Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel mechanism of transcriptional repression of p27kip1 through Notch/HRT2 signaling in vascular smooth muscle cells

Summary Vascular smooth muscle cell (VSMC) proliferation occurs in vascular obstructive events such as atherosclerosis and restenosis. We previously showed that Notch receptors are induced in smooth muscle cells during vascular remodeling. Our goal was to determine the mechanisms employed by Notch signaling to regulate proliferation. Activation of Notch1 and Notch4 induced the VSMC-selective target genes HRT1 and HRT2, promoted cell cycle transit in smooth muscle cells, and led to loss of density-dependent growth inhibition. This was associated with a reduction in levels of the cyclin-dependent kinase inhibitor (cdk) p27kip1.Over-expression of p27 kip1 resulted in a dose-dependent rescue of the Notch-induced phenotype and exit from the cell cycle. In addition, HRT2 expression was sufficient to promote S-phase entry, and we demonstrate that HRT2 interacts directly with the p27 kip1 promoter to repress transcription. Transcriptional repression occurred within the ∼774bp minimal p27kip1 promoter region and mutational analysis demonstrated that repression is largely dependent on a conserved class-C domain. Our data show that Notch signaling acts to promote a proliferative phenotype in VSMC by modulation of the G1/S-phase checkpoint. In addition, we define a novel mechanism by which the Notch effector, HRT2, interacts directly with the class-C domain of the p27kip1 promoter, repressing its expression. These studies identify a novel transcriptional target of HRT2, and show that Notch effectors directly control cell cycle regulatory components. We suggest that this mechanism is relevant to hyperproliferative states in VSMC seen during vascular remodeling and repair.
Characteristics of emergency room patients that predict hospitalization or disposition to alternative treatments.

OBJECTIVE The purpose of the study was to identify variables that predicted three different dispositions of patients seen in a psychiatric emergency room: hospitalization, an emergency housing program, and an outpatient crisis program. METHODS Social, psychiatric, demographic, and vocational characteristics of 50 patients in each disposition group were examined to learn whether they varied sufficiently to explain the different dispositions. RESULTS Patients in the hospitalized group were most psychologically impaired and those in the crisis program group least impaired. Patients referred to emergency housing were more moderately impaired but not always significantly different in impairment from hospitalized patients. Discriminant analysis yielded a model of 11 variables whose combined effect accounted for 79 percent of the variance. Psychiatric determinants were the most important predictors, although social, vocational, and demographic variables were also significant. Using these predictors, 76 percent of the original sample and 63 percent of a cross-validation sample were correctly classified by disposition group. CONCLUSIONS The results confirmed the importance of psychiatric determinants in the dispositional process. The similarity between hospitalized patients and those assigned to emergency housing suggests that some hospitalized patients would be good candidates for alternative treatment.
Different effect of hyperglycemia on stroke outcome in non-diabetic and diabetic patients — a cohort study

Abstract Objectives: Relationship between hyperglycemia and stroke outcome is unclear, partly due to the small sample size in most studies, and partly due to lack of consensus concerning the cutoff level for hyperglycemia. Methods: In a cohort study, we investigated whether on-admission hyperglycemia is an independent predictor for 30-day case fatality by analyzing data of 2496 consecutive computed tomography (CT) verified acute ischemic stroke patients (2077 non-diabetic and 419 diabetic) included in the prospective, hospital-based Debrecen Stroke Database. Instead of using an arbitrary cutoff level for hyperglycemia, quartiles of on-admission glucose level were used for Kaplan–Meier survival curves and Cox proportional hazard modeling. Results: The four quartiles of serum glucose level were in the range as follows: <5·2 mmol/l, 5·201–6·1 mmol/l, 6·101–7·5 mmol/l, and >7·501 mmol/l (n = 664, 618, 597, and 617, respectively). Among all 2496 participants, the adjusted hazard ratios for death increased with each quartile of admission glucose 1·96 [95% confidence interval (CI): 1·07–3·60; P = 0·03], 1·56 (95% CI: 0·83–2·94; P = 0·17), and 3·04 (95% CI: 1·70–5·44; P<0·0001) for the second, third, and fourth quartiles, respectively). Upon stratification with respect to diabetes, we found similarly high risk for poor outcome among non-diabetic patients, while the risk was considerably lower among diabetic patients. Discussion: These data suggest that even mild elevation of on-admission glucose levels is an independent predictor of 30-day case fatality. So, we propose that the ideal target blood glucose level is lower for non-diabetic than diabetic patients.
Overlap and specificity of genetic and environmental influences on mathematics and reading disability in 10-year-old twins.

