Miracle-dz/UniFAR-FTUs huggingface dataset:
Auxin Responses in Mutants of the Arabidopsis CONSTITUTIVE PHOTOMORPHOGENIC9 Signalosome1[C][W][OA]

The CONSTITUTIVE PHOTOMORPHOGENIC9 (COP9) signalosome (CSN) is an evolutionarily conserved multiprotein complex that interacts with cullin-RING type E3 ubiquitin ligases (CRLs). CSN subunit 5 (CSN5), which, when incorporated into CSN, can deconjugate the NEDD8 modification from the cullin subunit of CRLs, is essential for CSN's role in controlling CRL activity. Whether the CSN5 monomer, which is maintained in csn mutants such as csn3 or csn4, has a functional role, remains to be established. We performed a comparative gene expression-profiling experiment with Arabidopsis (Arabidopsis thaliana) csn3, csn4, and csn5 mutants, and we show here that these mutants cannot be distinguished at the transcriptional level. Furthermore, we show that csn3 csn5 mutants are morphologically indistinguishable from csn3 or csn5 mutants. Taken together, these data suggest that the CSN5 monomer does not have a function that leads to transcriptional or morphological changes in the csn mutants. We further examined auxin responses in csn mutants. Whereas CSN had previously been shown to be required for the auxin response-regulatory E3 complexes, specifically SCFTIR1, the csn mutant phenotype suggests that CSN is not essential for auxin responses. We present physiological and genetic data that indicate that auxin responses are indeed only partially impaired in csn mutants and that this is not the result of maternally contributed CSN. Finally, we discuss these findings in the context of the current understanding of the role of neddylation and CSN-mediated deneddylation for CRL activity.
On Convergence Rates of Linearized Proximal Algorithms for Convex Composite Optimization with Applications

In the present paper, we investigate a linearized proximal algorithm (LPA) for solving a convex composite optimization problem. Each iteration of the LPA is a proximal minimization of the convex composite function with the inner function being linearized at the current iterate. The LPA has the attractive computational advantage that the solution of each subproblem is a singleton, which avoids the difficulty as in the Gauss--Newton method (GNM) of finding a solution with minimum norm among the set of minima of its subproblem, while still maintaining the same local convergence rate as that of the GNM. Under the assumptions of local weak sharp minima of order $p$ ($p \in [1,2]$) and a quasi-regularity condition, we establish a local superlinear convergence rate for the LPA. We also propose a globalization strategy for the LPA based on a backtracking line-search and an inexact version of the LPA. We further apply the LPA to solve a (possibly nonconvex) feasibility problem, as well as a sensor network localiza.
Community‐acquired bacteremic pneumococcal pneumonia in children: diagnosis and serotyping by real‐time polymerase chain reaction using blood samples.

BACKGROUND The aim of this study was to use real-time polymerase chain reaction (RT-PCR) on blood samples to diagnose and serotype pneumococcal infection in a large cohort of Italian children hospitalized for community-acquired pneumonia. METHODS We conducted an observational study from April 2007 through June 2009 of children aged 0-16 years with a diagnosis of community-acquired pneumonia admitted to 83 pediatric hospitals in Italy. RESULTS Seven hundred fifty-three children were studied. RT-PCR found pneumococcal infection in 80 (10.6%) of 753 patients. In 292 patients, culture and RT-PCR were simultaneously performed. Streptococcus pneumoniae was identified in 47 of 292 patients; 45 (15.4%) tested positive by RT-PCR and 11 (3.8%) tested positive by culture. RT-PCR was significantly more sensitive than culture in revealing bacteremic pneumonia (odds ratio, 30.6; 95% confidence interval, 5.8-97.5; P<.001). Complicated pneumonia was found in 162 (21.5%) of 753 children; 152 (93.8%) of these 162 had parapneumonic effusion, and 51 (33.6%) had empyema. Children with complicated pneumonia were significantly older. Pneumococcal bacteremia was found by RT-PCR to occur significantly more frequently in children with complications (38 [23.5%] of 162) than in children with uncomplicated pneumonia (44 [7.4%] of 591; odds ratio, 3.8; 95% confidence interval, 2.30-6.30; P<.001). RT-PCR allowed serotyping from blood in 92.5% of patients. More than two-thirds of the pneumonia cases were due to nonpneumococcal conjugate vaccine 7 serotypes. Serotype 1 was the most frequent serotype (26 [32.5%] of 80) and was significantly associated with complications (50.0% in patients with complicated pneumonia vs 18.2% in patients with uncomplicated pneumonia; odds ratio, 4.5, 95% confidence interval, 1.48-14.03; P=.005) and older age. Serotype 19A was second in frequency (15.0%) and was significantly associated with younger age. CONCLUSIONS RT-PCR allows diagnosis and serotyping of pneumococcal bacteremic community-acquired pneumonia in children and is an important tool for evaluating serotype distribution in culture-negative samples.
High dose Intravenous Anti-D Immune Globulin is More Effective and Safe in Indian Paediatric Patients of Immune Thrombocytopenic Purpura.

