Miracle-dz/UniFAR-FTUs huggingface dataset:
Prediagnosis Sleep Duration, Napping, and Mortality Among Colorectal Cancer Survivors in a Large US Cohort

Study Objectives Prediagnosis lifestyle factors can influence colorectal cancer (CRC) survival. Sleep deficiency is linked to metabolic dysfunction and chronic inflammation, which may contribute to higher mortality from cardiometabolic conditions and promote tumor progression. We hypothesized that prediagnosis sleep deficiency would be associated with poor CRC survival. No previous study has examined either nighttime sleep or daytime napping in relation to survival among men and women diagnosed with CRC. Methods We examined self-reported sleep duration and napping prior to diagnosis in relation to mortality among 4869 CRC survivors in the NIH-AARP Diet and Health Study. Vital status was ascertained by linkage to the Social Security Administration Death Master File and the National Death Index. We examined the associations of sleep and napping with mortality using traditional Cox regression (total mortality) and Compositing Risk Regression (cardiovascular disease [CVD] and CRC mortality). Models were adjusted for confounders (demographics, cancer stage, grade and treatment, smoking, physical activity, and sedentary behavior) as well as possible mediators (body mass index and health status) in separate models. Results Compared to participants reporting 7-8 hours of sleep per day, those who reported <5 hr had a 36% higher all-cause mortality risk (Hazard Ratio (95% Confidence Interval), 1.36 (1.08-1.72)). Short sleep (<5 hr) was also associated with a 54% increase in CRC mortality (Substitution Hazard Ratio (95% Confidence Interval), 1.54 (1.11-2.14)) after adjusting for confounders and accounting for competing causes of death. Compared to no napping, napping 1 hr or more per day was associated with significantly higher total and CVD mortality but not CRC mortality. Conclusion Prediagnosis short sleep and long napping were associated with higher mortality among CRC survivors.
Ability to Induce Atrial Fibrillation in the Peri-operative Period Is Associated with Phosphorylation-dependent Inhibition of TWIK Protein-related Acid-sensitive Potassium Channel 1 (TASK-1)*

Background: Peri-operative atrial fibrillation (AF) is a common complication of thoracic surgery linked to inflammation. Results: TASK-1 current is absent from atrial myocytes isolated from AF dogs. The inhibition is phosphorylation-dependent, and threonine 383 is a PKC target in this model. Conclusion: TASK-1 inhibition and phosphorylation are associated with peri-operative AF. Significance: TASK-1 inhibition and phosphorylation are markers of peri-operative AF and are potential therapeutic targets. Peri-operative atrial fibrillation (peri-op AF) is a common complication following thoracic surgery. This arrhythmia is thought to be triggered by an inflammatory response and can be reproduced in various animal models. Previous work has shown that the lipid inflammatory mediator, platelet-activating factor (PAF), synthesized by activated neutrophils, can induce atrial and ventricular arrhythmias as well as repolarization abnormalities in isolated ventricular myocytes. We have previously shown that carbamylated PAF-induced repolarization abnormalities result from the protein kinase C (PKC) ϵ-dependent phosphorylation of the two-pore domain potassium channel TASK-1. We now demonstrate that canine peri-op AF is associated with the phosphorylation-dependent loss of TASK-1 current. Further studies identified threonine 383 in the C terminus of human and canine TASK-1 as the phosphorylation site required for PAF-dependent inhibition of the channel. Using a novel phosphorylation site-specific antibody targeting the phosphorylated channel, we have determined that peri-op AF is associated with the loss of TASK-1 current and increased phosphorylation of TASK-1 at this site.
Variation at the GABAA receptor gene, Rho 1 (GABRR1) associated with susceptibility to bipolar schizoaffective disorder

We have previously reported evidence that variation at GABAA receptor genes is associated with susceptibility to bipolar disorder with schizophrenia‐like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene‐wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene‐wide P = 0.0058; experiment‐wide corrected significance P = 0.052). © 2010 Wiley‐Liss, Inc.
The Human Lagging Strand DNA Polymerase δ Holoenzyme Is Distributive*

