Miracle-dz/UniFAR-FTUs huggingface dataset:
Development and validation of an international risk prediction algorithm for episodes of major depression in general practice attendees: the PredictD study.

CONTEXT Strategies for prevention of depression are hindered by lack of evidence about the combined predictive effect of known risk factors. OBJECTIVES To develop a risk algorithm for onset of major depression. DESIGN Cohort of adult general practice attendees followed up at 6 and 12 months. We measured 39 known risk factors to construct a risk model for onset of major depression using stepwise logistic regression. We corrected the model for overfitting and tested it in an external population. SETTING General practices in 6 European countries and in Chile. PARTICIPANTS In Europe and Chile, 10 045 attendees were recruited April 2003 to February 2005. The algorithm was developed in 5216 European attendees who were not depressed at recruitment and had follow-up data on depression status. It was tested in 1732 patients in Chile who were not depressed at recruitment. Main Outcome Measure DSM-IV major depression. RESULTS Sixty-six percent of people approached participated, of whom 89.5% participated again at 6 months and 85.9%, at 12 months. Nine of the 10 factors in the risk algorithm were age, sex, educational level achieved, results of lifetime screen for depression, family history of psychological difficulties, physical health and mental health subscale scores on the Short Form 12, unsupported difficulties in paid or unpaid work, and experiences of discrimination. Country was the tenth factor. The algorithm's average C index across countries was 0.790 (95% confidence interval [CI], 0.767-0.813). Effect size for difference in predicted log odds of depression between European attendees who became depressed and those who did not was 1.28 (95% CI, 1.17-1.40). Application of the algorithm in Chilean attendees resulted in a C index of 0.710 (95% CI, 0.670-0.749). CONCLUSION This first risk algorithm for onset of major depression functions as well as similar risk algorithms for cardiovascular events and may be useful in prevention of depression.
Identification and characterization of aspartate residues that play key roles in the allosteric regulation of a transcription factor: aspartate 274 is essential for inducer binding in lac repressor.

To explore the roles of three aspartate residues, Asp88, Asp130, and Asp274, found in the proposed inducer binding site of lac repressor [Sams, C. F. , Vyas, N. K. , Quiocho, F. A. , & Matthews, K. S. (1984) Nature 310, 429-430], each site was substituted with alanine, glutamate, lysine, or asparagine by site-specific mutagenesis. The mutations at the Asp88 site resulted in a 5-13-fold decrease in inducer binding affinity, largely due to an increase in the inducer dissociation rate constants for these mutants. In addition, the mutant proteins Asp88-->Ala and Asp88-->Lys exhibited altered allosteric behavior for inducer binding. These data conflict with the original hypothesis placing Asp88 in the inducer binding site, but are in agreement with a recent model that places this amino acid close to the subunit interface involved in cooperativity associated with inducer binding [Nichols, J. C. , Vyas, N. K. , Quiocho, F. A. , & Matthews, K. S. (1993) J. Biol. Chem. 268, 17602-17612; Chen, J., & Matthews, K. S. (1992) J. Biol. Chem. 267, 13843-13850]. Substitution at Asp130 did not alter the inducer binding affinity nor other binding activities. Thus, this amino acid is not crucial in the binding to beta-substituted monosaccharides or in protein function. In stark contrast, all mutant proteins with substitutions at the Asp274 site exhibited no detectable inducer binding. With the exception of Asp274-->Lys, the structures of these mutant proteins appear to be similar to wild-type. The data demonstrate that Asp274 plays a crucial role in inducer binding of this transcriptional regulator.
Inhibitory control of the human dorsolateral prefrontal cortex during the anti‐saccade paradigm − a transcranial magnetic stimulation study

