The Genetics and Epigenetics of Centromeres in Cancer

The centromere is an essential structure required for the faithful segregation of chromosomes during mitosis, a process that is significantly dysregulated in cancer. The nucleic acid sequences that dominate the centromeric landscape are α-satellites, arrays of 171 base-pair monomer units arranged into higher-order arrays throughout the centromere. Nucleosomes that replace the canonical histone H3 with the centromeric H3 variant CENPA epigenetically mark the centromeric locus. Modern genomics and epigenomics are, however, unable to navigate the highly repetitive structure of this region, a technical shortcoming that greatly hinders the ability to study their role in human malignancy, which is the second leading cause of death globally. Methodologies aimed at characterizing centromeric sequence and function are thus needed to effectively study the genetics and molecular biology of the centromere in cancer. Our group has developed quantitative PCR assays capable of detecting chromosome-specific α-satellite sequences. This novel methodology has enabled us to study centromeres in the contexts of normal biology and human disease. We demonstrate in this thesis that centromeres undergo both genetic and epigenetic alterations in the setting of cancer. Specifically, centromeric α-satellite sequences and pericentromeric HERV-K111 retroviral sequences experience copy number reductions and sequence homogenization in neoplastic cells and tissue. Furthermore, CENPA, the H3 variant that defines centromeric chromatin, was observed to be overexpressed across multiple cancer types, with functional significance to prostate cancer phenotypes. Intriguingly, we show that overexpressed CENPA possesses a previously uncharacterized function as a putative regulator of gene transcription of important cell cycle, centromere, and kinetochore genes, through ectopic localization to their respective transcriptional start sites. Our findings collectively underscore the necessity of studying diseases of cell division (i.e. cancer) from the perspectives of centromere genetics and epigenetics. Further insight into the mechanistic underpinnings of centromere derangements in cancer will provide additional molecular context to our understanding of this fundamental structure, thus providing opportunities to therapeutically reconfigure centromeres to structurally emulate their normal conformation. Repairing the form and function of this structure that is ubiquitously important for cancer proliferation may prove to be a viable and efficacious therapeutic strategy that has pan-cancer clinical potential.PHDCancer Biology PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/167914/1/aksaha_1.pd

Evaluation of anti-inflammatory effect of beetroot extract in animal models

Background: Inflammation is complex biological response of body tissues to foreign particles or pathogens. However, adverse effects of anti-inflammatory drugs, necessitate the search for a novel compound from herbal origin. Beta vulgaris rubra or red beetroot, a vegetable plant, is known to possess various beneficial effects. Present study aimed to evaluate the anti inflammatory effect of beet roots in animal models.Methods: Carrageenan-induced and Complete Freund’s adjuvant-induced rat paw edema model were used to assess the acute and chronic anti- inflammatory potential of the Beetroot as compared to standard drug, Diclofenac Sodium.Results: Oral administration of Beetroot extract showed carrageenan-induced rat paw edema inhibition by 26.9%, 34.6% and 50% for beetroot 100mg/Kg, 200mg/Kg and 400mg/Kg, respectively, at the end of four hours. In vivo results noted that percentage inhibition of paw volume and ankle diameter of the Complete Freund’s adjuvant-induced rats were significantly higher for the groups consuming 100 and 200mg/Kg Beetroot extracts. Paw volume of the rats in these two groups reduced by 35% and 30% respectively as compared to the control.Conclusions: Thus, beetroot was found to possess anti-inflammatory property in animals. Further investigations are essential to validate the bioactive components responsible for this property

System Analysis and Design of Armament Integrated Management System

Proof and trial activity in a dynamic test range is a complex, sensitive, and herculean activity. It is a system comprising critical functions that accept various armament inputs and produces proof results as output, processing various critical data and sensitive activities in between. Automation of the existing system is a step for reliable, secure, smooth operation and easy maintainability of the system that makes it synchronized with the latest development of range technology. Understanding the flow of data through these functions requires extensive study to realize different inter-linked activities involved with the functions of this system. This paper presents the flow of activities in the automation of dynamic test range of Proof & Experimental Establishment through context level diagram, process flow diagram, data flow diagram, and entity-relationship diagram. Realization of armament integrated management system will be through resilient and high bandwidth network backbone which is a part of this paper. Cloud computing is the latest development in the information technology. This paper also analyses the appropriate model of cloud computing for porting the system in the cloud.Science Journal, Vol. 64, No. 6, November 2014, pp.524-529, DOI:http://dx.doi.org/10.14429/dsj.64.811

Histologic and morphometric study of human placenta in gestational diabetes mellitus

Aims: The aim was to study morphometry, site of umbilical cord insertion and histological changes in placentae of women with gestational diabetes mellitus and compare the results with those of normal pregnancies and observe the perinatal outcome. Methods: It was an observational, correlational study of 130 placenta specimens collected from labour room and operation theatre of Department of Gynaecology & Obstetrics, Institute of Post Graduate Medical Education and Research, Kolkata. The subjects were mothers who attended antenatal clinic of the hospital regularly and delivered their babies in the same hospital. Cases were selected randomly, and divided in two groups: group A consisted of mothers having normal, uncomplicated pregnancy, group B consisted of mothers whose pregnancies were complicated by gestational diabetes mellitus. Morphometry, site of umbilical cord insertion and histological changes in placentae of all women were recorded. Perinatal outcome of the cases were also registered. The statistical methods used were chi-square test and Mann-Whitney U test.Results: It was observed that the placentae of diabetic mothers were significantly bigger in size, weight, volume, area, thickness, diameter and circumference than those of normal mothers. Also, in diabetic mothers, there was significant increase in villous oedema, fibrin deposition, calcification and congestion of blood vessels. These placental changes were significantly correlated with birth weights of babies. Out of 70 mothers in Group B, 65 had live births, 5 had still-born babies.Conclusions: Placentae of women with GDM showed several changes that may be associated with impaired functioning, leading to bad perinatal outcome

