Miracle-dz/UniFAR-FTUs huggingface dataset:
Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

Significance Cardiac hypertrophy and dysfunction in response to sustained hormonal and mechanical stress are sentinel features of most forms of heart disease. Activation of non–voltage-gated transient receptor potential canonical channels TRPC3 and TRPC6 may contribute to this pathophysiology and provide a therapeutic target. Effects from combined selective inhibition have not been tested previously. Here we report the capability of highly selective TRPC3/6 inhibitors to block pathological hypertrophic signaling in several cell types, including adult cardiac myocytes. We show in vivo redundancy of each channel; individual gene deletion was not protective against sustained pressure overload, whereas combined deletion ameliorated the response. These data strongly support a role for both channels in cardiac disease and the utility of selective combined inhibition. Chronic neurohormonal and mechanical stresses are central features of heart disease. Increasing evidence supports a role for the transient receptor potential canonical channels TRPC3 and TRPC6 in this pathophysiology. Channel expression for both is normally very low but is increased by cardiac disease, and genetic gain- or loss-of-function studies support contributions to hypertrophy and dysfunction. Selective small-molecule inhibitors remain scarce, and none target both channels, which may be useful given the high homology among them and evidence of redundant signaling. Here we tested selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A; IC50, 3–21 nM against TRPC3 and TRPC6) and found dose-dependent blockade of cell hypertrophy signaling triggered by angiotensin II or endothelin-1 in HEK293T cells as well as in neonatal and adult cardiac myocytes. In vivo efficacy in mice and rats was greatly limited by rapid metabolism and high protein binding, although antifibrotic effects with pressure overload were observed. Intriguingly, although gene deletion of TRPC3 or TRPC6 alone did not protect against hypertrophy or dysfunction from pressure overload, combined deletion was protective, supporting the value of dual inhibition. Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management.
Cerebral hyperthermia in children after cardiopulmonary bypass.

BACKGROUND Cerebral hyperthermia after hypothermic cardiopulmonary bypass has been poorly documented for adults and never in children. This study was designed to monitor brain temperature during and up to 6 h after cardiopulmonary bypass in infants and children. METHODS Fifteen infants and children, between 3 months and 6 yr of age, were studied. A right retrograde jugular bulb catheter was used to measure the jugular venous bulb temperature (JVBT) during the procedure and the first 6 h in the critical care unit. The temperature of the blood from the bypass machine was measured at the aorta through the cannula using an indwelling temperature probe. All data were acquired every minute. RESULTS The age of the patients ranged from 3 to 71 months (median, 15 months). The mean weight was 11.5 +/- 8.4 kg. The mean JVBT recorded at the end of cardiopulmonary bypass was 36.9 +/- 1.4 degrees C but reached 39.6 +/- 0.8 degrees C after six h (P < 0.01). The kinetics of brain rewarming was determined by the slope of the mean JVBT and corresponded to y +/- 0.006x + 37.21 (r2 = 0.97). The JVBT differed from the tympanic temperature after 200 min (P < 0.01) and the lower esophageal (P < 0.05) and rectal (P < 0.001) temperatures after 300 min. After 6 h, the tympanic, rectal, and lower esophageal temperatures were 37.8 +/- 0.9, 37.7 +/- 0.6, and 38.4 +/- 0.7 degrees C, respectively, whereas the JVBT was 39.6 +/- 0.8 degrees C (P < 0.001). However, the correlation coefficients between the JVBT and the tympanic, rectal, and esophageal temperatures were 0.98, 0. 85, and 0.97, respectively. No complications were recorded with placement of the jugular bulb catheter. CONCLUSIONS Mean JVBT was significantly increased over the mean core temperature at all times from rewarming by cardiopulmonary bypass onward. Although the lower esophageal, rectal, and tympanic temperatures correlated well with JVBT, all three failed to reflect JVBT during recovery. This observation might help to elucidate factors involved in the functional and structural neurologic injury known to occur in pediatric patients.
Investigation of Vascular Endothelial Growth Factor Gene Polymorphisms and Its Association with Clinicopathologic Characteristics in Gastric Cancer