In the anti‐saccade paradigm, subjects are instructed not to make a reflexive saccade to an appearing lateral target but to make an intentional saccade to the opposite side instead. The inhibition of reflexive saccade triggering is under the control of the dorsolateral prefrontal cortex (DLPFC). The critical time interval at which this inhibition takes place during the paradigm, however, is not exactly known. In the present study, we used single‐pulse transcranial magnetic stimulation (TMS) to interfere with DLPFC function in 15 healthy subjects. TMS was applied over the right DLPFC either 100 ms before the onset of the visual target (i.e. −100 ms), at target onset (i.e. 0 ms) or 100 ms after target onset (i.e. +100 ms). Stimulation 100 ms before target onset significantly increased the percentage of anti‐saccade errors to both sides, while stimulation at, or after, target onset had no significant effect. All three stimulation conditions had no significant influence on saccade latency of correct or erroneous anti‐saccades. These findings show that the critical time interval at which the DLPFC controls the suppression of a reflexive saccade in the anti‐saccade paradigm is before target onset. In addition, the results suggest the view that the triggering of correct anti‐saccades is not under direct control of the DLPFC.
ANO2 is the cilial calcium-activated chloride channel that may mediate olfactory amplification

For vertebrate olfactory signal transduction, a calcium-activated chloride conductance serves as a major amplification step. However, the molecular identity of the olfactory calcium-activated chloride channel (CaCC) is unknown. Here we report a proteomic screen for cilial membrane proteins of mouse olfactory sensory neurons (OSNs) that identified all the known olfactory transduction components as well as Anoctamin 2 (ANO2). Ano2 transcripts were expressed specifically in OSNs in the olfactory epithelium, and ANO2::EGFP fusion protein localized to the OSN cilia when expressed in vivo using an adenoviral vector. Patch-clamp analysis revealed that ANO2, when expressed in HEK-293 cells, forms a CaCC and exhibits channel properties closely resembling the native olfactory CaCC. Considering these findings together, we propose that ANO2 constitutes the olfactory calcium-activated chloride channel.
Improving antidepressant adherence and depression outcomes in primary care: the treatment initiation and participation (TIP) program.

OBJECTIVE To test the impact of a novel psychosocial intervention to improve antidepressant adherence and depression outcomes among older adults prescribed pharmacotherapy by their primary care physician (PCP). DESIGN A randomized controlled pilot study was conducted to examine the usefulness of the Treatment Initiation and Participation (TIP) program as an intervention to improve antidepressant adherence and depression outcomes. SETTING The study was conducted at two primary care clinics in New York city: one clinic served geriatric adults and the second clinic served a diverse group of mixed aged adults. PARTICIPANTS The sample consisted of adults aged 60 years and older with major depression who were recommended antidepressant therapy by their PCPs. INTERVENTION All participants were prescribed antidepressant therapy and randomly assigned to either the intervention (TIP) or the treatment as usual (TAU) group. The TIP intervention identifies and targets psychological barriers to depression care, especially stigma, as well as fears and misconceptions of depression and its treatment. TIP participants are encouraged to develop a treatment goal and create an adherence strategy. MEASUREMENT Study participants were assessed at entry, 6, 12, and 24 weeks later. Adherence was measured based on self-report with chart verification. Depression severity was measured using the Hamilton Depression Rating Scale. RESULTS Participants in TIP were significantly more adherent to their antidepressant pharmacotherapy at all assessment time points and had a significantly greater decrease in depressive symptoms than older adults who received TAU. CONCLUSION The results provide support for the usefulness of TIP as a brief intervention to improve adherence to depression medication treatment provided in primary care settings.
[Annexin V for flow cytometric detection of phosphatidylserine expression on lymphoma cells undergoing apoptosis].

OBJECTIVE To quantitatively analyze apoptotic and secondary necrotic cells under apoptosis conditions. METHODS The cells of Burkitt lymphoma cell line Raji were incubated with 1.0 mumol/L dexamethasone (DEX) for 2, 4 and 8 h, then stained with Annexin V-FITC (fluorescein isothiocyanate conjugated) which was used to detect the exposure of phosphatidylserine (PS) on the out membrane resulting from a loss of phospholipid asymmetry in the early stage of apoptosis, and also stained with propidium iodide (PI) which allows the analysis of secondary necrotic cells related with cell membrane and DNA damage, then apoptotic cells was quantified by flow cytometry (FMC). Furthermore, Annexin+/PI- and Annexin+/PI+ cells were sorted by fluoresence-activated cell sorter (FACS), and identified by electron microscopy (EM) and DNA gel electrophoresis. RESULTS The results revealed that the percentage of apoptotic cells was increased and correlated well with incubation time (r = 0.97). The sensitivity of this method was shown by its detection limit 0.02%; the method was reproducible, and the coefficient variance (CV) was 4.2%. Meanwhile, the Annexin+/PI- and Annexin+/PI+ cells were identified as apoptotic and necrotic cells under EM, and the DNA extracted from the Annexin+/PI- cells was characterized by "ladder pattern". CONCLUSION Annexin V assay for analyzing apoptotic cells is specific, sensitive, accurate, reproducible and quantitative for apoptosis investigation.
Continuation and Maintenance Use of Antidepressants in Recurrent Depression