Pseudo-stem banana fiber as a potential low-cost adsorbent to remove methylene blue from synthetic wastewater

In this work, pseudo-stem banana (Musa acuminata) (PBF) fiber was utilized as a potential low-cost natural adsorbent to uptake methylene blue (MB) dye from synthetic wastewater by batch adsorption process. Different adsorption factors like contact time, pH, initial concentration, and adsorbent dosage were explored and found that the separation process is strongly pH dependent. Additionally, the adsorption data were fitted with various adsorption isotherms like Langmuir, Freundlich, Temkin, and Dubinin-Radhushkevich models to detect the adsorption equilibrium phenomena. Reaction kinetics was inspected using pseudo-first-order and second-order kinetic models. Mass transfer and intra-particle diffusion analyses indicate the adsorption mechanism of the system described particularly in the context. Furthermore, scanning electron spectroscopy (SEM) and Fourier transformed infrared spectroscopy (FTIR) were conducted to get the morphology and surface properties of the adsorbent, respectively. As a result, the as-prepared banana fiber can be proposed as a cheap suitable adsorbent to separate dyestuffs from industrial wastewater.Peer reviewe

A new model for diabetes-focused capacity building – lessons from Sri Lanka

Abstract Sri Lanka is experiencing a rapid increase in the number of people with diabetes mellitus (DM) due to population growth and aging. Physician shortages, outdated technology, and insufficient health education have contributed to the difficulties associated with managing the burden of disease. New models of chronic disease management are needed to address the increasing prevalence of DM. Medical students, business students, and faculty members from the University of Michigan partnered with the Grace Girls’ Home, Trincomalee General Hospital, and Selvanayakapuram Central Hospital to identify and train diabetes-focused medical assistants (MAs) to collect and enter patient data and educate patients about their disease. Return visits to these MAs were encouraged so that patient progress and disease progression could be tracked longitudinally. Data entry was conducted through a cloud-based mechanism, facilitating patient management and descriptive characterization of the population. We implemented this pilot program in June 2016 in coordination with Trincomalee General Hospital and Selvanayakapuram Central Hospital. Over a 12-month period, 93 patients were systematically assessed by the medical assistants. All patients received education and were provided materials after the visit to better inform them about the importance of controlling their disease. Fifteen percent (14/93) of patients returned for follow-up consultation. Trained MAs have the potential to provide support to physicians working in congested health systems in low-resource settings. Public investment in training programs for MAs and greater acceptance by physicians and patients will be essential for handling the growing burden associated with chronic illnesses like DM. Trained MAs may also play a role in improved patient education and awareness regarding diabetes self-management.https://deepblue.lib.umich.edu/bitstream/2027.42/146742/1/40842_2018_Article_74.pd

Expansion of a novel endogenous retrovirus throughout the pericentromeres of modern humans

Abstract Background Approximately 8% of the human genome consists of sequences of retroviral origin, a result of ancestral infections of the germ line over millions of years of evolution. The most recent of these infections is attributed to members of the human endogenous retrovirus type-K (HERV-K) (HML-2) family. We recently reported that a previously undetected, large group of HERV-K (HML-2) proviruses, which are descendants of the ancestral K111 infection, are spread throughout human centromeres. Results Studying the genomes of certain cell lines and the DNA of healthy individuals that seemingly lack K111, we discover new HERV-K (HML-2) members hidden in pericentromeres of several human chromosomes. All are related through a common ancestor, termed K222, which is a virus that infected the germ line approximately 25 million years ago. K222 exists as a single copy in the genomes of baboons and high order primates, but not New World monkeys, suggesting that progenitor K222 infected the primate germ line after the split between New and Old World monkeys. K222 exists in modern humans at multiple loci spread across the pericentromeres of nine chromosomes, indicating it was amplified during the evolution of modern humans. Conclusions Copying of K222 may have occurred through recombination of the pericentromeres of different chromosomes during human evolution. Evidence of recombination between K111 and K222 suggests that these retroviral sequences have been templates for frequent cross-over events during the process of centromere recombination in humans.http://deepblue.lib.umich.edu/bitstream/2027.42/111301/1/13059_2015_Article_641.pd

Whole-Genome Sequence of Drug-Resistant Mycobacterium tuberculosis Strain S7, Isolated from a Patient with Pulmonary Tuberculosis

Over the past decades, drug-resistant Mycobacterium tuberculosis strains have presented a significant challenge, with inadequate diagnosis of tuberculosis (TB) cases. Here, we report the draft whole-genome sequence of drug-resistant M. tuberculosis strain S7, which was isolated from a patient from Tripura, India, who was diagnosed with pulmonary TB