Objective: Vascular endothelial growth factor (VEGF) is known to be a potent proangiogenic factor. This study evaluates the potential association of three VEGF gene polymorphisms (–460T > C, +405G > C, and 936C > T) with the susceptibility to and clinicopathologic characteristics of gastric cancer. Methods: The VEGF genotypes were determined using paraffin-embedded tissue from 413 patients who underwent a surgical resection and peripheral blood lymphocytes from 413 healthy controls by PCR-RFLP assay. Results: There was no difference in the allele frequency of –460T > C polymorphism. However, for the +405G > C polymorphism, the +405C allele was associated with a significantly decreased susceptibility to gastric cancer [odds ratio (OR) 0.686; 95% confidence interval (CI) 0.564–0.834]. Although there was no significant difference in the distribution of the 936C > T polymorphism between the two groups, the 936T allele was associated with a decreased susceptibility to gastric cancer (OR 0.757; 95% CI 0.591–0.970). In the haplotype analyses, the haplotype TCT (OR 0.405; 95% CI 0.263–0.624) was most closely associated with a decreased susceptibility to gastric cancer. However, no significant association was observed between the frequency of the genotypes or alleles and the clinicopathologic characteristics of gastric cancer. Conclusion: These observations imply that the VEGF gene polymorphisms may be associated with the susceptibility to gastric cancer. However, further studies of other VEGF sequence variants and their biological functions are needed to understand the role of the VEGF polymorphisms in determining the susceptibility to gastric cancer.
The Dynamics of Entry and Exit in Post-Secondary Education

THE DYNAMICS OF ENTRY AND EXIT IN POST-SECONDARY EDUCATION Joniada Milla Advisor: University of Guelph, 2013 Thanasis Stengos This thesis brings to the forefront of the existing literature the importance of analyzing transitional dynamics among different levels of schooling and to the labor market. I perform empirical analyses using confidential longitudinal survey data from Statistics Canada; employing program evaluation techniques, and regression modelling. The first chapter is joint work with Louis Christofides, Michael Hoy and Thanasis Stengos. We explore the forces that shape the development of aspirations and the achievement of grades during high school and the role that these aspirations, grades, and other variables play in educational outcomes such as going to university and graduating. We find that parental expectations and peer effects have a significant impact on educational outcomes through grades, aspirations, and their interconnectedness. Apart from this indirect path, parents and peers also influence educational outcomes directly. Policy measures that operate on parental influences may modify educational outcomes in desired directions. The second chapter estimates the wage returns to university quality. I distinguish between two distinct measures of university quality. The first is a survey-based university reputation ranking, and the second is a new ranking, which I construct from several university characteristics in order to objectively reflect the university quality. The findings
Murine endotoxin-induced uveitis, but not immune complex-induced uveitis, is dependent on the IL-8 receptor homolog.

PURPOSE To determine the roles of the murine interleukin-8 receptor homolog (mIL-8Rh, neutrophil chemokine CXC receptor 2) and macrophage inflammatory protein-1alpha (MIP-1alpha, a CC chemokine) in two eye inflammation models: endotoxin-induced uveitis (EIU) and immune complex-induced uveitis (reverse passive Arthus reaction (RPAR) uveitis). METHODS For the EIU model, 250 ng E.coli endotoxin was injected into the vitreous of mIL-8Rh-/- mice or heterozygous littermate mIL-8Rh+/- controls and into MIP-1alpha-/- mice or congenic MIP-1alpha+/+ controls. Eyes were harvested after 24 h for histologic characterization of infiltrating cells and IL-6 bioassays. For the RPAR model, mouse antiserum against human serum albumin (HSA) was injected into the vitreous of mIL-8Rh-/-, mIL-8Rh+/-, MIP-1alpha-/-, and MIP-1alpha+/+ mice. Twenty-four hours later, animals were challenged with intravenous HSA. Eyes were harvested after 4 h for analysis. RESULTS RPAR resulted in the deposition of immune complexes at the ciliary area and iris with the subsequent development of uveitis. Genetic deficiency of mIL-8Rh reduced the median number of infiltrating cells in EIU by 63% (p < 0.01) but had no effect on RPAR-induced inflammation. In the EIU model, macrophages comprised a much higher percentage (45%) of infiltrating cells in mice lacking mIL-8Rh than in controls (17%). Loss of the MIP-1alpha gene had no apparent effect on RPAR uveitis and a 39% reduction of infiltrating cells in EIU that was not statistically significant. IL-6 activity in aqueous humor was much less in mice with RPAR uveitis than in those with EIU. Neither gene deletion had a significant impact on IL-6 levels in either disease model. CONCLUSIONS Chemokines acting via mIL-8Rh have a significant role in the induction of neutrophil infiltration during EIU but not during RPAR uveitis. MIP-1alpha is not critical for either EIU or RPAR-induced uveitis. The differential dependence on IL-8-like chemokines is in accord with the two forms ofuveitis having different etiologies and, therefore, potentially different optimal therapies.
The Effect of Anti-Corruption Campaign on Shareholder Value in a Weak Institutional Environment: Evidence from China