Background: Maintenance antidepressant (AD) medication is the most commonly used preventive strategy in a highly recurrent disease, i.e. depression. Little is known about the discontinuation of maintenance AD use and the association with recurrence in daily clinical practice. The purpose was to examine the discontinuation rate of maintenance AD in daily clinical practice in recurrently depressed patients and the associated risk of recurrence. Methods: Prospectively AD maintenance medication and recurrence were examined in 172 euthymic patients with recurrent depression. AD user profiles before recurrence (nonusers, intermittent users, continuous users) were examined and related to recurrence over a 2-year follow-up period. Results: Less than half of the patients (42%) used AD continuously. Taking into account the minimal required adequate used dosage (≧20 mg fluoxetine equivalent), only 26% of the patients used AD as recommended by international guidelines. Despite continuous use of AD, 60.4% relapsed in 2 years. This relapse rate was comparable to the rate of the intermittent users (63.6%). In patients who stopped taking AD after remission and who received additional preventive CT, the recurrence rates were significantly lower than in non-AD-using patients treated with usual care (8 vs. 46%). Conclusions: The majority of recurrently depressed patients treated with AD discontinue maintenance AD therapy in daily primary and secondary clinical practice. AD seems to offer poor protection against relapse in this patient group. Patients who stopped using AD experienced less relapse, especially if they were treated with preventive CT. Alternative maintenance treatments (including preventive cognitive therapy after discontinuation of AD) should be studied in recurrently depressed patients with intermittent good remission, not only in secondary but also in primary care.
Hepatic microsomal cytochrome P450S and chlorinated hydrocarbons in largha and ribbon seals from Hokkaido, Japan: Differential response of seal species to ah receptor agonist exposure

From 16 largha seals (Phoca larghá) and 15 ribbon seals (Phoca fasciata) in the coastal waters of Hokkaido, Japan, blubber chlorinated hydrocarbon (CHC) levels and hepatic cytochrome P450 (CYP) catalytic activities and their immunochemically detected protein content levels were measured. Concentrations of DDTs (2,2‐bis(4‐chlorophenyl)‐1,1‐dichloroethylene, p,p′‐DDE; 2,2‐bis(4‐chlorophenyl)‐1,1‐dichloroethane, p,p′‐DDD; dichlorodiphenyltrichloroethane, p,p′‐DDT), polychlorinated biphenyl congeners (PCBs), and chlordane compounds (oxychlordane, chlordanes, and nonachlors) in both species were in the range of 290 to 5,300, 420 to 4,000, and 130 to 1,500 ng/g lipid weight, respectively. Aryl hydrocarbon receptor (AhR) agonists, non‐ortho (IUPAC 77 and 126) and mono‐ortho (IUPAC 105, 118, and 156) coplanar PCB congeners, were also detected, and the 2,3,7,8‐tetrachlordibenzo‐p‐dioxin (TCDD) toxic equivalents (TEQs) were 4.9 to 120 pg TEQ/g lipid weight. Cross‐reactive proteins with polyclonal antibodies against rat CYP1A1 and CYP3A2 were notably detected in seal liver microsomes. Interestingly, a polyclonal antibody against rat CYP2B1 recognized proteins only at trace levels. In largha seals, both levels of alkoxyresorufin‐ (methoxy‐, ethoxy‐, pentoxy‐, and benzyloxyresorufin) O‐dealkylase (AROD) activities and proteins detected by polyclonal antibodies against rat CYP1A1 were significantly correlated with the concentrations of individual coplanar PCB congeners, total TEQs, and total PCBs. Threshold concentrations for TEQs in blubber of the largha seal to induce hepatic CYP1A protein and EROD activity were estimated to be 8.5 and 19 pg TEQ/g fat weight, respectively. In ribbon seals, similar correlations were not detected, although the TEQ levels were not significantly lower than those in largha seals. These results suggest that AROD activity and CYP1A1 protein in the liver of the largha seal could be a biomarker for the exposure to AhR agonists such as coplanar PCB congeners. This study also indicates differences in AhR‐mediated responses to the CHC exposures between largha and ribbon seals.
EVALUATION OF STATISTICAL TESTS FOR ETHNO-SNP SELECTION

