Heregulin induces expression, DNA binding activity and transactivating functions of basic leucine zipper activating transcription factor 4

Heregulin β1 (HRG), a combinatorial ligand for human epidermal growth factor receptor 3 and human epidermal growth factor receptor 4 receptors, is a regulatory secretory polypeptide with distinct biological effects such as growth stimulation, differentiation, invasiveness and migration in breast cancer cells. The mechanism underlying the diverse functions of HRG is not well established, but it is believed to be dependent on the induced changes in expression of specific cellular gene products, their modification, or both. The binding of basic leucine zipper transcription factors to the cAMP response element is known to activate a variety of gene products with a role or roles in growth regulation. In the studies presented here, we identified basic leucine zipper Activating Transcription Factor (ATF) 4 as one of the HRG-inducible gene product. We demonstrated that HRG stimulation of human cancer cells induces expression of ATF4 mRNA and protein, ATF4 DNA binding activity and ATF4 transactivating function. Consistent with its role as a transcriptional activator, HRG-stimulated ATF4 protein stimulated the transcription from an artificial promoter with three tandem ATF sites or from a naturally occurring promoter with ATF4 sites such as E-selectin. We also demonstrated a preferential role of the HRG-stimulated mitogen-activated protein kinase pathway, but not the phosphatidylinositol 3′-kinase pathway, in supporting the observed increase in ATF4 DNA binding activity and transcription from E-selectin promoter in HRG-stimulated cells. Because ATF4 binding sites are present in a variety of growth-regulating cellular genes, these findings suggest that the stimulation of ATF4 expression and its transactivating functions may constitute an important mechanism of HRG-mediated regulation of putative genes with diversified functions. The present study is the first demonstration of regulation of expression and transactivation ability of ATF4 by any polypeptide growth factor

Inequity in smoking cessation clinical trials testing pharmacotherapies: exclusion of smokers with mental health disorders

Objectives People suffering from mental health disorder (MHDs) are often under-represented in clinical research though the reasons for their exclusion are rarely recorded. As they have higher rates of smoking and nicotine dependence, it is crucial that they are adequately represented in clinical trials of established pharmacotherapy interventions for smoking cessation. This review aims to examine the practice of excluding smokers with MHDs and reasons for such exclusion in clinical trials evaluating pharmacotherapy treatments for smoking cessation. Data source The Cochrane database of systematic reviews was searched until September 2020 for reviews on smoking cessation using pharmacotherapies. Study selection Randomised controlled trials (RCTs) within the selected Cochrane reviews were included. Data extraction Conducted by one author and independently verified by three authors. Data synthesis We included 279 RCTs from 13 Cochrane reviews. Of all studies, 51 (18.3%) explicitly excluded participants with any MHDs, 152 (54.5%) conditionally excluded based on certain MHD criteria and 76 (27.2%) provided insufficient information to ascertain either inclusion or exclusion. Studies of antidepressant medications used for smoking cessation were found to be 3.33 times more likely (95% CI 1.38 to 8.01, p=0.007) to conditionally exclude smokers with MHDs than explicitly exclude compared with studies of nicotine replacement therapy. Conclusion Smokers with MHDs are not sufficiently represented in RCTs examining the safety and effectiveness of smoking cessation medications. Greater access to clinical trial participation needs to be facilitated for this group to better address access to appropriate pharmacotherapeutic interventions in this vulnerable population

Analysis of experimental designs with unequal group variances.

This thesis deals with weighted (generalised) least squares estimation and analysis for some common experimental designs with the error variance heteroscedastic with respect to the levels of one factor, namely, the treatments or (for split-plot designs) sub-plot treatments. The simple regression model with error variance heteroscedastic with respect to the values of the independent variable, is also considered briefly. The observations in any of the analyses considered are grouped in such a way that the error variance is constant within groups but varies from group to group. On the assumption that the group variances are known, the weighted least squares estimators of the linear parameters and the corresponding analysis (Aitken, 1934-35; Plackett, I960, pp. 47-49) are provided for each design or model. An expression for joint confidence intervals of parametric contrasts for the heteroscedastic models is also obtained. The estimators of the linear parameters and other statistics usually involve actual weights, the reciprocals of the group variances. The actual weights are not usually known. The estimators of the group variances are therefore derived for each design or model. for some designs, the minimum norm quadratic unbiased estimators (Rao, 1970; 1973, pp. 303-305) of group variances are independently distributed as multiples of x2. For other designs, almost unbiased estimators (Horn et al., 1975) of group variances have negligible bias and are approximately independently distri-buted as multiples of x2 Reciprocals of these estimators are used as the estimated weights. The weighted least squares estimators of the linear parameters or variance components and other statistics including test-statistics using estimated weights, are generally biased. It is shown in the thesis how a major part of the bias can be removed; the procedure stems from a theorem due to Meier (1953). The estimators and other statistics using estimated weights are adjusted accordingly. A modified form of this theorem is also proved for correlated estimators of the group variances. A small Monte Carlo study conducted for completely randomised designs showed that the performances of the adjusted statistics are more or less satisfactory. The designs and models covered in this thesis are: completely randomised designs, the general two-way model with proportional cell frequencies, general block designs, randomised complete block designs, latin square designs, split-plot designs with two treatment factors and the linear regression model. For the first three designs, both the fixed-effects models and random or mixed models are considered whereas only the fixed-effects models are dealt with for the remaining three designs