INTRODUCTION Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. AIM To compare the safety and efficacy of higher dose (75μg/kg) intravenous Anti-D immune globulin against the standard dose of 50μg/kg for the management of ITP in Indian patients. MATERIALS AND METHODS One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50μg/kg (standard dose) or 75μg /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. RESULTS Seventy one out of 84 patients treated with Anti-D at 75μg/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50μg/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. CONCLUSION A 75μg/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50μg dose for treatment of newly diagnosed Indian patients of ITP.
Big Science

The Central Question of Medicine Staring at landscapes made of pill containers amidst mountains of paperwork, patients contemplate their troubling present and their uncertain future. What is best for me? What is best for my family? At least 3 challenges await those seeking an answer to this central question of medicine. The first challenge results from the paucity of trustworthy comparative effectiveness research that directly addresses patient dilemmas. The second challenge relates to what each person values and would consider best for their own situation. Fitting treatments within the context of each person’s life is the third challenge. Ongoing treatments, to work, have to fit into people’s daily routines, weaving seamlessly and constantly into their day-today activities. It is hard to predict how a new intervention will interact with the existing care plan, and how the care plan will work with each day’s plan. Clinicians cannot discover patient values, preferences, and contexts without interacting meaningfully with patients. To find what is best, clinicians must partner with patients to think, talk, and feel through their situation, use the best research evidence, and craft together the best treatment plan while minimally disrupting their lives. What sort of evidence enterprise can support that work? Here, I propose that the evidence necessary to support patientcentered care requires a fundamental change in the culture of research. Finding what is best for patients requires generous collaboration for Big Science.
Dialectical behavior therapy for borderline personality disorder: theoretical and empirical foundations

Dialectical behavior therapy (DBT) is a cognitive‐behavioral psychotherapy developed by Linehan for parasuicidal patients with a diagnosis of borderline personality disorder (BPD). DBT is based on a biosocial theory that views BPD as primarily a dysfunction of the emotion regulation system. The treatment is organized around a hierarchy of behavioral goals that vary in different modes of therapy. In two randomized trials, DBT has shown superiority in reducing para‐suicide, medical risk of parasuicides, number of hospital days, dropout from treatment and anger while improving social adjustment. Most gains were maintained through a 1‐year follow‐up. In one process study testing DBT theory, dialectical techniques balancing acceptance and change were more effective than pure change or acceptance techniques in reducing suicidal behavior.
Analysis and Decomposition in Frege and Russell

