Effect of Non-Coding RNA on Post-Transcriptional Gene Silencing of Alzheimer Disease

A large amount of hidden biological information is contained in the human genome, which is not expressed or revealed in the form of proteins; the usual end product form of gene expression. Instead, most of such information is in the form of non-coding RNAs (ncRNAs). ncRNAs correspond to genes that are transcribed, but do not get translated into proteins. This part of the genome was, till recently, considered as ‘junk’. The term ‘junk’ implied lack of any discernible function of these RNA. More than 98% of the human genomic size encompasses these non-coding RNAs. But, recent research has evidently brought out the indispensible contribution of non-coding RNA in controlling and regulating gene expression. ncRNA such as siRNAs and microRNAs have been reported to greatly help in causing post-transcriptional gene silencing (PTGS) in cells through RNA interference (RNAi) pathway. In this work, we have investigated the possibility of using siRNAs and microRNAs to aid in gene silencing of early onset Alzheimer’s disease genes. 
Alzheimer’s disease specific mutations and their corresponding positions in mRNA have been identified for six genes; Presenilin-1, Presenilin-2, APP (amyloid beta precursor protein), APBB3, BACE-1 and PSENEN. 

Small interfering RNAs (siRNAs) that can cause PTGS through RNA interference pathway have been designed. RNA analysis has been done to verify complementarity of antisense siRNA sequence with target mRNA sequence. Interaction studies have been done computationally between these antisense siRNA strands and seven Argonaute proteins. From the interaction studies, only one of the seven Argonaute proteins; 1Q8K, was found to have interaction with the siRNAs indicating the importance and uniqueness of this particular protein in RISC (RNA induced silencing complex). 

The interaction studies have been carried out for the microRNAs also. Out of the 700 mature human microRNAs collected, 394 microRNAs have been identified to show partial complementarity with their target sequence on PSEN-1 mRNA. Of these 394, five microRNAs have shown partial complementarity to early onset Alzheimer’s disease specific mutations in PSEN-1 mRNA. Interaction studies have been done between these microRNAs and Argonaute proteins. Thus, design, characterization and analysis of ncRNAs that contribute to post transcriptional gene silencing of Alzheimer’s disease have been achieved.
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EMR Adoption: A User Perception Study

Despite promise of significant benefits, inadequate user acceptance has frequently limited the impact of EMR implementations. Using an action research approach, our team is participating in an EMR implementation at Aravind Eye Care System (AECS), one of the largest eye hospitals in the world, to observe its current practices, measure user perceptions of EMR, plan interventions, and assess their impact. Our proximate research objective is to develop interventions based on sound conceptual foundations and empirical validation rather than in an ad hoc manner, to facilitate EMR acceptance by AECS hospital staff. The ensuing goal is to learn from the post intervention findings to develop guidelines for EMR implementations, particularly in a developing country context. In this paper we report on the first phase of this study, and these initial results show how even simple analysis of perception patterns can help to customize and shape intervention plans

Simultaneous Quantitative Determination of Metoprolol, Atorvastatin and Ramipril in Capsules by a Validated Stability-Indicating RP-UPLC Method

A simple ultra performance liquid chromatographic (UPLC) method has been developed for the simultaneous estimation of Metoprolol (MT), Atorvastatin (AT) and Ramipril (RM) from capsule dosage form. The method was developed using Zorbax® XDB-C18 (4.6 mm × 50 mm, 1.8 μm) column with a mobile phase consisting of 0.06% ortho phosphoric acid in Milli Q® water having an ion pair reagent, 0.0045 M Sodium lauryl sulphate as buffer, at ratio of buffer: Acetonitrile (50:50 v/v), at 55°C column temperature with a flow rate of 1.0 ml/min. Detection was carried out with ultra-violet detection at 210 nm for RM, MT and AT respectively. The retention times were about 1.3, 2.1 and 2.6 min for MT, AT and RM respectively, the method was validated for linearity, accuracy, precision, specificity, robustness and ruggedness. The % mean recoveries are 101.9, 102.1 and 101.4 for MT, AT and RM respectively. The method was found to be rugged and robust and can be successfully used to determine the three drugs and its combinations

Synchronous dual malignancy: a rare case report of carcinoma breast with carcinoma gall bladder

Incidence of multiple primary cancers is reported to be between 0.18% to 17.2% in various studies. Occurrence of breast and gall bladder malignancy as synchronous malignancy is very rare. We are reporting one of such rare case. Our patient, a 64 years old lady had a unique presentation. She underwent laparoscopic cholecystectomy for a clinical diagnosis of cholelithiasis. Histopathology turned out to be adenocarcinoma of the gall bladder (Stage II A). A clinical examination done at the time of presentation to our institute revealed suspicious thickening of the skin of the left breast and a subsequent tru-cut biopsy revealed infiltrating ductal carcinoma. Hormone receptor immunohistochemistry revealed oestrogen receptor (ER) negative progesterone receptor (PR) negative and Her2neu negative tumour. Further evaluation revealed a widespread metastatic disease. She was treated with palliative radiotherapy, chemotherapy and zolendronate. She had an aggressive clinical course and succumbed to her illness within four months after diagnosis of dual malignancy. There is a high incidence of gall bladder carcinoma along the Gangetic belt of Northern India. Presence of dual malignancy with gall bladder carcinoma as one primary in these geographic location needs to be further explored for sporadic environmental factors or other genetic alterations as possible causative factors

Do Gestational Obesity and Gestational Diabetes Have an Independent Effect on Neonatal Adiposity? Results of Mediation Analysis from a Cohort Study in South India.