Atypical Idiopathic Intracranial Hypertension Presenting as Cyclic Vomiting Syndrome: A Case Report

BACKGROUND: Idiopathic intracranial hypertension is a disorder of increased intracranial pressure in the absence of cerebrospinal outflow obstruction, mass lesion, or other underlying cause. It is a rare phenomenon in prepubertal children and is most typically found in women of childbearing age. The classic presentation consists of headaches, nausea, vomiting, and visual changes; however, children present more atypically. We report a case of idiopathic intracranial hypertension in an otherwise healthy, 4-year-old child with atypical symptoms resembling those of cyclic vomiting syndrome. CASE PRESENTATION: A 4-year-old Caucasian, otherwise healthy, male child presented to our emergency department with episodic intermittent early-morning vomiting occurring once every 1-3 weeks without interepisodic symptoms, starting 10 months prior. With outpatient metabolic, autoimmune, endocrine, allergy, and gastroenterology work-up all unremarkable, he was initially diagnosed with cyclic vomiting syndrome. Discovery of mild optic nerve sheath distension on magnetic resonance imaging of the brain 10 months after symptom onset led to inpatient admission and a lumbar puncture notable for an opening pressure of 47 mmHg, with normal cell count and protein levels. He had no changes in visual acuity or optic disc edema on dilated fundoscopic examination. The patient was started on acetazolamide, with resolution of episodic emesis at his last follow-up visit 12 weeks after discharge. CONCLUSIONS: Idiopathic intracranial hypertension presents atypically in prepubescent children, with about one-fourth presenting asymptomatically, and only 13-52% presenting with classic symptoms. With a prevalence of only 0.6-0.7 per 100,000, much remains unknown regarding the underlying pathophysiology in this demographic. Cyclic vomiting syndrome, however, has a much higher prevalence in this age group, with a prevalence of 0.4-1.9 per 100. It is thought to be an idiopathic, periodic disorder of childhood, often linked to neurological conditions such as abdominal migraines, epilepsy, mitochondrial disorders, and structural lesions such as chiari malformation and posterior fossa tumors. While cyclic vomiting syndrome is thought to have a benign course, untreated idiopathic intracranial hypertension can have long-term detrimental effects, such as visual loss or even blindness. We present a case of idiopathic intracranial hypertension presenting with symptoms resembling cyclic vomiting syndrome in a 4-year-old child, diagnosed 10 months after initial onset of symptoms. We aim to demonstrate the need for a high level of clinical suspicion and the need for further investigation into underlying pathophysiology in this vulnerable population

In vitro clonal propagation of locally cultivated pink colour Gladiolus var. Neelima through Cormel-sprout culture

Micropropagation provides an economic advantage for the propagation of a particular crop like gladiolus, a beautiful flowering plant which emits expression of love. Propagation by conventional method is a slow process and pathogen keep on accumulation generation after generation which reduces yield and quality of flower and also generates insufficient propagules. An efficient propagation system could overcome those variabilities and meet the increasing demand of propagules production for the growing of gladiolus in the country while it is an exporting plant in Bangladesh. Moreover, establishment of a plant regeneration system through direct organogenesis or via callus is also a prerequisite to further in vitro genetic manipulation of the cultivar. Demand for disease free planting materials is increasing day by day and crop like vegetatively propagated plant is an appropriate means to generate propagules through in vitro techniques. Production of sufficient numbers of plants of a unique genotype is possible using in vitro culture system. In this study, the effect of various concentrations and combinations of plant growth regulators for in vitro regeneration of gladiolus was described using cormel-sprout as explants. However, an efficient in vitro plant regeneration protocol in locally cultivated pink colour Gladiolus var. Neelima was established on MS media with various hormonal supplements using cormel-sprout as explants. Ninety (90) percent of the explants responded for shooting on 0.5 mg/L BA + 0.5 mg/L Kin within the culture initiation period of 90 days. The average number of shoot per explants was 8 ±1.20 and the average shoot length of 12.40 ±2.15 cm were observed in this medium. Shoots are rooted well when they were excised individually and implanted on half strength of MS medium supplemented with 1.0 mg/l IBA, in which 90% of the shoot induced roots. The average number of root per shoot was 10 ± 1.20 and the average root length of 8.50 ± 1.25 cm were observed in this medium after culture of 30 days. Eighty (80) percent of the in vitro raised plantlets were survived in the natural environment

