MECHANISM AND FUNCTION OF SPLICEOSOMAL CLEAVAGE IN FISSION YEAST

Telomerase is the ribonucleoprotein complex that replenishes lost DNA sequences at the ends of chromosomes. At its core, telomerase consists of an RNA subunit (TERC) that provides the template and a catalytic protein component (TERT). Insufficient telomerase activity leads to various disorders like dyskeratosis congenita, aplastic anemia and idiopathic pulmonary fibrosis. How different mutations in the same gene lead to disparate symptoms and disorders is not clear. The overall objective of my project is to understand the biogenesis of telomerase in the genetically tractable eukaryote S. pombe, whose telomere maintenance machinery closely resembles that of humans. Our laboratory has previously shown that the mature 3' end of S. pombe telomerase RNA (TER1) is generated by the first step of spliceosomal splicing. The cis- and trans- acting factors that distinguish the single step spliceosomal cleavage in TER1 from the two-step splicing reaction that removes introns in other genes are being investigated. We now demonstrate that a strong branch site (BS), a long distance to the 3' splice site (SS) and a weak polypyrimidine tract (Py) tract act synergistically to attenuate the transition from the first to the second step of splicing. The observation that a strong BS antagonizes the second step of splicing in the context of TER1 suggests that the BS-U2 snRNA interactions are disrupted after the first step and thus earlier than previously thought. The slow transition from first to second step triggers the Prp22 DExD/H-box helicase- dependent rejection of the cleaved products and Prp43-dependent discard of the splicing intermediates. Related to this work, we have established that the spliceosome generates the 3' ends of telomerase RNA in S. cryophilus and S. octosporus albeit via a different mechanism involving U6 snRNA hyperstabilization at the 5'ss. Our findings explain how the spliceosome can function in 3' end processing and provide new insights into the mechanism of splicing

Influenza Surveillance: 2014–2015 H1N1 “Swine”-Derived Influenza Viruses from India

The 2014-2015 H1N1 outbreak in India has reportedly led to 800 fatalities. The reported influenza hemagglutinin sequences from India indicate that these viruses contain amino acid changes linked to enhanced virulence and are potentially antigenically distinct from the current vaccine containing 2009 (Cal0709) H1N1 viral hemagglutinin.United States. National Institutes of Health (R37 GM057073-13)United States. National Institutes of Health (1R01AI111395

Precedence-type Test based on Progressively Censored Samples

In this paper, we introduce precedence-type tests for testing the hypothesis that two distribution functions are equal, which is an extension of the precedence life-test rst proposed by Nelson (1963), when the two samples are progressively Type-II censored. The null distributions of the test statistics are derived. Critical values for some combination of sample sizes and censoring schemes for the proposed tests are presented. Then, we present the exact power functions under the Lehmann alternative, and compare the exact power as well as simulated power (under location-shift) of the proposed precedence test based on nonparametric estimates of CDF with other precedence-type tests. We then examine the power properties of the proposed test procedures through Monte Carlo simulations. Two examples are presented to illustrate all the test procedures discussed here. Finally, we make some concluding remarks.Precedence test; Product-limit estimator; Type-II progressive censoring; Life-testing; level of significance; power; Lehmann alternative; Monte Carlo simulations

On The Center Sets and Center Numbers of Some Graph Classes

For a set $S$ of vertices and the vertex $v$ in a connected graph $G$, $\displaystyle\max_{x \in S}d(x,v)$ is called the $S$-eccentricity of $v$ in $G$. The set of vertices with minimum $S$-eccentricity is called the $S$-center of $G$. Any set $A$ of vertices of $G$ such that $A$ is an $S$-center for some set $S$ of vertices of $G$ is called a center set. We identify the center sets of certain classes of graphs namely, Block graphs, $K_{m,n}$, $K_n-e$, wheel graphs, odd cycles and symmetric even graphs and enumerate them for many of these graph classes. We also introduce the concept of center number which is defined as the number of distinct center sets of a graph and determine the center number of some graph classes