Background: Human DNA Pol δ holoenzyme carries out the lagging strand DNA synthesis. Results: Human DNA Pol δ holoenzyme is distributive with nucleotide incorporation rates a hundredfold slower than its prokaryotes/phage counterparts. Conclusion: Human DNA Pol δ holoenzyme dissociates and reassembles during DNA replication. Significance: Probing the characteristics of Pol δ holoenzyme is important for elucidating its mechanistic details and function in vivo. Polymerase δ is widely accepted as the lagging strand replicative DNA polymerase in eukaryotic cells. It forms a replication complex in the presence of replication factor C and proliferating cell nuclear antigen to perform efficient DNA synthesis in vivo. In this study, the human lagging strand holoenzyme was reconstituted in vitro. The rate of DNA synthesis of this holoenzyme, measured with a singly primed ssM13 DNA substrate, is 4.0 ± 0.4 nucleotides. Results from adenosine 5′-(3-thiotriphosphate) tetralithium salt (ATPγS) inhibition experiments revealed the nonprocessive characteristic of the human DNA polymerase (Pol δ) holoenzyme (150 bp for one binding event), consistent with data from chase experiments with catalytically inactive mutant Pol δAA. The ATPase activity of replication factor C was characterized and found to be stimulated ∼10-fold in the presence of both proliferating cell nuclear antigen and DNA, but the activity was not shut down by Pol δ in accord with rapid association/dissociation of the holoenzyme to/from DNA. It is noted that high concentrations of ATP inhibit the holoenzyme DNA synthesis activity, most likely due to its inhibition of the clamp loading process.
Daytime Sleepiness Increases With Age in Early Adolescence: A Sleep Restriction Dose–Response Study

Study Objectives Daytime sleepiness increases across adolescence. This increase is commonly attributed to insufficient sleep durations resulting from increasingly limited time in bed. We tested the effects of 3 sleep schedules on daytime sleepiness and whether these effects changed with age in early adolescence. Methods In 77 children ranging in age from 9.9 to 14 years, objective (multiple sleep latency test [MSLT]) and subjective (Karolinska sleepiness scale [KSS]) sleepiness was measured following 4 consecutive nights of either 7, 8.5, or 10 hours in bed. All participants completed all 3 sleep schedules. The order in which they completed the schedules was not randomized but was accounted for in all statistical analyses. Results Time in bed restriction decreased sleep duration and increased objective and subjective daytime sleepiness. Although the sleep durations did not change with age, the likelihood of falling asleep during the MSLT increased with age. Nevertheless, sleep restriction produced a greater increase in MSLT-measured sleepiness in younger participants. Subjective sleepiness measured with the KSS increased with shorter sleep duration, but this effect did not change with age. Conclusions Increasing objective daytime sleepiness in early adolescence cannot simply be attributed to reduced sleep due to restricted sleep schedules. We propose that some of the increased daytime sleepiness of adolescents is a consequence of adolescent brain reorganization driven by synaptic pruning which decreases the intensity of waking brain activity.
Can Motivational Interviewing be Truly Integrated with Person-centered Counselling?

This article examines whether Motivational Interviewing (MI) can be truly integrated with Carl Rogers' person-centered approach (PCA) to counselling. While the ‘spirit’ of MI has much in common with PCA, it is argued that the theory and practice of MI indicates several fundamental differences with PCA that distinguishes the ways that each perspective may contribute to rehabilitation counselling. These differences are discussed in relation to the unique aspects of their underlying assumptions, how they define clients' problems, and how they articulate the role of counsellor and successful outcome. Recent meta-analyses have indicated the beneficial aspects of both approaches. Empirical evidence for the efficacy of both MI and PCA is strong across a diverse range of client groups and health care settings. However, the highly variable effectiveness of both MI and PCA suggests that further process-outcome research is needed. Implications for rehabilitation counsellors are discussed.
Dysbindin‐1 gene contributes differentially to early‐ and adult‐onset forms of functional psychosis