A blind hierarchical coherent search for gravitational-wave signals from coalescing compact binaries in a network of interferometric detectors

We describe a hierarchical data analysis pipeline for coherently searching for gravitational wave (GW) signals from non-spinning compact binary coalescences (CBCs) in the data of multiple earth-based detectors. It assumes no prior information on the sky position of the source or the time of occurrence of its transient signals and, hence, is termed "blind". The pipeline computes the coherent network search statistic that is optimal in stationary, Gaussian noise, and allows for the computation of a suite of alternative statistics and signal-based discriminators that can improve its performance in real data. Unlike the coincident multi-detector search statistics employed so far, the coherent statistics are different in the sense that they check for the consistency of the signal amplitudes and phases in the different detectors with their different orientations and with the signal arrival times in them. The first stage of the hierarchical pipeline constructs coincidences of triggers from the multiple interferometers, by requiring their proximity in time and component masses. The second stage follows up on these coincident triggers by computing the coherent statistics. The performance of the hierarchical coherent pipeline on Gaussian data is shown to be better than the pipeline with just the first (coincidence) stage.Comment: 12 pages, 3 figures, accepted for publication in Classical and Quantum Gravit

Seasonal and Altitudinal Prevalence of Fascioliasis in Buffalo in Eastern Nepal

Buffalo is the most important livestock commodities for milk, meat production and several other multipurpose uses distributed densely from southern tarai to northern mid-hills in Nepal. Among several internal parasitic diseases fascioliasis is highly economic one caused by Fasciola in buffaloes. However, there are only few studies carried on prevalence of fascioliasis emphasizing buffaloes in relation to seasonal (summer and rainy, and winter) and altitudinal variations. Therefore, we examined prevalence of fascioliasis seasonally and vertically. For the purpose, we selected two districts of eastern Nepal and sampled from low altitude area known as Madhesha ranging from 175-200, Dhankuta from 800-1200 m, and Murtidhunga from 1800-2200 m elevation from the sea level, representing tarai, mid hills and high hills, respectively. Altogether from February 2013 to January 2014 at every two months interval we collected 798 fecal samples from buffaloes; 282 from Murtidhunga, 239 from Dhankuta and 277 from Madhesha. The samples were examined microscopically for the presence of Fasciola eggs using sedimentation technique. Results showed that overall prevalence of fascioliasis in buffaloes was 39.9% (319/798), ranging highest 42.6%in Madhesha followed by 39.7% in Murtidhunga and 37.2% in Dhankuta, respectively. The prevalence of fascioliasis was found to be significantly (p <0.05) high in winter (44.9%) comparing to rainy season (34.4%). The prevalence of fascioliasis in buffaloes was relatively higher in low altitude than high altitude, although it was not statistically significant (p <0.05). In our findings the female buffaloes showed higher prevalence for fascioliasis than in male. Since the fascioliasis in buffaloes is highly endemic, thus strategic deworming in high risk period is recommended along with measure to prevent pasture contamination with buffalo feces

A proposal and a theoretical analysis of an enhanced surface plasmon coupled emission structure for single molecule detection

We propose a structure that can be used for enhanced single molecule detection using surface plasmon coupled emission (SPCE). In the proposed structure, instead of a single metal layer on the glass prism of a typical SPCE structure for fluorescence microscopy, a metal-dielectric-metal structure is used. We theoretically show that the proposed structure significantly decreases the excitation volume of the fluorescently labeled sample, and simultaneously increases the peak SPCE intensity and SPCE power. Therefore, the signal-to-noise ratio and sensitivity of an SPCE based fluorescence microscopy system can be significantly increased using the proposed structure, which will be helpful for enhanced single molecule detection, especially, in a less pure biological sample