BACKGROUND To what extent do genetic and environmental influences on reading disability overlap with those on mathematics disability? Multivariate genetic research on the normal range of variation in unselected samples has led to a Generalist Genes Hypothesis which posits that the same genes largely affect individual differences in these abilities in the normal range. However, little is known about the etiology of co-morbidity for the disability extremes of reading and mathematics. METHOD From 2596 pairs of 10-year-old monozygotic and dizygotic twins assessed on a web-based battery of reading and mathematics tests, we selected the lowest 15% on reading and on mathematics. We conducted bivariate DeFries-Fulker (DF) extremes analyses to assess overlap and specificity of genetic and environmental influences on reading and mathematics disability defined by a 15% cut-off. RESULTS Both reading and mathematics disability are moderately heritable (47% and 43%, respectively) and show only modest shared environmental influence (16% and 20%). There is substantial phenotypic co-morbidity between reading and mathematics disability. Bivariate DF extremes analyses yielded a genetic correlation of . 67 between reading disability and mathematics disability, suggesting that they are affected largely by the same genetic factors. The shared environmental correlation is . 96 and the non-shared environmental correlation is . 08. CONCLUSIONS In line with the Generalist Genes Hypothesis, the same set of generalist genes largely affects mathematical and reading disabilities. The dissociation between the disabilities occurs largely due to independent non-shared environmental influences.
Seasonal variation in fitness variables in professional soccer players.

BACKGROUND There have been many studies on soccer, but few evaluations of the physiological function of professional soccer players. The aim of this work was to evaluate seasonal variation--from September to February--in anthropometric and physiological variables in a Spanish professional soccer team (n=15). METHODS Anthropometric measurements were obtained following the standardised techniques adopted by the International Society for the Advancement of Kinanthropometry (ISAK). A maximal treadmill test with breath-by-breath gas analysis was carried out to evaluate the aerobic condition and a Jump test was used to measure muscle performance and strength in the lower limbs. RESULTS There were no significant variations in body mass, although a statistically significant decrease (p<0.05) in fat percentage and sum of six skinfolds was observed. The somatotype (Heath-Carter) was mesomorphic without any change observed throughout the season. The mean VO2max in the first test (65.5 ml x kg(-1) x min(-1)) had not changed by the second one (66.4 ml x kg(-1) x min(-1)). There were no significant differences in maximal heart rate (185 vs 185 beats x min(-1)) and treadmill speed at VO2max (16.1 vs 15.8 km x h(-1)). At the anaerobic threshold, there were significant differences (p<0.05) in speed (12.4 vs 13.1 km x h(-1)) and heart rate (164 vs 168 beats x min(-1)) as the season progressed. When the data were expressed as a percentage of maximal values obtained, we observed that the speed in the first test was 77 and 83% in the second test. For heart rate, values were 89 and 91%, and for oxygen uptake 77 and 79%. The Jump test did not show any significant change during the season. CONCLUSIONS We can conclude from these results that professional soccer players have good fitness from the beginning of the Spanish League--with a high VO2max--and the changes observed depend on the initial values.
Phosphotyrosines 627 and 659 of Gab1 Constitute a Bisphosphoryl Tyrosine-based Activation Motif (BTAM) Conferring Binding and Activation of SHP2*