We examine the economic consequences of China’s 2012 anti-corruption campaign. We find no evidence that the anti-corruption campaign had a significant impact on shareholder value of publicly listed Chinese firms as a whole. However, we find that the anti-corruption campaign had an immediate negative impact on the consumption of luxury goods and services. There is evidence that the impact of the campaign on luxury goods and services consumption is permanent. We also find that the negative impact of the campaign on luxury goods and services consumption propagated gradually from more developed provinces to less developed provinces.
The Cryptococcus neoformans GAL7 gene and its use as an inducible promoter

A Cryptococcus neoformans galactose auxotroph was created by ultraviolet light mutagenesis and complemented with a C. neoformans genomic library. The translated sequence of the complementing DNA revealed a high degree of simlarity to a number of UDP glucose‐D‐gatactose‐1‐phosphate uridylyitransferases. Expression of C. neoformans GAL7 mRNA followed a pattern similar to Saccharomyces cerevisiae expression; it was first observed within 2.5 min of induction and fully induced by 30 min. The gene was completely repressed in the presence of glucose. The GAL7 promoter was isolated and used to construct a promoter cassette. Two genes were tested in this cassette for galactose regulation by creating GAL7 promoter fusions with their coding regions. MFα, which encodes a pheromone, was found to produce filaments only in transformants that were induced by galactose. A second gene, β‐glucuronidase (gusA), which is a commonly used reporter gene, was tested and also found to be expressed. When the GAL7 p::GUS fusion was used to quantify inducibitity of the GAL7 promoter, the level of enzyme activity was at least 500‐fold greater for cells grown in galactose than for cells grown in glucose. The GAL7 promoter is the first inducible promoter characterized in C neoformans and the GUS gene is the first heterologous gene shown to be expressed in this yeast pathogen.
Growth, convergence and trade: The services sector in India’s states

India’s success story in services is well documented at the national level, but similar literature does not exist for India’s states. In this paper, we bridge this gap in research by looking at India’s services growth at the sub-national level and in doing so, also challenge existing literature by arguing that this growth has positive implications for income distribution. We find that even as per capita income is not converging across India’s states, per capita services are; evidence is provided both in terms of traditional measures of sigma- and beta-convergence and more recent panel unit root tests. A more disaggregated analysis of services sectors reveals convergence in railways, public administration and financial services. Finally, a Jensen & Kletzer (2005) approach to determining tradability provides evidence of most services being “traded” across India’s states, suggesting the role of such trade in the services growth and convergence story.
Analyses of 24-hour growth hormone profiles in children: relation to growth.

