Miracle-dz/UniFAR-FTUs huggingface dataset:
No evidence that extended tracts of homozygosity are associated with Alzheimer's disease

We sought to investigate the contribution of extended runs of homozygosity in a genome‐wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease. © 2011 Wiley‐Liss, Inc.
Additive effects of serotonergic and dopaminergic polymorphisms on trait impulsivity

Twin studies suggest 45% heritability of trait impulsivity. Results from candidate gene studies to date are contradictory; impulsivity phenotypes were measured by different behavioral and questionnaire methods related either to the dopaminergic or to the serotonergic system. Here we report an association study of both dopaminergic (COMT rs4680, DRD4 48 bp VNTR, DRD2/ANKK1 rs1800497) and serotonergic (HTR1A rs6925, HTR1B rs13212041, SLC6A4 5‐HTTLPR) gene polymorphisms and trait impulsivity assessed with the Barratt Impulsiveness Scale (BIS‐11) in a sample of 687 Caucasian young adults. Results showed lower impulsivity in the presence of the DRD4 7‐repeat (P = 0.006) and the HTR1B rs13212041 alleles (P = 0.003). These findings stayed significant after Bonferroni correction. A multivariate analysis using Bayesian networks confirmed independent effects of these two polymorphisms and provided a coherent characterization of the system of dependencies with respect to the impulsivity construct as well as its subscales. These results clearly suggest an additive effect of dopaminergic and serotonergic polymorphisms on trait impulsivity. © 2012 Wiley Periodicals, Inc.
Muscles: Testing and Function, with Posture and Pain

The Limited 50th Anniversary Edition of this classic text celebrates 50 years in the market. Ten pages commemorate the life and work of Florence and Henry Kendall and a portion of the proceeds will be donated to the Foundation for Physical Therapy. Ideal for both students and clinicians, this textbook offers unparalleled coverage of manual muscle testing, plus covers the evaluation and treatment of faulty and painful postural conditions.
Single ability among activities of daily living as a predictor of agitation.

AIMS The aims of this study were to investigate whether the interaction effect between restraint and functional ability, and single ability during activities of daily living can predict agitation among residents with dementia. BACKGROUND Agitated behaviour is one of the most common symptoms of dementia and might endanger the patients themselves, caregivers and institutions. However, the prevalence of problem behaviours and its associated factors at long-term care facilities in Taiwan are less understood. DESIGN A direct observation was used to observe the agitated behaviours of residents with dementia in special care units. METHODS Residents of dementia special care units who were diagnosed with dementia in eight long-term care facilities were recruited. Measurements included: demographic data, the Barthel Index, the Mini-Mental State Examination and the Cohen-Mansfield Agitation Inventory. RESULTS The number of subjects who were identified with problem behaviours was 163 (43.5%). Significant differences in sex, being restrained, restrained time, age, family visits, functional status and mental status were found between the agitated and non-agitated groups. However, mental status, family visits, walking ability, being restrained and getting in and off toilet were five independent factors associated with agitated behaviours after controlling for all other factors. CONCLUSIONS It is recommended that strategies be constructed to encourage the family to periodically visit older residents and to develop restraint-free environments in long-term care facilities. RELEVANCE TO CLINICAL PRACTICE Residents with dementia require significant daily living support and behaviour management as their illness progress.
The Crystal Structure of the Protein-Disulfide Isomerase Family Member ERp27 Provides Insights into Its Substrate Binding Capabilities*