A major Grb2-associated binder-1 (Gab1) binding partner in epidermal growth factor (EGF)-stimulated cells is protein-tyrosine phosphatase (PTPase) SHP2, which contains tandem SH2 domains. The SHP2 PTPase activity is required for activation of the extracellular signal-regulated kinase (ERK) subfamily of mitogen-activated protein (MAP) kinase by EGF. To investigate the mechanism by which Gab1 and SHP2 mediate ERK activation, we characterized the Gab1-SHP2 interaction. We found that both Tyr-627 and Tyr-659 of Gab1 were required for SHP2 binding to Gab1 and for ERK2 activation by EGF. Far Western blot analysis suggested that the tandem SH2 domains of SHP2 bind to Gab1 in a specific orientation, in which the N-SH2 domain binds to phosphotyrosine (Tyr(P))-627 and the C-SH2 domain binds to Tyr(P)-659. When assayed with peptide substrates, SHP2 PTPase was activated by a bisphosphopeptide containing both Tyr(P)-627 and Tyr(P)-659, but not by monophosphopeptides containing Tyr(P)-627 or Tyr(P)-659 or a mixture of these monophosphopeptides. These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2. Remarkably, while a constitutively active SHP2 (SHP2ΔN) could not rescue the defect of a SHP2-binding defective Gab1 (Gab1FF) in ERK2 activation, expression of a Gab1FF-SHP2ΔN chimera resulted in constitutive activation of ERK2 in transfected cells. Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. Consistently, substrate-trapping experiments with a SHP2 catalytic inactive mutant suggested that Gab1 was a SHP2 PTPase substrate in the cells. Therefore, Gab1 not only is a SHP2 activator but also is a target of its PTPase.
Expressive Talking Among Caregivers of Hematopoietic Stem Cell Transplant Survivors: Acceptability and Concurrent Subjective, Objective, and Physiologic Indicators of Emotion

This study sought to examine the effects of an expressive talking intervention for 58 caregiving partners of hematopoietic stem cell transplant survivors, persons known to experience distress. Caregivers were randomly assigned to a three-session emotional expression (EE) or control condition. Subjective, objective, and physiologic indicators of emotion were assessed. Relative to controls, EE participants experienced more negative emotion, uttered more negative emotion words, and perceived the exercises as more helpful and meaningful. The trajectory of skin conductance and the use of cognitive mechanism words increased across EE sessions, suggesting sustained emotional engagement. Future research is warranted to determine the optimal dose and timing of EE for this population.
Intensive rehabilitation of emotionally distressed patients after coronary by‐pass grafting

Abstract. Perski A, Osuchowski K, Andersson L, Sanden Å, Feleke E, Anderson G (Karolinska Institute and Hospital of the National Social Insurance Board, Nynäshamn, Sweden). Intensive rehabilitation of emotionally distressed patients after coronary by‐pass grafting. J Intern Med 1999; 246: 253–263.
Mechanical properties of xenogeneic small-intestinal submucosa when used as an aortic graft in the dog.

Small-intestinal submucosa (SIS) has been shown to induce tissue remodelling in vivo when used as a vascular graft. The present study investigated in physical and mechanical properties of remodeled aortic grafts derived from xenogeneic SIS material. Eight infrarenal aortic grafts were implanted in mongrel dogs. The grafts were explanted at 1 or 2 months and tested for compliance and hoop mechanical properties. The morphologic changes within the grafts were also characterized. The remodeling process produced graft structures which were significantly stronger than both the normal artery (P = .012) and the original SIS graft (P = .0001), and the compliance of these structures was one third that of normal artery and similar to the original SIS grafts. The remodeled grafts were > 10 times the thickness of the implanted SIS. Immunohistochemical analysis of remodeled tissues suggest that the SIS material was degraded and resorbed over time. The remodeling process transformed a material which was physically and mechanically quite different from normal aorta into a blood conduit which had the physical and mechanical properties needed to function in this mammalian arterial system.
Association between the vasa vasorum and the atherosclerotic changes in cardiac allograft vasculopathy: volumetric analysis.