PURPOSE: Neonates born to mothers with obesity or gestational diabetes mellitus (GDM) have an increased chance of various metabolic disorders later in life. In India, it is unclear whether maternal obesity or GDM is related to offspring adiposity. We aimed to understand the independent effect of maternal obesity and GDM with neonatal adiposity and whether GDM has a mediating effect between maternal obesity and neonatal adiposity. METHODS: We recruited a cohort of 1120 women (between April 2016 and February 2019) from the public hospitals in Bangalore, India, who voluntarily agreed to participate and provided written informed consent. The primary outcome was neonatal adiposity, defined as the sum of skinfold thickness >85th percentile. Exposure included maternal obesity, defined as >90th percentile of skinfold thickness. GDM, the potential mediator, was classified using the World Health Organization criteria by oral glucose tolerance test. Binary logistic regression was applied to test the effect of maternal obesity and GDM on neonatal adiposity, adjusting for potential confounders. We used Paramed command in STATA version 14 for analyzing mediating effects. RESULTS: We found that maternal obesity (odds ratio (OR)=2.16, 95% CI 1.46, 3.18) and GDM (OR=2.21, 95% CI1.38, 3.52) have an independent effect on neonatal adiposity. GDM significantly mediates 25.2% of the total effect between maternal obesity and neonatal adiposity, (natural direct effect OR = 1.16 95% CI 1.04, 1.30) with significant direct effect of maternal obesity (natural direct effect OR = 1.90 95% CI 1.16, 3.10) and significant total effect (OR=2.20 95% CI 1.35, 3.58). CONCLUSION: We showed that maternal obesity and GDM are independently associated with offspring adiposity. Also, GDM mediates the association of maternal obesity on adiposity in children. Interventions focused on obesity prevention in women, and effective screening and management of GDM may contribute to reducing childhood obesity in India

Small for gestational age babies and depressive symptoms of mothers during pregnancy: Results from a birth cohort in India

Background: Annually, more than a million Low birthweight (LBW) are born in India, often afflicting disadvantaged families. Several studies have undertaken association of poverty, nutritional status, and obstetric factors with LBW. Through our study, we aimed to examine the possibility of any relation between Edinburgh Postnatal Depression Scale (EPDS) score measured during pregnancy with incidence of babies born Small for Gestational Age (SGA). Moreover, we explored if there is any utility for identifying a cut-off point of EPDS for predicting SGA.Methods: Pregnant women attending the antenatal clinic at a public hospital between 14 to 32 weeks were recruited from April 2016 to Oct 2017. The EPDS was administered to assess depression through face-to-face interviews. Newborn anthropometry was performed post-delivery. For analysis, birth weight 90th percentile as Large for Gestational Age (LGA).Results: Prevalence of depressive symptoms (EPDS score >11) was 16.5% (n=108/654) in antenatal mothers. These women delivered a higher proportion of SGA babies (21.3 v/s 15.8) and LGA (9.3 v/s 3.3) compared to women with no symptoms. The odds of women giving birth to a child with SGA were twice as high for women with EPDS scores >11 (adjusted OR = 2.03; 95% CI = 1.12 – 3.70) compared to the women with EPDS scores of ≤11. In terms of Area under curve (AUC), EPDS 11 cut off (AUC: 0.757, CI 0.707- 0.806) was same as EPDS 12 cut-off (AUC: 0.757, CI 0.708- 0.807), which was slightly lower than EPDS 13 cut off (AUC: 0.759 CI 0.709- 0.809).Conclusions: We found a strong association of antenatal depressive symptoms during pregnancy with SGA measured by EPDS. Thus, we recommend implementation of timely and effective screening, diagnostic services, and evidence-based antenatal mental health services in order to combat SGA, and further associated-metabolic syndromes

Design and evaluation of virtual human mediated tasks for assessment of depression and anxiety

Virtual human technologies are now being widely explored as therapy tools for mental health disorders including depression and anxiety. These technologies leverage the ability of the virtual agents to engage in naturalistic social interactions with a user to elicit behavioural expressions which are indicative of depression and anxiety. Research efforts have focused on optimising the human-like expressive capabilities of the virtual human, but less attention has been given to investigating the effect of virtual human mediation on the expressivity of the user. In addition, it is still not clear what an optimal task is or what task characteristics are likely to sustain long term user engagement. To this end, this paper describes the design and evaluation of virtual human-mediated tasks in a user study of 56 participants. Half the participants complete tasks guided by a virtual human, while the other half are guided by text on screen. Self-reported PHQ9 scores, biosignals and participants' ratings of tasks are collected. Findings show that virtual-human mediation influences behavioural expressiveness and this observation differs for different depression severity levels. It further shows that virtual human mediation improves users' disposition towards tasks

Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance.

Hematopoietic stem cells (HSCs) have the potential to replenish the blood system for the lifetime of the organism. Their 2 defining properties, self-renewal and differentiation, are tightly regulated by the epigenetic machineries. Using conditional gene-knockout models, we demonstrated a critical requirement of lysine acetyltransferase 5 (Kat5, also known as Tip60) for murine HSC maintenance in both the embryonic and adult stages, which depends on its acetyltransferase activity. Genome-wide chromatin and transcriptome profiling in murine hematopoietic stem and progenitor cells revealed that Tip60 colocalizes with c-Myc and that Tip60 deletion suppress the expression of Myc target genes, which are associated with critical biological processes for HSC maintenance, cell cycling, and DNA repair. Notably, acetylated H2A.Z (acH2A.Z) was enriched at the Tip60-bound active chromatin, and Tip60 deletion induced a robust reduction in the acH2A.Z/H2A.Z ratio. These results uncover a critical epigenetic regulatory layer for HSC maintenance, at least in part through Tip60-dependent H2A.Z acetylation to activate Myc target genes.Cancer Research UK, Wellcome Trust, National Institutes of Health, Singapore state fundin