Motivation: SNPs have shown a lot of promises in disease association, personalized medicine, and population classification studies. The completion of International Hapmap Project has facilitated the SNP-based ethnoclassification. Due to the large amount of SNPs in the human genome, it is desirable to find a small set of informative SNPs for the classification task. Previous studies tried to find ethnically related SNPs from all the chromosomes and mitochondria and genotype data are usually treated as numeric data. Here, we focus on two small ethnically related genomic pieces in order to reduce noise. We apply a categorical statistical testing method to find marker SNPs. We evaluate its performance with two non-categorical statistical methods.
Direct Association of Sprouty-related Protein with an EVH1 Domain (SPRED) 1 or SPRED2 with DYRK1A Modifies Substrate/Kinase Interactions*

The mammalian SPRED (Sprouty-related protein with an EVH1 domain) proteins include a family of three members, SPRED1–3. Currently, little is known about their biochemistry. The best described, SPRED1, has been shown to inhibit the Ras/ERK pathway downstream of Ras. All three SPREDs have a cysteine-rich domain (CRD) that has high homology to the CRD of the Sprouty family of proteins, several of which are also Ras/ERK inhibitors. In the belief that binding partners would clarify SPRED function, we assayed for their associated proteins. Here, we describe the direct and endogenous interaction of SPRED1 and SPRED2 with the novel kinase, DYRK1A. DYRK1A has become the subject of recent research focus as it plays a central role in Caenorhabditis elegans oocyte maturation and egg activation, and there is strong evidence that it could be involved in Down syndrome in humans. Both SPRED1 and SPRED2 inhibit the ability of DYRK1A to phosphorylate its substrates, Tau and STAT3. This inhibition occurs via an interaction of the CRD of the SPREDs with the kinase domain of DYRK1A. DYRK1A substrates must bind to the kinase to enable phosphorylation, and SPRED proteins compete for the same binding site to modify this process. Our accumulated evidence indicates that the SPRED proteins are likely physiological modifiers of DYRK1A.
The E3 Ubiquitin Ligase MARCH6 Degrades Squalene Monooxygenase and Affects 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase and the Cholesterol Synthesis Pathway

ABSTRACT The mevalonate pathway is used by cells to produce sterol and nonsterol metabolites and is subject to tight metabolic regulation. We recently reported that squalene monooxygenase (SM), an enzyme controlling a rate-limiting step in cholesterol biosynthesis, is subject to cholesterol-dependent proteasomal degradation. However, the E3-ubiquitin (E3) ligase mediating this effect was not established. Using a candidate approach, we identify the E3 ligase membrane-associated RING finger 6 (MARCH6, also known as TEB4) as the ligase controlling degradation of SM. We find that MARCH6 and SM physically interact, and consistent with MARCH6 acting as an E3 ligase, its overexpression reduces SM abundance in a RING-dependent manner. Reciprocally, knockdown of MARCH6 increases the level of SM protein and prevents its cholesterol-regulated degradation. Additionally, this increases cell-associated SM activity but is unexpectedly accompanied by increased flux upstream of SM. Prompted by this observation, we found that knockdown of MARCH6 also controls the level of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) in hepatocytes and model cell lines. In conclusion, MARCH6 controls abundance of both SM and HMGCR, establishing it as a major regulator of flux through the cholesterol synthesis pathway.
Supralinear Ca2+ Influx into Dendritic Tufts of Layer 2/3 Neocortical Pyramidal Neurons In Vitro and In Vivo

