Epistasis and the sensitivity of phenotypic screens for beta thalassaemia

Genetic disorders of haemoglobin, particularly the sickle cell diseases and the alpha and beta thalassaemias, are the commonest inherited disorders worldwide. The majority of affected births occur in low-income and lower-middle income countries. Screening programmes are a vital tool to counter these haemoglobinopathies by: (i) identifying individual carriers and allowing them to make informed reproductive choices, and (ii) generating population level gene-frequency estimates, to help ensure the optimal allocation of public health resources. For both of these functions it is vital that the screen performed is suitably sensitive. One popular first-stage screening option to detect carriers of beta thalassaemia in low-income countries is the One Tube Osmotic Fragility Test (OTOFT). Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts. We demonstrate that interactions between the carrier states for beta thalassaemia and alpha thalassaemia, glucose-6-phosphate dehydrogenase deficiency and Southeast Asian Ovalocytosis have the potential to reduce the sensitivity of OTOFTs for beta thalassaemia heterozygosity to below 70%. Our results therefore caution against the widespread application of OTOFTs in regions where these erythrocyte variants co-occur

Localization of gravity in brane world with arbitrary extra dimensions

We study the induced 4-dimensional linearized Einstein field equations in an m-dimensional bulk space by means of a confining potential. It is shown that in this approach the mass of graviton is quantized. The cosmological constant problem is also addressed within the context of this approach. We show that the difference between the values of the cosmological constant in particle physics and cosmology stems from our measurements in two different scales, small and large.Comment: 8 pages. arXiv admin note: substantial text overlap with arXiv:gr-qc/0408004, arXiv:gr-qc/0607067, arXiv:0704.1035, arXiv:0707.3558, arXiv:0710.266

The Autoimmune Manifestations in Patients with Genetic Defects in the B Cell Development and Differentiation Stages

Purpose: Primary B cell defects manifesting as predominantly antibody deficiencies result from variable inborn errors of the B cell lineage and their development, including impairments in early bone marrow development, class switch recombination (CSR), or terminal B cell differentiation. In this study, we aimed to investigate autoimmunity in monogenic patients with B cell development and differentiation defects. Methods: Patients with known genetic defects in the B cell development and differentiation were recruited from the Iranian inborn errors of immunity registry. Results: A total of 393 patients with a known genetic defect in the B cell development and differentiation (257 males; 65.4%) with a median age of 12 (6-20) years were enrolled in this study. After categorizing patients, 109 patients had intrinsic B cell defects. More than half of the patients had defects in one of the ATM (85 patients), BTK (76 patients), LRBA (34 patients), and DOCK8 (33 patients) genes. Fifteen patients (3.8%) showed autoimmune complications as their first manifestation. During the course of the disease, autoimmunity was reported in 81 (20.6%) patients at a median age of 4 (2-7) years, among which 65 patients had mixed intrinsic and extrinsic and 16 had intrinsic B cell defects. The comparison between patients with the mentioned four main gene defects showed that the patient group with LRBA defect had a significantly higher frequency of autoimmunity compared to those with other gene defects. Based on the B cell defect stage, 13% of patients with early B cell defect, 17% of patients with CSR defect, and 40% of patients who had terminal B cell defect presented at least one type of autoimmunity. Conclusion: Our results demonstrated that gene mutations involved in human B cell terminal stage development mainly LRBA gene defect have the highest association with autoimmunity