The relationship between height and amount of GH measured during a 24-h period was studied in 127 children who were growing at different rates. Of the children, 88 were prepubertal (3-16 yr old) and 39 were pubertal (10-16 yr old). The height of each child was expressed as the SD score, i.e. height in relation to the sex- and age-matched Swedish reference groups, and spontaneous GH secretion was estimated by taking integrated 20-min blood samples for a 24-h period, i.e. 72 samples/child. In a few children, discrete samples were taken in parallel with the integrated 20-min samples with virtually the same results. Plasma GH was estimated in each sample using a polyclonal RIA method. To compare different 24-h GH profiles, the profiles were analyzed using a computer program (Pulsar). One objective of the study was to determine if less frequent sampling and/or shorter sampling periods yielded the same information as that obtained by 20-min sampling for the whole 24-h period. To determine if less frequent sampling provided the same information as that obtained by the 20-min period, we simulated 40- and 60-min periods by pooling two or three consecutive samples. No difference was found between 20- and 40-min sampling, but with 60-min sampling the mean calculated baseline plasma GH concentrations increased, and the GH concentration within peaks [the area under the curve above the baseline (AUCb)] decreased markedly. A 30-min sampling interval thus seems to be a valid practical compromise. To determine if sampling periods shorter than 24 h provided the same information, we divided the profiles, which started at 0900 h, into two 12-h, three 8-h and four 6-h periods. A graded decrease in AUCb and a corresponding increase in the baseline was found with the shorter periods, indicating that the whole 24-h period is necessary for GH sampling. Another objective of the study was to determine whether there was a correlation between 24-h GH secretion and the height, age, and sex of the children. In the prepubertal children, the height (in SD scores) was highly correlated (r = 0.69; P less than 0.001) with GH AUCb during the 24-h period. Height also correlated with AUCb estimated over shorter time periods; the correlation diminished with decreasing time. In the pubertal children, a nonlinear correlation (r = 0.36; P less than 0.05) was found between height and 24-h GH (AUCb). (ABSTRACT TRUNCATED AT 400 WORDS)
Long‐term effect of neuronal nitric oxide synthase over‐expression on cardiac neurotransmission mediated by a lentiviral vector

Short‐term over‐expression of neuronal nitric oxide synthase (nNOS) with adenoviral gene transfer into peripheral cardiac autonomic neurons can facilitate cholinergic neurotransmission, and inhibit sympathetic transmission, by regulating cyclic nucleotide‐dependent pathways coupled to neuronal calcium entry. We tested the idea whether cardiac neuromodulation by nNOS could be sustained by long‐term over‐expression of the enzyme following lentiviral gene transfer. We developed a lentiviral vector with an elongation factor 1 (EF1α) promoter to drive nNOS or enhanced green fluorescent protein (eGFP) expression. Lenti. EF1α‐nNOS or Lenti. EF1α‐eGFP was transferred to the right atrium of Spague–Dawley (SD) rats and acetylcholine (ACh) or noradrenaline (NA) release to field stimulation was measured 4 months after gene transfer. Atria transduced with Lenti. EF1α‐nNOS had higher nNOS expression compared to the atria treated with Lenti. EF1α‐eGFP (P < 0.05). We also detected significant increases (P < 0.05) in atrial cGMP and cAMP levels in the same tissue. Immunohistochemistry revealed co‐localisation of eGFP in intrinsic cholinergic neurons (choline acetyltransferase positive) and intrinsic adrenergic neurons (tyrosine hydroxylase positive) following gene transfer. nNOS‐transduced animals displayed enhanced ACh release (P < 0.05) and reduced NA release (P < 0.05) compared to the eGFP‐treated group. nNOS‐specific inhibition reversed the enhanced ACh release. Persistent nNOS over‐expression mediated by a lentiviral vector can modulate sympatho‐vagal control of cardiac excitability. This approach may provide a new tool to target impaired cardiac autonomic phenotypes that are disrupted by several cardiovascular pathologies.
Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer's disease with and without depression.