Michael Dummett has long argued that Frege is committed to recognizing a distinction between two sorts of analysis of propositional contents: ‘analysis’, which reveals the entities that one must grasp in order to apprehend a given propositional content; and ‘decomposition’, which is used in recognizing the validity of certain inferences. Whereas any propositional content admits of a unique ultimate ‘analysis’ into simple constituents, it also admits of distinct ‘decompositions’, no one of which is ultimately privileged over the others. I argue that although Russell accepts this distinction between analysis and decomposition, Frege does not. In particular, I consider claims which Dummett makes regarding how ‘analysis’ and ‘decomposition’ are related to two different models Frege at least suggests in discussing the composition of thoughts, the part/whole model and the function/argument model; and I argue that in each case, while Russell accepts views which Dummett attributes to Frege, Frege does not.
High serum level of the soluble form of CD30 molecule in the early phase of HIV‐1 infection as an independent predictor of progression to AIDS

ObjectiveTo determine the serum levels of the soluble form of the CD30 (sCD30) activation molecule in the early phase of HIV-1 infection, and to investigate the possible correlation with evolution to AIDS. MethodssCD30 values were determined by an enzyme-linked immunosorbent assay (ELISA) on serum samples collected at the time of the first evidence of HIV-1 infection in 110 individuals with a median follow-up of 56 months (range, 12–88 months), at the A1 (74 cases) or A2 (36 cases) stages of the 1993 revised Centers for Disease Control and Prevention classification. The data were evaluated using established clinical and immunological parameters, including circulating CD4+ T-cell count. The controls were 110 blood donors and 51 HIV-1 -negative subjects belonging to groups at risk for HIV-1 infection. ResultsElevated sCD30 levels ( 20 U/ml) were found in 83.6% of HIV-1 -infected cases and in 47% of at-risk seronegatives. Data analysis revealed that HIV-1-infected patients with higher sCD30 levels (>35 U/ml) experienced faster disease progression (P = 0.0002). This was also the case in patients at the earliest stage (A1) of HIV infection (P = 0.0027). In these latter cases the predictive value of sCD30 was independent of the initial absolute number of circulating CD4+lymphocytes. ConclusionsSerum levels of sCD30 are increased in the large majority of patients in the early phase of HIV-1 infection and represent an indicator of progression to AIDS independent of other prognostic parameters.
Relation of Serotonin Transporter Genetic Variation to Efficacy of Escitalopram for Generalized Anxiety Disorder in Older Adults

Objective: Generalized anxiety disorder (GAD) is common in older adults and can be treated with selective serotonin reuptake inhibitors (SSRIs). Genetic variation in the serotonin transporter gene promoter region is posited to be associated with SSRI efficacy: 2 polymorphisms (5-HTTLPR S/L and rs25531 g/a) form a haplotype with the La combination having higher transcription activity than other haplotypes. We hypothesized that GAD patients with no La haplotypes (La−) have lower SSRI treatment efficacy than those with 1 to 2 La haplotypes (La+). Method: The study enrolled subjects aged 60 years or older with a principal diagnosis of GAD into a 12-week, randomized trial of escitalopram versus placebo. One hundred fifty subjects were genotyped for the serotonin transporter promoter region haplotype and were divided into La− and La+ genotype groups; the primary analyses were done in European Americans only (n = 125; n = 59 with escitalopram and n = 66 with placebo). Results: Escitalopram had no efficacy in the La− group versus moderate efficacy in the La+ group. This genetic moderation of SSRI efficacy was due to a higher placebo response in La− subjects, compared with La+ subjects. Drug concentration did not affect the genetic results. Exploratory analyses suggest that La− subjects had greater variability of anxiety symptoms unrelated to treatment. Conclusions: The serotonin transporter promoter haplotype is associated with variability in SSRI efficacy for late-life GAD. The variability may result from a genetic effect on anxiety symptom variability unrelated to treatment, rather than a pharmacodynamic effect that has been previously assumed. Further research is needed to understand the pharmacogenetic mechanism of this haplotype.
Mck1, a member of the glycogen synthase kinase 3 family of protein kinases, is a negative regulator of pyruvate kinase in the yeast Saccharomyces cerevisiae

An interaction between the Saccharomyces cerevisiae protein kinase Mck1 and pyruvate kinase (Pyk1) was detected by using the two-hybrid method. Purified Mck1 was able to phosphorylate purified Pyk1 on Ser in vitro. Pyruvate kinase activity was elevated in mck1 delta cells. Several of the phenotypes of mck1 delta mutants are similar to those observed in cells overexpressing PYK1. Co-overexpression of MCK1 suppressed all of the phenotypes associated with PYK1 overexpression. These results indicate that Mck1 negatively regulates pyruvate kinase activity, possibly by direct phosphorylation.
Attenuation of Blood Flow Pulsatility along the Atlas Slope: A Physiologic Property of the Distal Vertebral Artery?