Search for annual and diurnal rate modulations in the LUX experiment

Various dark matter models predict annual and diurnal modulations of dark matter interaction rates in Earth-based experiments as a result of the Earth’s motion in the halo. Observation of such features can provide generic evidence for detection of dark matter interactions. This paper reports a search for both annual and diurnal rate modulations in the LUX dark matter experiment using over 20 calendar months of data acquired between 2013 and 2016. This search focuses on electron recoil events at low energies, where leptophilic dark matter interactions are expected to occur and where the DAMA experiment has observed a strong rate modulation for over two decades. By using the innermost volume of the LUX detector and developing robust cuts and corrections, we obtained a stable event rate of 2.3±0.2  cpd/keVee/tonne, which is among the lowest in all dark matter experiments. No statistically significant annual modulation was observed in energy windows up to 26  keVee. Between 2 and 6  keVee, this analysis demonstrates the most sensitive annual modulation search up to date, with 9.2σ tension with the DAMA/LIBRA result. We also report no observation of diurnal modulations above 0.2  cpd/keVee/tonne amplitude between 2 and 6  keVee.Various dark matter models predict annual and diurnal modulations of dark matter interaction rates in Earth-based experiments as a result of the Earth's motion in the halo. Observation of such features can provide generic evidence for detection of dark matter interactions. This paper reports a search for both annual and diurnal rate modulations in the LUX dark matter experiment using over 20 calendar months of data acquired between 2013 and 2016. This search focuses on electron recoil events at low energies, where leptophilic dark matter interactions are expected to occur and where the DAMA experiment has observed a strong rate modulation for over two decades. By using the innermost volume of the LUX detector and developing robust cuts and corrections, we obtained a stable event rate of 2.3$\pm$0.2~cpd/keV$_{\text{ee}}$/tonne, which is among the lowest in all dark matter experiments. No statistically significant annual modulation was observed in energy windows up to 26~keV$_{\text{ee}}$. Between 2 and 6~keV$_{\text{ee}}$, this analysis demonstrates the most sensitive annual modulation search up to date, with 9.2$\sigma$ tension with the DAMA/LIBRA result. We also report no observation of diurnal modulations above 0.2~cpd/keV$_{\text{ee}}$/tonne amplitude between 2 and 6~keV$_{\text{ee}}$

A study on relationship between anthracosis and pulmonary tuberculosis

Background & Objective: Anthracosis is a bronchoscopic finding characterized by the presence of black pigments in the bronchial mucosa. In this study we examined the relationship between anthracosis and pulmonary tuberculosis in a sample size much larger than previous studies in order to alleviate the ambiguities and controversy surrounding this issue. Materials & Methods: This cross-sectional study was conducted from April 2010 to October 2016 on patients referred to the hospital for bronchoscopy due to any respiratory problem. Bronchoalveolar lavage (BAL) was sampled during bronchoscopy and the smears and cultures of tuberculosis mycobacterium acquired from the samples were examined. Results: In this study, 2377 patients were studied. The patients aged between 30 and 96 years, and of all patients, 1397 individuals were male. The prevalence of pulmonary tuberculosis among patients with and without anthracosis was 9.24 and 3.07, respectively (P<0.001). The frequency ratio of females with anthracosis in comparison with males with anthracosis showed that the prevalence of this disease among females is higher than in males (P<0.001). Conclusion: Pulmonary tuberculosis and anthracosis are related to each other and there is a direct relationship between the prevalence of pulmonary anthracosis and age and the female sex. © 2020

Effects of valproic acid and pioglitazone on cell cycle progression and proliferation of T-cell acute lymphoblastic leukemia Jurkat cells

Objective(s): T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor. Administration of chemical compounds influencing apoptosis and T cell development has been discussed as promising novel therapeutic strategies. Valproic acid (VPA) as a recently emerged anti-neoplastic histone deacetylase (HDAC) inhibitor and pioglitazone (PGZ) as a high-affinity peroxisome proliferator-activated receptor-gamma (PPARγ) agonist have been shown to induce apoptosis and cell cycle arrest in different studies. Here, we aimed to investigate the underlying molecular mechanisms involved in anti-proliferative effects of these compounds on human Jurkat cells. Materials and Methods: Treated cells were evaluated for cell cycle progression and apoptosis using flowcytometry and MTT viability assay. Real-time RT-PCR was carried out to measure the alterations in key genes associated with cell death and cell cycle arrest. Results: Our findings illustrated that both VPA and PGZ can inhibit Jurkat E6.1 cells in vitro after 24 hr; however, PGZ 400 μM presents the most anti-proliferative effect. Interestingly, treated cells have been arrested in G2/M with deregulated cell division cycle 25A (Cdc25A) phosphatase and cyclin-dependent kinase inhibitor 1B (CDKN1B or p27) expression. Expression of cyclin D1 gene was inhibited when DNA synthesis entry was declined. Cell cycle deregulation in PGZ and VPA-exposed cells generated an increase in the proportion of aneuploid cell population, which has not reported before. Conclusion: These findings define that anti-proliferative effects of PGZ and VPA on Jurkat cell line are mediated by cell cycle deregulation. Thus, we suggest PGZ and VPA may relieve potential therapeutic application against apoptosis-resistant malignancies. © 2016, Mashhad University of Medical Sciences. All rights reserved