AIMS The current study was designed to test that vasa vasorum (VV) plays a role in the progression of cardiac allograft vasculopathy (CAV) in patients with heart transplantation (HTX). METHODS AND RESULTS Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) were performed in the left anterior descending artery in 19 segments of 19 HTX patients (median 2.1 years from HTX). Each segment is composed of both the continuous lesions: (i) CAV area: intimal thickness >0.5 mm with 5 mm length and (ii) VV area: intimal thickness ≤0.5 mm with 5 mm length. The per cent VV volume (VV volume/vessel volume × 100, %VV) was evaluated in the VV area with OCT (in CAV area VV cannot be assessed because of limited penetration power of OCT). A year later, the association between the baseline %VV and the change in per cent plaque volume (plaque volume/vessel volume × 100, %PV) was evaluated with IVUS. To a normal distribution, Δ%PV (follow-up %PV-initial %PV) was undergone square root transformation. The correlations between the %VV at baseline study and square root-Δ%PV were significant both in the CAV area and in the VV area (r = 0.787, P < 0.001 and r = 0.701, P < 0.001, respectively). In multivariable analysis, only the %VV was significantly correlated with square root-Δ%PV in both areas. CONCLUSION The current study demonstrated a significant association between the VV volume and the progression of plaque volume in both the CAV area and the VV area. Thus, VV may be a potential predictor and possible therapeutic target to attenuate CAV.
N‐glycosylation proteomic characterization and cross‐species comparison of milk fat globule membrane proteins from mammals

Glycosylation of proteins has been implicated in various biological functions and has received much attention; however, glycoprotein components and inter‐species complexity have not yet been elucidated fully in milk proteins. N‐linked glycosylation sites and glycoproteins in milk fat globule membrane (MFGM) fractions were investigated by combining N‐glycosylated peptides enrichment and high‐accuracy Q Exactive identification, to map the N‐glycoproteome profiles in Holstein and Jersey cows, buffaloes, yaks, goats, camels, horses, and humans. A total of 399 N‐glycoproteins with 677 glycosylation sites were identified in the MFGM fractions of the studied mammals. Most glycosylation sites in humans were classified as known and those in the other studied mammals as unknown, according to Swiss‐Prot annotations. Functionally, most of the identified glycoproteins were associated with the ‘response to stimulus’ GO category. N‐glycosylated protein components of MFGM fractions from Holstein and Jersey cows, buffaloes, yaks, and goats were more similar to each other compared with those of camels, horses and human. The findings increased the number of known N‐glycosylation sites in the milk from dairy animal species, revealed the complexity of the MFGM glycoproteome, and provided useful information to further explore the mechanism of MFGM glycoproteins biosynthesis among the studied mammals.
Adiponectin receptor and adiponectin signaling in human tissue among patients with end-stage renal disease.

BACKGROUND Adiponectin plasma levels in chronic kidney disease (CKD) are two to three times higher than in individuals with normal kidney function. Despite adiponectin's anti-diabetic, anti-inflammatory and anti-atherogenic properties, patients with CKD have insulin resistance, systemic inflammation and accelerated atherogenesis. Hence, although adiponectin production is increased by adipose tissue in end-stage renal disease (ESRD), it is unclear if its effects on metabolism remain intact. METHODS To determine if there is adiponectin resistance in ESRD, we measured tissue levels of adiponectin receptor-1 (AdipoR1) and adiponectin downstream effectors in ESRD patients compared with normal kidney function controls. Blood and tissue samples were obtained from participants at the time of kidney transplantation or kidney donation. A follow-up blood sample was obtained 3-6 months after transplantation. RESULTS AdipoR1 was higher in muscle and peripheral blood mononuclear cells collected from ESRD patients. There was also a nonsignificant increase in AdipoR1 in visceral fat of ESRD compared with controls. Compared with controls, phosphorylation of the adiponectin downstream effector adenosine monophosphate-activated protein kinase (AMPK) was higher in ESRD while acetyl-CoA carboxylase phosphorylation (ACC-P) and carnitine palmitoyl transferase-1 (CPT-1) levels were lower. In vitro, exposure of C2C12 cells to uremic serum resulted in upregulation of AdipoR1 and increased phosphorylation of AMPK but decreased ACC-P and CPT-1 expression. CONCLUSION Both our in vivo and in vitro observations indicate that uremia results in upregulation of AdipoR1 but adiponectin resistance at the post-receptor level.
Evolution of Ethics in Clinical Research and Ethics Committee