Fair Sets of Some Class of Graphs

Given a non empty set $S$ of vertices of a graph, the partiality of a vertex with respect to $S$ is the difference between maximum and minimum of the distances of the vertex to the vertices of $S$. The vertices with minimum partiality constitute the fair center of the set. Any vertex set which is the fair center of some set of vertices is called a fair set. In this paper we prove that the induced subgraph of any fair set is connected in the case of trees and characterise block graphs as the class of chordal graphs for which the induced subgraph of all fair sets are connected. The fair sets of $K_{n}$, $K_{m,n}$, $K_{n}-e$, wheel graphs, odd cycles and symmetric even graphs are identified. The fair sets of the Cartesian product graphs are also discussed.Comment: 14 pages, 4 figure

Outcome analysis of surgically managed unstable burst fracture

Background:Burst fractures are common injuries of dorsolumbar spine. In indicated cases, surgery is the treatment of choice. Significant controversy exists regarding surgical intervention for these fractures. Posterior decompression, anterior decompression and instrumentation, and combined anterior decompression and posterior instrumentation have been recommended in various studies. Here we are going to evaluate unstable burst fractures of thoracic and lumbar spine treated by isolated anterior decompression and instrumented fusion with TSM-Bone graft composite.Methods: Prospective study of thirty-six cases of unstable fracture of thoracic and lumbar spine treated in Sri Ramachandra Medical centre from January 2011 to January 2014. The inclusion criteria were burst fractures of thoracic or lumbar spine complete or incomplete neurological deficit and burst fractures of thoracic or lumbar spine without neurological deficit but with mechanical instability. The exclusion criteria were pathological fractures, chance fracture, stable burst, wedge compression and osteoporotic compression fractures. The results were analyzed during the follow-up using the Pain – Visual analogue scale, Fusion status and radiographic parameter – K-angle .For pain score were given as 3,2,1 for absent, moderate and severe pain respectively. Regarding fusion status score of 3,2,1 were given when fusion was good, fair and no sign of fusion respectively.Results:Mean pre-operative K-angle was 28o. Average loss of correction at final follow up was 3o.Mean correction of K-angle was 140.Moderate to severe loss of correction of K- angle was observed in 4 patients. Mild to moderate pain in 5 patients treated with analgesics. Average TSM subsidence was 3mm.Conclusions:Bone graft composite provides stable biomechanical support to deficient anterior column in burst fractures and allows early rehabilitation and mobilization. Neural recovery may occur after anterior decompression, stabilization and fusion with TSM-Bone graft composite in dorsolumbar burst fractures with incomplete cord injury

Pipeline Interventions

We introduce the \emph{pipeline intervention} problem, defined by a layered directed acyclic graph and a set of stochastic matrices governing transitions between successive layers. The graph is a stylized model for how people from different populations are presented opportunities, eventually leading to some reward. In our model, individuals are born into an initial position (i.e. some node in the first layer of the graph) according to a fixed probability distribution, and then stochastically progress through the graph according to the transition matrices, until they reach a node in the final layer of the graph; each node in the final layer has a \emph{reward} associated with it. The pipeline intervention problem asks how to best make costly changes to the transition matrices governing people's stochastic transitions through the graph, subject to a budget constraint. We consider two objectives: social welfare maximization, and a fairness-motivated maximin objective that seeks to maximize the value to the population (starting node) with the \emph{least} expected value. We consider two variants of the maximin objective that turn out to be distinct, depending on whether we demand a deterministic solution or allow randomization. For each objective, we give an efficient approximation algorithm (an additive FPTAS) for constant width networks. We also tightly characterize the "price of fairness" in our setting: the ratio between the highest achievable social welfare and the highest social welfare consistent with a maximin optimal solution. Finally we show that for polynomial width networks, even approximating the maximin objective to any constant factor is NP hard, even for networks with constant depth. This shows that the restriction on the width in our positive results is essential