BACKGROUND AND PURPOSE: Physiologic and pathologic arterial tortuosity may attenuate blood flow pulsatility. The aim of this prospective study was to assess a potential effect of the curved V3 segment (Atlas slope) of the vertebral artery on arterial flow pulsatility. The pulsatility index and resistance index were used to assess blood flow pulsatility. MATERIALS AND METHODS: Twenty-one healthy volunteers (17 men, 4 women; mean age, 32 years) were examined with a 3T MR imaging system. Blood velocities were measured at 2 locations below (I and II) and at 1 location above the V3 segment (III) of the vertebral artery by using a high-resolution 2D-phase-contrast sequence with multidirectional velocity-encoding. RESULTS: Pulsatility and resistance indices decreased along all measurement locations from proximal to distal. The pulsatility index decreased significantly from location II to III and from I to II. However, the decrease was more pronounced along the Atlas slope than in the straight-vessel section below. The decrease of the resistance index was highly significant along the Atlas slope (location II to III). The decrease from location I to II was small and not significant. CONCLUSIONS: The pronounced decrease in pulsatility and resistance indices along the interindividually uniformly bent V3 segment compared with a straight segment of the vertebral artery indicates a physiologic attenuating effect of the Atlas slope on arterial flow pulsatility. A similar effect has been described for the carotid siphon. A physiologic reduction of pulsatility in brain-supplying arteries would be in accordance with several recent publications reporting a correlation of increased arterial flow pulsatility with leukoencephalopathy and lacunar stroke.
The Unc-119 Family of Neural Proteins is Functionally Conserved Between Humans, Drosophila and C. Elegans

C. elegans animals mutant for the unc-119 gene exhibit movement, sensory and behavioral abnormalities. Consistent with a nervous system role, unc-119 reporter genes are expressed throughout the C. elegans nervous system. The UNC-119 protein has strong sequence similarity to the predicted protein from a human gene, HRG4/HsUNC-119, whose transcript is abundant in the retina. Using these similarities, we have identified a Drosphila homolog, DmUNC-119, which is expressed in the Drosophila nervous system. The predicted C. elegans, human and Drosophila gene products are conserved across two domains. Expression of portions of HRG4/HsUNC-119 or DmUNC-119, directed by the unc-119 promoter, can fully rescue the C. elegans unc-119 mutant phenotype. We tested the ability of portions of HRG4/HsUNC-119 to rescue, and found that its function in C. elegans requires the conserved carboxyl terminus, while the dissimilar amino terminus is dispensable. UNC-119, HRG4 and DmUNC-119 constitute members of a new class of neural genes whose common function has been maintained through metazoan evolution.
Unusually High Frequency MHC Class I Alleles in Mauritian Origin Cynomolgus Macaques

Acute shortages of Indian origin Rhesus macaques significantly hinder HIV/AIDS research. Cellular immune responses are particularly difficult to study because only a subset of animals possess MHC class I (MHC I) alleles with defined peptide-binding specificities. To expand the pool of nonhuman primates suitable for studies of cellular immunity, we defined 66 MHC I alleles in Cynomolgus macaques (Macaca fascicularis) of Chinese, Vietnamese, and Mauritian origin. Most MHC I alleles were found only in animals from a single geographic origin, suggesting that Cynomolgus macaques from different origins are not interchangeable in studies of cellular immunity. Animals from Mauritius may be particularly valuable because >50% of these Cynomolgus macaques share the MHC class I allele combination Mafa-B*430101, Mafa-B*440101, and Mafa-B*460101. The increased MHC I allele sharing of Mauritian origin Cynomolgus macaques may dramatically reduce the overall number of animals needed to study cellular immune responses in nonhuman primates while simultaneously reducing the confounding effects of genetic heterogeneity in HIV/AIDS research.
Performance of Children with Attention Deficit Hyperactivity Disorder (ADHD) on a Test Battery of Impulsiveness