Dysbindin‐1 is a relatively ubiquitous protein in the brain which is involved in the modulation of synaptic homeostasis. The dysbindin‐1 gene (DTNBP1) has been associated with schizophrenia and bipolar disorder diagnoses. However, its contribution to the severity of the clinical and neurocognitive expression of these disorders remains controversial. We aimed to explore the association between DTNBP1 and the phenotypes which are more directly linked with the underlying biology, such as age at onset and neurocognitive impairment. The present family sample comprised 894 Caucasian individuals: 268 patients affected by functional psychosis [58% with illness onset before 18 years, mean age at onset (SD): 14.71 (2.10)], 483 parents and 143 siblings. Ten DTNBP1 single nucleotide polymorphisms were genotyped in all individuals and their transmission disequilibrium was tested in relation to: (i) the risk for psychosis; (ii) patients' age at onset; and (iii) familial neurocognitive performance (including IQ estimation and executive functioning). In early‐onset families a 5‐marker haplotype encompassing exons 2–4 and the surrounding introns was significantly over‐transmitted to cases, while in adult‐onset families two haplotypes corresponding to the region between introns 4 and 7 were over‐transmitted to cases. Estimated IQ was associated with the rs760666 marker in the whole sample, whereas a significant association between executive functioning and the rs2619522 marker appeared in early‐onset families. Our findings confirm the role of the dysbindin‐1 gene in the risk for functional psychosis and show a differential haplotypic risk pattern in families with early as opposed to adult onset in the affected offspring. © 2011 Wiley‐Liss, Inc.
βIII Spectrin Regulates the Structural Integrity and the Secretory Protein Transport of the Golgi Complex*

Background: βIII spectrin function at the Golgi remains unclear. Results: βIII spectrin is enriched in distal Golgi compartments and supports anterograde transport. PI4P is determinant for the βIII spectrin association with Golgi membranes. Conclusion: βIII spectrin is necessary for the structural and functional organization of the Golgi. Significance: We provide new in vivo insights of the role of βIII spectrin at the Golgi. A spectrin-based cytoskeleton is associated with endomembranes, including the Golgi complex and cytoplasmic vesicles, but its role remains poorly understood. Using new generated antibodies to specific peptide sequences of the human βIII spectrin, we here show its distribution in the Golgi complex, where it is enriched in the trans-Golgi and trans-Golgi network. The use of a drug-inducible enzymatic assay that depletes the Golgi-associated pool of PI4P as well as the expression of PH domains of Golgi proteins that specifically recognize this phosphoinositide both displaced βIII spectrin from the Golgi. However, the interference with actin dynamics using actin toxins did not affect the localization of βIII spectrin to Golgi membranes. Depletion of βIII spectrin using siRNA technology and the microinjection of anti-βIII spectrin antibodies into the cytoplasm lead to the fragmentation of the Golgi. At ultrastructural level, Golgi fragments showed swollen distal Golgi cisternae and vesicular structures. Using a variety of protein transport assays, we show that the endoplasmic reticulum-to-Golgi and post-Golgi protein transports were impaired in βIII spectrin-depleted cells. However, the internalization of the Shiga toxin subunit B to the endoplasmic reticulum was unaffected. We state that βIII spectrin constitutes a major skeletal component of distal Golgi compartments, where it is necessary to maintain its structural integrity and secretory activity, and unlike actin, PI4P appears to be highly relevant for the association of βIII spectrin the Golgi complex.
Association of GWAS loci with PD in China

Genome‐wide association studies (GWAS) have identified numerous single‐nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinson's disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case–control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS‐linked data and research on ethnic specific effect of common variants. © 2011 Wiley‐Liss, Inc.
Photosensitivity of Kinase Activation by Blue Light Involves the Lifetime of a Cysteinyl-Flavin Adduct Intermediate, S390, in the Photoreaction Cycle of the LOV2 Domain in Phototropin, a Plant Blue Light Receptor*