Enabling Fairness in Cloud Computing Infrastructures

Cloud computing has emerged as a key technology in many ways over the past few years, evidenced by the fact that 93% of the organizations is either running applications or experimenting with Infrastructure-as-a-Service (IaaS) cloud. Hence, to meet the demands of a large set of target audience, IaaS cloud service providers consolidate applications belonging to multiple tenants. However, consolidation of applications leads to performance interference with each other as these applications end up competing for the shared resources violating QoS of the executing tenants. This dissertation investigates the implications of interference in consolidated cloud computing environments to enable fairness in the execution of applications across tenants. In this context, this dissertation identifies three key issues in cloud computing infrastructures. We observe that tenants using IaaS public clouds share multi-core datacenter servers. In such a situation, we identify that the applications belonging to tenants might compete for shared architectural resources like Last Level Cache (LLC) and bandwidth to memory, slowing down the execution time of applications. This necessitates a need for a technique that can accurately estimate the slowdown in execution time caused due to multi-tenant execution. Such slowdown estimates can be used to bill tenants appropriately enabling fairness among tenants. For private datacenters, where performance degradation cannot be tolerated, it becomes critical to detect interference and investigate its root cause. Under such circumstances, there is a need for a real-time, lightweight and scalable mechanism that can detect performance degradation and identify the root cause resource which applications are contending for (I/O, network, CPU, Shared Cache). Finally, the advent of microservice computing environments, calls for a need to rethink resource management strategies in multi-tenant execution scenarios. Specifically, we observe that the visibility enabled by microservices execution framework can be exploited to achieve high throughput and resource utilization while still meeting Service Level Agreements (SLAs) in multi-tenant execution scenarios. To enable this, we propose techniques that can dynamically batch and reorder requests propagating through individual microservice stages within an application.PHDComputer Science & EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149844/1/ramsri_1.pd

Broadly Neutralizing Influenza Hemagglutinin Stem-Specific Antibody CR8020 Targets Residues that Are Prone to Escape due to Host Selection Pressure

Broadly neutralizing antibodies (bNAb) that target a conserved region of a viral antigen hold significant therapeutic promise. CR8020 is a bNAb that targets the stem region of influenza A virus (IAV) hemagglutinin (HA). CR8020 is currently being evaluated for prophylactic use against group 2 IAVs in phase II studies. Structural and computational analyses reported here indicate that CR8020 targets HA residues that are prone to antigenic drift and host selection pressure. Critically, CR8020 escape mutation is seen in certain H7N9 viruses from recent outbreaks. Furthermore, the ability of the bNAb Fc region to effectively engage activating Fcγ receptors (FCγR) is essential for antibody efficacy. In this regard, our data indicate that the membrane could sterically hinder the formation of HA-CR8020-FcγRIIa/HA-IgG-FcγRIIIa ternary complexes. Altogether, our analyses suggest that epitope mutability and accessibility to immune complex assembly are important attributes to consider when evaluating bNAb candidates for clinical development.National Institutes of Health (U.S.) (Merit Award R37 GM057073-13)Singapore. National Research Foundation (Singapore-MIT Alliance for Research and Technology

Dose to swallowing structures and dysphagia in head and neck Intensity Modulated Radiation Therapy – A long term prospective analysis

AimTo analyse the long term swallowing function in head and neck cancer patients and correlate with the dose to midline swallowing structures.BackgroundThe use of concurrent chemo radiation (CRT) as the present standard of care resulted in high rates of early and late toxicities. Dysphagia, aspiration, and xerostomia are early as well as late effects of radiation. Not many studies on the dysphagia scores during radiation and follow-up period have correlated dose to the swallowing structures, hence this study.Materials and MethodsHistologically proven head and neck cancer patients treated with intensity modulated radiation therapy were accrued in this study. The pharyngeal constrictors, larynx and cervical oesophagus were contoured and labelled as midline swallowing structures. The volume of the midline swallowing structures which were outside the PTV was delineated separately and was given a mean dose constraint of 45Gy. Dysphagia was assessed at baseline, weekly intervals during irradiation and follow-up at six years. The dose to the structures for swallowing was correlated with degree of dysphagia.ResultsThere was a gradual increase in the dysphagia grade during the course of radiation. There was a significant recovery of late dysphagia compared to dysphagia during the completion of radiation therapy in patients who receive