Ethics are the moral values of human behavior and the principles which govern these values. The situation becomes challenging for a doctor when he assumes the role of researcher. The doctor-researcher has to serve both the roles and at times the zeal of an investigator has the potential to cloud the morality of the physician inside. It is very important to realize that exploiting the faith of patients is an offence that tantamount to a crime. Medical science is one discipline where the advancement of knowledge is hugely guided by research and mankind has benefitted from many experiments. However benefit and risk are the two faces of the same coin. Various unethical human experiments made us realize that the whims of researchers need to be reined and led to the evolution of the first guidelines for researcher, the Nuremberg code. Thereafter the Good Clinical Practice guidelines serve as the guiding doctrine of clinical research. The principles of ethics rest on the four pillars of autonomy, beneficence, justice, non-maleficence and recently two more pillars are added which includes, confidentiality and honesty. Ethics committees serve as a guardian of these principles. The multidisciplinary Ethics Committee ensures a competent review of the ethical aspects of the project proposal submitted and does it free from any bias or external influence. Ethical review of clinical trial applications follows a decentralized process in India, and requires Ethics Committee approval for each trial site. All Ethics committees have to be registered with Drug Controller General of India (DCGI) without which they cannot approve any clinical trial protocol and has come into effect from 25th February 2013.
Prediction of metabolic fluxes by incorporating genomic context and flux-converging pattern analyses

Flux balance analysis (FBA) of a genome-scale metabolic model allows calculation of intracellular fluxes by optimizing an objective function, such as maximization of cell growth, under given constraints, and has found numerous applications in the field of systems biology and biotechnology. Due to the underdetermined nature of the system, however, it has limitations such as inaccurate prediction of fluxes and existence of multiple solutions for an optimal objective value. Here, we report a strategy for accurate prediction of metabolic fluxes by FBA combined with systematic and condition-independent constraints that restrict the achievable flux ranges of grouped reactions by genomic context and flux-converging pattern analyses. Analyses of three types of genomic contexts, conserved genomic neighborhood, gene fusion events, and co-occurrence of genes across multiple organisms, were performed to suggest a group of fluxes that are likely on or off simultaneously. The flux ranges of these grouped reactions were constrained by flux-converging pattern analysis. FBA of the Escherichia coli genome-scale metabolic model was carried out under several different genotypic (pykF, zwf, ppc, and sucA mutants) and environmental (altered carbon source) conditions by applying these constraints, which resulted in flux values that were in good agreement with the experimentally measured 13C-based fluxes. Thus, this strategy will be useful for accurately predicting the intracellular fluxes of large metabolic networks when their experimental determination is difficult.
CORTISOL DECREASES AND SEROTONIN AND DOPAMINE INCREASE FOLLOWING MASSAGE THERAPY

In this article the positive effects of massage therapy on biochemistry are reviewed including decreased levels of cortisol and increased levels of serotonin and dopamine. The research reviewed includes studies on depression (including sex abuse and eating disorder studies), pain syndrome studies, research on auto-immune conditions (including asthma and chronic fatigue), immune studies (including HIV and breast cancer), and studies on the reduction of stress on the job, the stress of aging, and pregnancy stress. In studies in which cortisol was assayed either in saliva or in urine, significant decreases were noted in cortisol levels (averaging decreases 31%). In studies in which the activating neurotransmitters (serotonin and dopamine) were assayed in urine, an average increase of 28% was noted for serotonin and an average increase of 31% was noted for dopamine. These studies combined suggest the stress-alleviating effects (decreased cortisol) and the activating effects (increased serotonin and dopamine) of massage therapy on a variety of medical conditions and stressful experiences.