Background: The plant photoreceptor “phototropin” is a light-regulated kinase containing the LOV photosensory domains. Results: Photosensitivity of the kinase activation involves the lifetime of an intermediate in the photocycle. Conclusion: Lifetime of the adduct state of LOV2 is a determinant in the activation of kinase. Significance: This work examines and explains the different photosensitivities observed for phototropin 1 and 2. Phototropin (phot) is a light-regulated protein kinase that mediates a variety of photoresponses in plants, such as phototropism, chloroplast positioning, and stomata opening. Arabidopsis has two homologues, phot1 and phot2, that share physiological functions depending on light intensity. A phot molecule has two photoreceptive light oxygen voltage-sensing domains, LOV1 and LOV2, and a Ser/Thr kinase domain. The LOV domains undergo a photocycle upon blue light (BL) stimulation, including transient adduct formation between the chromophore and a conserved cysteine (S390 intermediate) that leads to activation of the kinase. To uncover the mechanism underlying the photoactivation of the kinase, we have introduced a kinase assay system composed of a phot1 LOV2-linker-kinase polypeptide as a light-regulated kinase and its N-terminal polypeptide as an artificial substrate (Okajima, K., Matsuoka, D., and Tokutomi, S. (2011) LOV2-linker-kinase phosphorylates LOV1-containing N-terminal polypeptide substrate via photoreaction of LOV2 in Arabidopsis phototropin1. FEBS Lett. 585, 3391–3395). In the present study, we extended the assay system to phot2 and compared the photochemistry and kinase activation by BL between phot1 and phot2 to gain insight into the molecular basis for the different photosensitivities of phot1 and phot2. Photosensitivity of kinase activation by BL and the lifetime of S390 of phot1 were 10 times higher and longer, respectively, than those of phot2. This correlation was confirmed by an amino acid substitution experiment with phot1 to shorten the lifetime of S390. The present results demonstrated that the photosensitivity of kinase activation in phot involves the lifetime of S390 in LOV2, suggesting that the lifetime is one of the key factors for the different photosensitivities observed for phot1 and phot2.
Replication study of genome‐wide associated SNPs with late‐onset Alzheimer's disease

Late‐onset Alzheimer's disease (LOAD) is a multifactorial disease with the potential involvement of multiple genes. Four recent genome‐wide association studies (GWAS) have found variants showing significant association with LOAD on chromosomes 6, 10, 11, 12, 14, 18, 19, and on the X chromosome. We examined a total of 12 significant SNPs from these studies to determine if the results could be replicated in an independent large case–control sample. We genotyped these 12 SNPs as well the E2/E3/E4 APOE polymorphisms in up to 993 Caucasian Americans with LOAD and up to 976 age‐matched healthy Caucasian Americans. We found no statistically significant associations between the 12 SNPs and the risk of AD. Stratification by APOE*4 carrier status also failed to reveal statistically significant associations. Additional analyses were performed to examine potential associations between the 12 SNPs and age‐at‐onset (AAO) and disease duration among AD cases. Significant associations were observed between AAO and ZNF224/rs3746319 (P = 0.002) and KCNMA1/rs16934131 (P = 0.0066). KCNMA1/rs16934131 also demonstrated statistically significant association with disease duration (P = 0.0002). Although we have been unable to replicate the reported GWAS association with AD risk in our sample, we have identified two new associations with AAO and disease duration that need to be confirmed in additional studies. © 2011 Wiley‐Liss, Inc.
Association study of Nogo‐related genes with schizophrenia in a Japanese case–control sample