Encapsulation of Leflunomide (LFD) in a novel niosomal formulation facilitated its delivery to THP-1 monocytic cells and enhanced Aryl hydrocarbon receptor (AhR) nuclear translocation and activation

Background: Leflunomide (LFD) is an Aryl hydrocarbon receptor (AhR) agonist and immunomodulatory drug with several side effects. Niosomes are novel drug delivery systems used to reduce the unfavorable effects of drugs by enhancing their bioavailability, controlling their release and targeting specific sites. Objectives: Here, we prepared niosomal formulations of LFD, evaluated their properties and delivered to THP-1 monocytic cells to study the activation and nuclear translocation of AhR. Methods: Four types of non-ionic surfactants were utilized to formulate niosomes by thin film hydration (TFH) method. Entrapment efficiency (EE ) of niosomes were quantified and dynamic light scattering (DLS) was performed. Transmission electron microscopy (TEM) was used to identify the morphology of LFD niosomes. Dialysis method was used to measure LFD release rate. MTS assay was adopted to examine the viability of the cells upon each treatment. The nuclear transfer of AhR was investigated by Immunocytochemistry (ICC). The mRNA expression of IL1β and CYP1A1 were evaluated using quantitative RT-PCR. Results: Span 60: cholesterol (1:1) showed the highest EE (70.00 ± 6.24), largest particles (419.00 ± 4.16 nm) and the best uniformity with the lowest PDI (0.291 ± 0.007). TEM micrographs of Span 60 (1:1) nanoparticles showed conventional spherical vesicles with internal aqueous spaces. The release rate of LFD from Span 60 (1:1) vesicles was slower. Although the viability of LFD niosome-treated THP-1 cells was decreased, they were associated with lower cytotoxic effects compared with the free LFD counterparts. Both free and niosomal LFD treatments intensified the nuclear translocation of AhR. The mRNA expression of CYP1A1 was overexpressed while IL1β was downregulated in both free and niosomal LFD treated combinations. Conclusion: LFD encapsulation in Span 60: cholesterol (1:1) niosomal formulation could be introduced as a suitable vehicle of transferring LFD to THP-1 cells, with minimal cytotoxic effects, enhancing the AhR nuclear translocation and activation and inducing immunomodulatory properties. Figure not available: see fulltext.. © 2019, Springer Nature Switzerland AG

Relationship between dietary patterns and mild cognitive impairment (MCI) in elderly women

Context: Mild cognitive impairment (MCI) is a transitional stage in cognitive performance between changes seen in normal aging and those observed in dementia. Early diagnosis and intervention during the initial stages of mild cognitive impairment can delay or prevent the onset of dementia. Preventive behavioral interventions, for instance changes in dietary patterns, can play a major role in reducing the burden of this disease. Aim: The aim of this study was to determine the association between dietary patterns and MCI in the elderly. Methods and material: The present case-control study was performed on 82 cases and 163 controls constituted by 60 year-old or older women. We conducted interviews and completed a general questionnaire, IPAQ, FFQ, and MMSE. We used factor analysis and principal component analysis to derive dietary patterns and the chi-square test, independent t-test, and logistic regression to analyze the data. Results: There were significant differences between the two groups in terms of educational level (P = 0.033), employment (p = 0.001), and the number of minutes of study (P =0.020). We identified three dietary patterns including unhealthy, Western, and healthy dietary patterns. There was a statistically significant difference between the two groups only in terms of the healthy dietary pattern (P = 0.004). The odds ratio of developing MCI in people who were in the highest tertile of the healthy dietary pattern was 50 lower than those in the first tertile (OR=0.496, 95CI: 0.261, 0.943). Conclusion: Our present study demonstrated that only the healthy dietary pattern was significantly associated with MCI and reduced the risk of the disease. It is recommended that further prospective studies be conducted to find more robust relationships. © Mattioli 1885