OBJECTIVE Few studies have examined pathological changes in serotonergic neurons in depression, particularly in elderly patients and in elderly patients in which depression occurs in dementia. The authors hypothesized that greater neurofibrillary pathology and fewer serotonergic neurons would be found in the dorsal raphe nuclei in depressed elderly subjects, compared with nondepressed elderly subjects, and in Alzheimer's disease patients with depression, compared to Alzheimer's disease patients without depression. METHOD In a postmortem study, immunocytochemistry and two-dimensional image analysis were used to measure neuronal density and neuritic pathology in serotonergic neurons in the dorsal raphe nuclei of elderly subjects with primary major depression (N=14), elderly Alzheimer's disease patients with (N=8) and without (N=7) comorbid depression, and nondepressed elderly comparison subjects (N=10). RESULTS No differences in neuritic pathology or neuronal density were found between the subjects with primary major depression and the nondepressed comparison subjects. The Alzheimer's disease subjects showed markedly fewer serotonergic neurons and associated higher levels of neuritic pathology, compared with the subjects with primary depression and the nondepressed comparison subjects, but the Alzheimer's disease subjects with comorbid major depression did not differ from the Alzheimer's disease subjects without depression on these measures. CONCLUSIONS The study found no evidence of a loss of serotonergic neurons or of neuritic pathology in the dorsal raphe nuclei in older people with depression, with or without comorbid Alzheimer's disease. These findings suggest that if serotonergic dysfunction occurs in older depressed subjects, it is not due to neuronal loss in the brainstem. Pathophysiological changes may lie elsewhere, such as in the frontal-subcortical circuits.
Customary justice for children in Egypt: an overview of the situation in the Governorate of Assyut

ABSTRACT This article analyses the profile of the criminal cases that are handled by the customary justice system for children in one governorate of Egypt. Data were collected during seventeen months through monthly semi-directive interviews with fourteen arbitrators. This provided information on 244 customary justice proceedings involving 296 children. The study is focused on 197 children, involved in 168 criminal cases. The analysis allows a description of the kind of offences treated, the distribution of presumed offenders and victims by gender, age and offence, the duration of the proceedings and the final outcome. The research shows that, in spite of decades of colonisation, old customary justice practices play a major role in Egypt today. Thus, customary justice, which has been elsewhere the source of many modern approaches to restorative justice, coexists in Egypt alongside Western-imported retributive criminal justice and a juvenile justice system that attempts to adhere to international standards.
THE LEVELS OF TEACHERS’ INVOLVEMENT IN MANAGERIAL DECISION MAKING IN SCHOOLS IN KENYA

Making decisions is one of the prime functions of educational management and in the current educational setup; more teachers are taking management roles in schools. This study therefore assessed the teachers’ involvement in managerial decision making in secondary schools within Keiyo district. The specific objectives were to: determine areas in which teachers are involved in decision making in secondary schools, establish levels of teachers’ involvements in decision making in secondary schools. The entire study was propounded on the basis of Vroom-Yetton-Jago Contingency Theory of participative decision making (1988). This study was conducted by cross-sectional survey design. Data were collected from a sample of 17 head teachers, 17 deputy head teachers, 51 head of departments and 51 class teachers. The instruments of data collection were: questionnaires, and interviews. Findings indicate that teachers in secondary schools are involved in managerial decisions but at lower levels. The study recommends that head teachers evaluate and identify teachers’ needs on managerial decisions in order to facilitate further training on the same. This in turn would encourage teachers’ participation and enhance team spirit in decision making that would result in efficiency in management of secondary schools. Key words: decision making, education, management, participation, teachers.
The Sentinel Node Procedure in Breast Cancer: Nuclear Medicine as the Starting Point

Axillary node status is a major prognostic factor in early breast cancer. Staging with sentinel node biopsy (SNB) leads to a substantial reduction in surgical morbidity. Recent multiinstitutional studies revealed SNB false-negative rates ranging from 5.5% to 16.7%, higher than the target (<5%) set by the 2005 guidelines of the American Society of Clinical Oncology. These alarming data point to the necessity of optimization. Dual mapping with radiotracer and blue dye, combining 2 different injection sites, and routinely using lymphoscintigraphy may improve accuracy. Factors associated with decreased sensitivity, such as prior excisional biopsy or neoadjuvant chemotherapy, should be recognized. The use of SNB in situations with a high prevalence of node positivity (large tumor, multifocality) is controversial. The risk of missed disease after negative SNB ranges from 1% to 4% in patients with T1 tumor and up to 15% in patients with T3. With peritumoral injection, internal mammary drainage is seen in about 20% of cases. Patients combining internal mammary drainage with a positive axillary sentinel node have close to a 50% probability of internal mammary involvement. Lymphoscintigraphy might thus be helpful in selecting patients for whom internal mammary radiation has a high benefit-to-risk ratio.