Pyramidal neurons in layer 2/3 of the neocortex are central to cortical circuitry, but the intrinsic properties of their dendrites are poorly understood. Here we study layer 2/3 apical dendrites in parallel experiments in acute brain slices and in anesthetized rats using whole-cell recordings and Ca2+ imaging. We find that backpropagation of action potentials into the dendritic arbor is actively supported by Na+ channels both in vitro and in vivo. Single action potentials evoke substantial Ca2+ influx in the apical trunk but little or none in the dendritic tuft. Supralinear Ca2+ influx is produced in the tuft, however, when an action potential is paired with synaptic input. This dendritic supralinearity enables layer 2/3 neurons to integrate ascending sensory input from layer 4 and associative input to layer 1.
Composite Service Selection Based on Dot Pattern Mining

There are complicated correlations among atomic Web services in a composite service. Considering the influence of such correlations on the quality of composite service is important to do service selection. Now, existing selection approaches don’t consider this issue. Using the idea of division, a dot pattern based composite service selection approach is presented in this paper. The main idea of this approach is that according to the correlation degree of atomic services, dividing the composite service into a series of composite service dots; then regarding the dot as selecting unit to do service selection based on the quality of corresponding dot patterns. Experimental results show that our selection approach can improve the quality of the selected composite service.
Resistance Exercise and Insulin Regulate AS160 and Interaction With 14-3-3 in Human Skeletal Muscle

A single bout of aerobic exercise can enhance insulin action, but whether a similar effect occurs after resistance exercise is unknown. Hyperinsulinemic-euglycemic clamps were performed on eight male subjects at rest and after a single bout and three repeated bouts of resistance exercise over 7 days. Skeletal muscle biopsies were taken before and after the clamp and immediately after a single exercise bout. Whole-body insulin action measured by glucose infusion rate decreased (P < 0.05) after a single exercise bout, whereas in response to repeated bouts of resistance exercise, the glucose infusion rate was similar to the rest trial. In skeletal muscle, Akt substrate of 160 kDa (AS160) phosphorylation, an Akt substrate implicated in the regulation of GLUT4 translocation, and its interaction with 14-3-3 was decreased (P < 0.05) only after a single exercise bout. Insulin increased (P < 0.05) phosphorylation of AS160 and its interaction with 14-3-3, but the insulin response was not influenced by resistance exercise. Phosphorylation of insulin receptor substrate-1 and Akt were similar to changes in AS160 phosphorylation after exercise and/or insulin. In conclusion, a single bout of resistance exercise impairs whole-body insulin action. Regulation of AS160 and interaction with 14-3-3 in skeletal muscle are influenced by resistance exercise and insulin but do not fully explain the effect of resistance exercise on whole-body insulin action.
Regulation of human aldoketoreductase 1C3 (AKR1C3) gene expression in the adipose tissue

Aldoketoreductase 1C3 (AKR1C3) is a functional prostaglandin F synthase and a negative modulator of the availability of ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ). AKR1C3 expression is known to be associated with adiposity, one of the components of the metabolic syndrome. The aim of this study was to characterize the expression of AKR1C3 in the adipose tissue and adipocytes and to investigate its potential role in the metabolic syndrome. Using microarray analysis and realtime PCR, we studied the expression of AKR1C3 in adipose tissue samples from obese subjects with or without metabolic complications, during very low calorie diet-induced weight loss, and its expression in isolated human adipocytes of different sizes. The adipose tissue AKR1C3 expression levels were marginally lower in obese subjects with the metabolic syndrome compared with the levels in healthy obese subjects when analyzed using microarray (p = 0.078) and realtime PCR (p < 0.05), suggesting a secondary or compensatory effect. The adipose tissue mRNA levels of AKR1C3 were reduced during and after dietinduced weight-loss compared to the levels before the start of the diet (p < 0.001 at all time-points). The gene expression of AKR1C3 correlated with both adipose tissue mRNA levels and serum levels of leptin before the start of the diet (p < 0.05 and p < 0.01, respectively). Furthermore, large adipocytes displayed a higher expression of AKR1C3 than small adipocytes (1.5-fold, p < 0.01). In conclusion, adipose tissue AKR1C3 expression may be affected by metabolic disease, and its levels are significantly reduced in response to dietinduced weight loss and correlate with leptin levels.