Background: ERp27 is a redox-inactive member of the protein-disulfide isomerase family. Results: The crystal structure of ERp27 reveals how the substrate-binding site can be modulated by conformational changes. Conclusion: ERp27 is induced during ER stress and binds misfolded proteins. Significance: ERp27 may act as a safety overflow under stress conditions, funneling excess misfolded protein onto ERp57. About one-third of all cellular proteins pass through the secretory pathway and hence undergo oxidative folding in the endoplasmic reticulum (ER). Protein-disulfide isomerase (PDI) and related members of the PDI family assist in the folding of substrates by catalyzing the oxidation of two cysteines and isomerization of disulfide bonds as well as by acting as chaperones. In this study, we present the crystal structure of ERp27, a redox-inactive member of the PDI family. The structure reveals its substrate-binding cleft, which is homologous to PDI, but is able to adapt in size and hydrophobicity. Isothermal titration calorimetry experiments demonstrate that ERp27 is able to distinguish between folded and unfolded substrates, only interacting with the latter. ERp27 is up-regulated during ER stress, thus presumably allowing it to bind accumulating misfolded substrates and present them to ERp57 for catalysis.
Construction of a Chondroitin Sulfate Library with Defined Structures and Analysis of Molecular Interactions*

Background: Chondroitin sulfate (CS) is a linear polysaccharide, composed of repeating disaccharide units and modified with sulfate groups at various positions. Results: A CS library was constructed with defined structures using CS polymerase and sulfotransferases. Conclusion: The CS library provided details of interactions with CS-binding molecules. Significance: Chemo-enzymatic synthesis provides a useful tool for studying the biological functions of CS. Chondroitin sulfate (CS) is a linear acidic polysaccharide, composed of repeating disaccharide units of glucuronic acid and N-acetyl-d-galactosamine and modified with sulfate residues at different positions, which plays various roles in development and disease. Here, we chemo-enzymatically synthesized various CS species with defined lengths and defined sulfate compositions, from chondroitin hexasaccharide conjugated with hexamethylenediamine at the reducing ends, using bacterial chondroitin polymerase and recombinant CS sulfotransferases, including chondroitin-4-sulfotransferase 1 (C4ST-1), chondroitin-6-sulfotransferase 1 (C6ST-1), N-acetylgalactosamine 4-sulfate 6-sulfotransferase (GalNAc4S-6ST), and uronosyl 2-sulfotransferase (UA2ST). Sequential modifications of CS with a series of CS sulfotransferases revealed their distinct features, including their substrate specificities. Reactions with chondroitin polymerase generated non-sulfated chondroitin, and those with C4ST-1 and C6ST-1 generated uniformly sulfated CS containing >95% 4S and 6S units, respectively. GalNAc4S-6ST and UA2ST generated highly sulfated CS possessing ∼90% corresponding disulfated disaccharide units. Sequential reactions with UA2ST and GalNAc4S-6ST generated further highly sulfated CS containing a mixed structure of disulfated units. Surprisingly, sequential reactions with GalNAc4S-6ST and UA2ST generated a novel CS molecule containing ∼29% trisulfated disaccharide units. Enzyme-linked immunosorbent assay and surface plasmon resonance analysis using the CS library and natural CS products modified with biotin at the reducing ends, revealed details of the interactions of CS species with anti-CS antibodies, and with CS-binding molecules such as midkine and pleiotrophin. Chemo-enzymatic synthesis enables the generation of CS chains of the desired lengths, compositions, and distinct structures, and the resulting library will be a useful tool for studies of CS functions.
Catechol‐O‐methyltransferase gene val158met polymorphism and depressive symptoms during early childhood

Catechol‐O‐Methyltransferase (COMT) is a critical regulator of catecholamine levels in the brain. A functional polymorphism of the COMT gene, val158met, has been linked to internalizing symptoms (i.e., depression and anxiety) in adolescents and adults. We extended this research by investigating whether the val158met polymorphism was associated with childhood symptoms of depression and anxiety in two independent samples of young children (Ns = 476 and 409). In both samples, preschool‐aged children were genotyped for the COMT val158met polymorphism. Symptoms of psychopathology were assessed via parent interviews and primary caregiver reports. In both samples, children homozygous for the val allele had higher levels of depressive symptoms compared to children with at least one copy of the met allele. Our findings extend previous research in older participants by showing links between the COMT val158met polymorphism and internalizing symptoms in early childhood. © 2013 Wiley Periodicals, Inc.
Reaffirmation of GAK, but not HLA‐DRA, as a Parkinson's disease susceptibility gene in a Taiwanese population

