those with wild/wild or wild/variant alleles, and in multivariate analysis, the CYP2A6 genotype was predictive for TTP and OS. Conclusion: Both S-1 and capecitabine were active and tolerable for elderly MGC patients. The CYP2A6 genotyping might guide treatment selection. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Bilateral early activity in the hip flexors associated with Falls in Stroke Survivors: Preliminary evidence from laboratory-induced falls

Stroke is the leading cause of disability in the US with an additional 800,000 incidents occurring each year (CDC, 2012). Falls present a major risk for stroke survivors, 40% of whom experience a serious fall within their first year (Persson et al., 2011). Up to 69% of falls by stroke survivors result in injuries. Despite the importance of the problem, there is surprisingly little information about what factors contribute to falls in stroke survivors. With few exceptions, the literature has focused on relating metrics of post-stroke static balance (where stepping did not occur) and impairment (clinical scores) to fall outcomes in the acute care setting or in the community (Divani et al., 2011; Ikai et al., 2003; Marigold et al., 2004; Marigold and Eng, 2006; Persson et al., 2011; Weerdesteyn et al., 2008).

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Fasciculation potentials and decremental responses in amyotrophic lateral sclerosis

Clinically-observed fasciculations and fasciculation potentials (FPs) in needle EMG are characteristic findings of amyotrophic lateral sclerosis (ALS) (Wilbourn, 1998) and have been postulated to reflect the hyperexcitability of the lower motor neuron (Bostock et al., 1995). Decremental responses (hereafter abbreviated as "decrement") in repetitive nerve stimulation (RNS) are also frequently observed in ALS patients (Mulder et al., 1959; Iwanami et al., 2011; Hatanaka et al., 2017). These are usually thought to reflect immature nerve terminals in newly-formed sprouts (Stålberg et al., 1975), although the precise mechanism is yet to be clarified.

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Detection radius of EMG for fasciculations: empiric study combining ultrasonography and electromyography

Fasciculation potentials are defined by spontaneous activity derived from one whole single motor unit or from part of it (Denny-Brown and Pennybacker 1938; Trojaborg and Buchthal 1965). The same fasciculations potentials may appear repetitively in the same location of a muscle. Occurring at a low intensity in most people, they may also present in "benign fasciculation syndrome" or as a symptom of a wide range of other types of motor neuron lesion (Scheel et al. 1997; Fermont et al. 2010; de Carvalho et al.

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High-resolution ultrasound in patients with Wartenberg’s migrant sensory neuritis, a case-control study

Wartenberg's migrant sensory neuritis (WMSN) is a rare and exclusively sensory neuropathy of unknown etiology, characterized by sudden numbness of one or multiple cutaneous nerves. Numbness may be preceded by pain in the area of distribution of the involved nerve. In some patients stretching of the affected nerve or moving the limb causes pain in the distribution of the involved nerve.(Nicolle et al., 2001; Stork et al., 2010, Wartenberg, 1958) Although any cutaneous sensory nerve can be involved, deficits most commonly reported involve the sensory branches of the peroneal nerve, the digital branches in the hands, the superficial radial nerve and the sural nerve.(Nicolle et al., 2001; Stork et al., 2010) The disease course is generally benign, usually recurrent, and the impact on daily life being limited.(Nicolle et al., 2001; Stork et al., 2010) An auto-immune etiology has been suggested, although patients who received immunomodulating treatment did not improve.(Nicolle et al., 2001; Simmad et al., 1999)

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Transcription: Shedding light on alternative promoter selection

Transcription: Shedding light on alternative promoter selection

Transcription: Shedding light on alternative promoter selection, Published online: 20 November 2017; doi:10.1038/nrg.2017.100

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Prioritizing diversity in human genomics research

Prioritizing diversity in human genomics research

Prioritizing diversity in human genomics research, Published online: 20 November 2017; doi:10.1038/nrg.2017.89

Including diverse populations in genomic studies has the potential to improve the use of genomic data in the clinic. Here, members of the National Human Genome Research Institute review the benefits of increasing diversity, the challenges to overcome and key recommendations for how to achieve this goal.

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Balancing the playing field: collaborative gaming for physical training

Multiplayer video games promoting exercise-based rehabilitation may facilitate motor learning, by increasing motivation through social interaction. However, a major design challenge is to enable meaningful int...

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