Many studies have suggested that myelin dysfunction may be causally involved in the pathogenesis of schizophrenia. Nogo (RTN4), myelin‐associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG) all bind to the common receptor, Nogo‐66 receptor 1 (RTN4R). We examined 68 single nucleotide polymorphisms (SNPs) (51 with genotyping and 17 with imputation analysis) from these four genes for genetic association with schizophrenia, using a 2,120 case–control sample from the Japanese population. Allelic tests showed nominally significant association of two RTN4 SNPs (P = 0.047 and 0.037 for rs11894868 and rs2968804, respectively) and two MAG SNPs (P = 0.034 and 0.029 for rs7249617 and rs16970218, respectively) with schizophrenia. The MAG SNP rs7249617 also showed nominal significance in a genotypic test (P = 0.017). In haplotype analysis, the MAG haplotype block including rs7249617 and rs16970218 showed nominal significance (P = 0.008). These associations did not remain significant after correction for multiple testing, possibly due to their small genetic effect. In the imputation analysis of RTN4, the untyped SNP rs2972090 showed nominally significant association (P = 0.032) and several imputed SNPs showed marginal associations. Moreover, in silico analysis (PolyPhen) of a missense variant (rs11677099: Asp357Val), which is in strong linkage disequilibrium with rs11894868, predicted a deleterious effect on Nogo protein function. Despite a failure to detect robust associations in this Japanese cohort, our nominally positive signals, taken together with previously reported biological and genetic findings, add further support to the “disturbed myelin system theory of schizophrenia” across different populations. © 2011 Wiley‐Liss, Inc.
Genome‐wide association analysis of age at onset in schizophrenia in a European‐American sample

We performed a genome‐wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene × gender interactions for AAO in schizophrenia (SCZ) using a European‐American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene × gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P = 3.10 × 10−7) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P = 4.30 × 10−6) and the third region was at 4p16.1 (rs17407555, P = 4.56 × 10−6, near RAF1P1, and rs4697924, P = 1.23 × 10−5 within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P = 2.10 × 10−6 and 2.33 × 10−6, respectively) and strong gene × gender interactions in influencing AAO (P = 9.23 × 10−7 and 1.15 × 10−6, respectively) while the second best region showing gene × gender interaction was at 7q22.3 (rs179863, P = 2.33 × 10−6). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P < 0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ. © 2011 Wiley‐Liss, Inc.
The Transcription Factors Grainyhead-like 2 and NK2-Homeobox 1 Form a Regulatory Loop That Coordinates Lung Epithelial Cell Morphogenesis and Differentiation*

Background: Grhl2 regulates cell-junction gene transcription in several epithelia but has not been fully characterized in lungs. Results: In lung epithelial cells GRHL2 regulates cell-cell interaction genes, collective cell migration, and Nkx2-1 transcription. Conversely, NKX2-1 regulates transcription of Grhl2. Conclusion: A Grhl2- and Nkx2-1-positive transcriptional loop coordinates morphogenesis and differentiation of lung epithelial cells. Significance: This regulatory loop reinforces normal lung epithelial cell identity. The Grainyhead family of transcription factors controls morphogenesis and differentiation of epithelial cell layers in multicellular organisms by regulating cell junction- and proliferation-related genes. Grainyhead-like 2 (Grhl2) is expressed in developing mouse lung epithelium and is required for normal lung organogenesis. The specific epithelial cells expressing Grhl2 and the genes regulated by Grhl2 in normal lungs are mostly unknown. In these studies we identified the NK2-homeobox 1 transcription factor (Nkx2-1) as a direct transcriptional target of Grhl2. By binding and transcriptional assays and by confocal microscopy we showed that these two transcription factors form a positive feedback loop in vivo and in cell lines and are co-expressed in lung bronchiolar and alveolar type II cells. The morphological changes observed in flattening lung alveolar type II cells in culture are associated with down-regulation of Grhl2 and Nkx2-1. Reduction of Grhl2 in lung epithelial cell lines results in lower expression levels of Nkx2-1 and of known Grhl2 target genes. By microarray analysis we identified that in addition to Cadherin1 and Claudin4, Grhl2 regulates other cell interaction genes such as semaphorins and their receptors, which also play a functional role in developing lung epithelium. Impaired collective cell migration observed in Grhl2 knockdown cell monolayers is associated with reduced expression of these genes and may contribute to the altered epithelial phenotype reported in Grhl2 mutant mice. Thus, Grhl2 functions at the nexus of a novel regulatory network, connecting lung epithelial cell identity, migration, and cell-cell interactions.