Recent genome‐wide association studies of Parkinson's disease (PD) in Caucasian populations have identified two new susceptibility loci, GAK and HLA‐DRA; however, only limited information exists regarding the involvement of these genes in PD risk in other ethnic groups. Here, we examined whether these genetic effects were consistent in a Taiwanese PD population. In a total 900 participants, including 448 PD patients and 452 control subjects, we genotyped the rs11248051 and rs1564282 variants of GAK, and the rs3129882 variant of HLA‐DRA. Logistic regression analysis was used to test for associations between genotype and PD under an additive model, adjusting for age and gender. Subjects with CT/TT genotypes of GAK rs11248051 had a modestly increased association with PD compared to those with CC genotype (OR = 1.37; 95% CI = 1.09, 1.87; P = 0.03). Carriers and non‐carriers exhibited indistinguishable phenotypes in regards to clinical presentation and onset age. We observed no association between PD risk and GAK rs1564282 or HLA‐DRA rs3129882 variant. The different genetic effects between Taiwanese and Caucasian populations may come from differences in population structure and geographic region‐specific genetic–environmental interactions. In conclusion, our results supported the association between the rs11248051 variant in GAK and PD risk in a Taiwanese population. Future functional studies of GAK in neuronal degeneration are warranted to unravel its role in the pathogenetic mechanism of PD. © 2013 Wiley Periodicals, Inc.
Parental presence during resuscitation in the PICU: the parents' experience. Sharing and surviving the resuscitation: a phenomenological study.

AIM AND OBJECTIVE To provide in-depth understanding of the meaning for parents who were present or absent during a resuscitation attempt on their child in the PICU. BACKGROUND Family presence during resuscitation remains a topic of debate with both benefits and disadvantages identified, yet few studies have asked parents of children in PICU to describe their experiences of being present or absent during this resuscitation and what this means to their understanding and coping. Additionally, minimal research has investigated parental presence during a successful resuscitation. DESIGN A qualitative design was used based upon van Manen's interpretative phenomenological approach. METHODS Fourteen parents of critically ill children from one paediatric intensive care unit in Australia, who had either survived or died following a resuscitation attempt were interviewed. RESULTS Four main themes were identified: (1) being only for a child; (2) making sense of a living nightmare; (3) maintaining hope in the face of reality; (4) living in a relationship with staff. CONCLUSIONS The findings underpin the inherent need for parents to choose to be present during resuscitation to make sense of the situation. Memories of the resuscitation were not long-lasting and distress was for the potential death of a child, rather than the resuscitation scene. Parents who did not witness their child's resuscitation were more distressed than those who did. Having the opportunity to make the decision to stay or leave was important for parents. Support during the resuscitation was best provided by experienced clinical nurses. RELEVANCE TO PRACTICE Recognition of the parents' compelling need to stay will improve nurses' understanding of how witnessing this event may assist family coping and functioning. Ways in which parents may be better supported in making the decision to stay or leave during resuscitation are identified.
Contribution of congenital heart disease to neuropsychiatric outcome in school‐age children with 22q11.2 deletion syndrome