Children with ADHD were compared to healthy controls on a task battery of cognitive control, measuring motor inhibition (Go/No-Go and Stop tasks), cognitive inhibition (motor Stroop and Switch tasks), sustained attention and time discrimination. Children with ADHD showed an inconsistent and premature response style across all 6 tasks. In addition they showed task-specific impairments in measures of sustained attention, time discrimination, and motor inhibition, but spared cognitive inhibition. Measures of impairment correlated with behavioral hyperactivity and with each other, suggesting that they measure interrelated aspects of a multifaceted construct of cognitive impulsiveness. The task battery as a whole showed 76% correct discrimination of cases and controls.
Depression after smoking cessation: case reports.

BACKGROUND Cigarette smokers with a history of major depression are at risk for developing depressive mood when they attempt cessation. Whether cessation can also provoke more severe depressions, however, has not been well documented. METHOD Six case reports of severe depressive episodes after smoking cessation are described. RESULTS Four cases occurred among smokers with a history of major depression but who were not depressed at the time of cessation. Two cases involved smokers with no previous history of major depression. Variability in both the timing and the outcome of the postcessation depressions was observed. CONCLUSION The risk that depressive states may emerge or be exacerbated after smoking cessation, particularly in patients with a history of major depression, must be kept in mind in the treatment of nicotine dependence.
Melatonin‐induced autophagy is associated with degradation of MyoD protein in C2C12 myoblast cells

Abstract: MyoD is a muscle‐specific transcriptional factor that acts as a master switch for skeletal muscle differentiation. This protein regulates myoblast proliferation and myogenic differentiation and is also a short‐lived regulatory protein that is degraded by the ubiquitin system. However, the lysosomal pathway of MyoD protein degradation remains unknown. In this study, we sought to determine whether melatonin (1, 2 mm)‐induced autophagy causes the degradation of MyoD protein in C2C12 myoblast cells. Melatonin induced a significant increase in expression of the microtubule‐associated protein 1 light chain 3 (LC3)‐II and Beclin‐1 proteins in a dose‐dependent manner. Melatonin treatment also significantly increased p‐ERK, Ras, and p‐Akt expressions in a dose‐dependent manner. However, Bax expression was high compared with the absence of melatonin treatment, and Bcl‐2 expression was high in the 0.1–0.5 mm melatonin treatments and low in the 1 and 2 mm melatonin treatments. Under the same conditions, cytosolic MyoD protein was significantly decreased in a dose‐dependent manner and completely eliminated by 36 hr. This decrease in MyoD protein involved ubiquitin‐mediated proteasomal activity with proteasome inhibitor MG132 or autophagy‐dependent lysosomal degradation with lysosomal inhibitor bafilomycin A1 (Baf‐A1). In the same condition, phosphorylation of the mammalian target of rapamycin, p‐mTOR, and p‐S6K expression with Baf‐A1 or Baf‐A1‐plus melatonin treatment were significantly decreased compared with the levels after treatment with melatonin only. Together, these results suggest that melatonin (1, 2 mm)‐induced autophagy results in partial lysosomal degradation of MyoD protein in C2C12 myoblast cells.
Higher IGFBP3 is associated with increased incidence of colorectal cancer in older men independently of IGF1

Insulin‐like growth factor 1 (IGF1) has anabolic and growth‐promoting effects, raising concerns regarding its potential to promote tumour growth. Circulating IGF1 is bound to binding proteins, which modulate bioavailability of IGF1. This study assessed the associations of IGF1 and its binding proteins 1 (IGFBP1) and 3 (IGFBP3) with cancer risk.