Children with 22q11.2 deletion syndrome (22q11DS) present with congenital heart disease (CHD) and high prevalence of psychiatric disorders and neurocognitive deficits. Although CHD has been implicated in neurodevelopment, its role in the neuropsychiatric outcome in 22q11DS is poorly understood. We investigated whether CHD contributes to the high prevalence of psychiatric disorders and neurocognitive impairments in 22q11DS. Fifty‐four children ages 8–14 years with 22q11DS and 16 age‐matched non‐deleted children with CHD participated. They were assessed using semi‐structured interviews and a Computerized Neurocognitive Battery. CHD status was assessed using available medical records. Prevalence of psychiatric disorders and cognitive profiles were compared among the groups. There were no significant differences between the prevalence of psychiatric disorders in the 22q11DS with and without CHD. In 22q11DS with CHD, the prevalence rates were 41% anxiety disorders, 37% ADHD and 71% psychosis spectrum. In 22q11DS without CHD, the rates were 33% anxiety disorders, 41% ADHD and 64% psychosis spectrum. In comparison, the non‐deleted CHD group had lower rates of psychopathology (25% anxiety disorders, 6% ADHD, and 13% psychosis spectrum). Similarly, the 22q11DS groups, regardless of CHD status, had significantly greater neurocognitive deficits across multiple domains, compared to the CHD‐only group. We conclude that CHD in this sample of children with 22q11.2DS does not have a major impact on the prevalence of psychiatric disorders and is not associated with increased neurocognitive deficits. These findings suggest that the 22q11.2 deletion status itself may confer significant neuropsychiatric vulnerability in this population. © 2013 Wiley Periodicals, Inc.
Effects of negative stressors on DNA methylation in the brain: Implications for mood and anxiety disorders

Stress is a major contributor to anxiety and mood disorders. The recent discovery of epigenetic changes in the brain resulting from stress has enhanced our understanding of the mechanism by which stress is able to promote these disorders. Although epigenetics encompasses chemical modifications that occur at both DNA and histones, much attention has been focused on stress‐induced DNA methylation changes on behavior. Here, we review the effect of stress‐induced DNA methylation changes on physiological mechanisms that govern behavior and cognition, dysregulation of which can be harmful to mental health. A literature review was performed in the areas of DNA methylation, stress, and their impact on the brain and psychiatric illness. Key findings center on genes involved in the hypothalamic‐pituitary‐adrenal axis, neurotransmission and neuroplasticity. Using animal models of different stress paradigms and clinical studies, we detail how DNA methylation changes to these genes can alter physiological mechanisms that influence behavior. Appropriate levels of gene expression in the brain play an important role in mental health. This dynamic control can be disrupted by stress‐induced changes to DNA methylation patterns. Advancement in other areas of epigenetics, such as histone modifications and the discovery of the novel DNA epigenetic mark, 5‐hydroxymethylcytosine, could provide additional avenues to consider when determining the epigenetic effects of stress on the brain. © 2014 Wiley Periodicals, Inc.
Phospholipid Flippases Lem3p-Dnf1p and Lem3p-Dnf2p Are Involved in the Sorting of the Tryptophan Permease Tat2p in Yeast*

Background: Lem3p-Dnf1p and Lem3p-Dnf2p are phospholipid flippases that generate phospholipid asymmetry in yeast. Results: The tryptophan permease Tat2p is missorted from the trans-Golgi network to the vacuole in the lem3Δ mutant. Conclusion: Phospholipid asymmetry supports plasma membrane transport of Tat2p by inhibiting its improper ubiquitination at the trans-Golgi network. Significance: Phospholipid asymmetry may be involved in proper sorting of membrane proteins. The type 4 P-type ATPases are flippases that generate phospholipid asymmetry in membranes. In budding yeast, heteromeric flippases, including Lem3p-Dnf1p and Lem3p-Dnf2p, translocate phospholipids to the cytoplasmic leaflet of membranes. Here, we report that Lem3p-Dnf1/2p are involved in transport of the tryptophan permease Tat2p to the plasma membrane. The lem3Δ mutant exhibited a tryptophan requirement due to the mislocalization of Tat2p to intracellular membranes. Tat2p was relocalized to the plasma membrane when trans-Golgi network (TGN)-to-endosome transport was inhibited. Inhibition of ubiquitination by mutations in ubiquitination machinery also rerouted Tat2p to the plasma membrane. Lem3p-Dnf1/2p are localized to endosomal/TGN membranes in addition to the plasma membrane. Endocytosis mutants, in which Lem3p-Dnf1/2p are sequestered to the plasma membrane, also exhibited the ubiquitination-dependent missorting of Tat2p. These results suggest that Tat2p is ubiquitinated at the TGN and missorted to the vacuolar pathway in the lem3Δ mutant. The NH2-terminal cytoplasmic region of Tat2p containing ubiquitination acceptor lysines interacted with liposomes containing acidic phospholipids, including phosphatidylserine. This interaction was abrogated by alanine substitution mutations in the basic amino acids downstream of the ubiquitination sites. Interestingly, a mutant Tat2p containing these substitutions was missorted in a ubiquitination-dependent manner. We propose the following model based on these results; Tat2p is not ubiquitinated when the NH2-terminal region is bound to membrane phospholipids, but if it dissociates from the membrane due to a low level of phosphatidylserine caused by perturbation of phospholipid asymmetry in the lem3Δ mutant, Tat2p is ubiquitinated and then transported from the TGN to the vacuole.
Reprogramming of the MicroRNA Transcriptome Mediates Resistance to Rapamycin*

Background: The role of miRNAs in the cellular response to mTOR inhibitors has never been tested. Results: Rapamycin resistance is associated with up-regulation of oncogenic miRNAs and down-regulation of tumor suppressor miRNAs. Conclusion: miRNAs influence the cellular response to mTOR inhibitors. Significance: miRNAs are potential markers and novel targets for cancer therapy involving mTOR inhibitors. The mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation that is often deregulated in cancer. Inhibitors of mTOR, including rapamycin and its analogues, are being evaluated as antitumor agents. For their promise to be fulfilled, it is of paramount importance to identify the mechanisms of resistance and develop novel therapies to overcome it. Given the emerging role of microRNAs (miRNAs) in tumorigenesis, we hypothesized that miRNAs could play important roles in the response of tumors to mTOR inhibitors. Long-term rapamycin treatment showed extensive reprogramming of miRNA expression, characterized by up-regulation of miR-17–92 and related clusters and down-regulation of tumor suppressor miRNAs. Inhibition of members of the miR-17–92 clusters or delivery of tumor suppressor miRNAs restored sensitivity to rapamycin. This study identifies miRNAs as new downstream components of the mTOR-signaling pathway, which may determine the response of tumors to mTOR inhibitors. It also identifies potential markers to assess the efficacy of treatment and provides novel therapeutic targets to treat rapamycin-resistant tumors.
An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults

Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self‐reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3′UTR and intron 8 of DAT1, the 10‐repeat and 6‐repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7‐repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS‐G and CAARS‐H (DSM‐IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS‐G was also found for the 7‐repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults. © 2015 Wiley Periodicals, Inc.
A Novel Regulatory Factor Recruits the Nucleosome Remodeling Complex to Wingless Integrated (Wnt) Signaling Gene Promoters in Mouse Embryonic Stem Cells*

Background: Nucleosome remodeling is integral in transcriptional control, yet the exact mechanisms involved remain to be elucidated. Results: CDK2AP1 is a novel regulatory factor that guides the NuRD complex. Conclusion: CDK2AP1 guides NuRD onto promoters involved in Wnt signaling of mouse embryonic stem cells. Significance: Understanding NuRD regulation is critical in understanding transcriptional regulation. The nucleosome remodeling and deacetylation (NuRD) complex is required for modulating the transcription of essential pluripotency genes in ESC self-renewal. MBD3 is considered a key player in the formation of a functional NuRD complex. The recruitment of MBD3 to methylated promoters may require other prerequisite factors. We show that cyclin-dependent kinase 2-associated protein 1 (CDK2AP1), an essential gene for early embryonic development, plays a role in pluripotency of ESC by engaging MBD3 to the promoter region of Wnt signaling genes. The occupancy of MBD3 on several promoters of Wnt genes was significantly lost in the absence of CDK2AP1, resulting in hyperactivation of Wnt. We propose that the transcriptional modulation of the Wnt pathway mediated by NuRD requires the presence of essential auxiliary components such as CDK2AP1, which may aid the association of the complex with specific focal regions of the target promoters.