Evidence that public database records for many cancer-associated genes reflect a splice form found in tumors and lack normal splice forms

Alternative splicing is widespread in the human genome, and it appears that many genes display different splice forms in cancerous tissue than in normal human tissues. However, since cDNAs for many cancer-associated genes were originally cloned from tumor samples, it is important to ask whether this repertoire of cDNAs provides a complete or representative picture of the transcript isoforms found in normal tissues. To answer this, we used bioinformatics and RT–PCR to identify novel splice forms, focusing on in-frame exonskips, for a panel of 50 cancer-associated genes in normal tissue samples. These data show that in nearly two-thirds of the genes, normal tissues expressed previously unknown splice forms, of which 40% were normally a dominant splice form. Surprisingly, the tumor-associated splice forms were twice as likely to be represented in GenBank than their normal tissue-associated splice forms, most likely because 70% of the mRNAs in GenBank for these genes were cloned from tumor samples. As an example, we describe a novel normal splice form of IKBβ, an important regulator of the NFκB pathway. Our data suggest that systematic re-evaluation of cancer genes' splice forms in normal tissue will yield insights into their distinct functions in normal tissues and in cancer. Our database contains 1308 novel normal splice forms, including many known cancer genes

An expectation-maximization algorithm for probabilistic reconstructions of full-length isoforms from splice graphs.

Reconstructing full-length transcript isoforms from sequence fragments (such as ESTs) is a major interest and challenge for bioinformatic analysis of pre-mRNA alternative splicing. This problem has been formulated as finding traversals across the splice graph, which is a directed acyclic graph (DAG) representation of gene structure and alternative splicing. In this manuscript we introduce a probabilistic formulation of the isoform reconstruction problem, and provide an expectation-maximization (EM) algorithm for its maximum likelihood solution. Using a series of simulated data and expressed sequences from real human genes, we demonstrate that our EM algorithm can correctly handle various situations of fragmentation and coupling in the input data. Our work establishes a general probabilistic framework for splice graph-based reconstructions of full-length isoforms

The ASAP II database: analysis and comparative genomics of alternative splicing in 15 animal species

We have greatly expanded the Alternative Splicing Annotation Project (ASAP) database: (i) its human alternative splicing data are expanded ∼3-fold over the previous ASAP database, to nearly 90 000 distinct alternative splicing events; (ii) it now provides genome-wide alternative splicing analyses for 15 vertebrate, insect and other animal species; (iii) it provides comprehensive comparative genomics information for comparing alternative splicing and splice site conservation across 17 aligned genomes, based on UCSC multigenome alignments; (iv) it provides an ∼2- to 3-fold expansion in detection of tissue-specific alternative splicing events, and of cancer versus normal specific alternative splicing events. We have also constructed a novel database linking orthologous exons and orthologous introns between genomes, based on multigenome alignment of 17 animal species. It can be a valuable resource for studies of gene structure evolution. ASAP II provides a new web interface enabling more detailed exploration of the data, and integrating comparative genomics information with alternative splicing data. We provide a set of tools for advanced data-mining of ASAP II with Pygr (the Python Graph Database Framework for Bioinformatics) including powerful features such as graph query, multigenome alignment query, etc. ASAP II is available at

Differential Fault Attack on Rasta and FiLIP-DSM

In this paper we propose Differential Fault Attack (DFA) on two Fully Homomorphic Encryption (FHE) friendly stream ciphers Rasta and . Design criteria of Rasta rely on affine layers and nonlinear layers, whereas relies on permutations and a nonlinear fil- ter function. Here we show that the secret key of these two ciphers can be recovered by injecting only 1 bit fault in the initial state. Our DFA on full round (# rounds = 6) Rasta with 219 block size requires only one block (i.e., 219 bits) of normal and faulty keystream bits. In the case of our DFA on FiLIP-430 (one instance of ), we need 30000 normal and faulty keystream bits

"Just as curry is needed to eat rice, antibiotics are needed to cure fever"-a qualitative study of individual, community and health system-level influences on community antibiotic practices in rural West Bengal, India.

OBJECTIVES: To understand community antibiotic practices and their drivers, comprehensively and in contextually sensitive ways, we explored the individual, community and health system-level factors influencing community antibiotic practices in rural West Bengal in India. DESIGN: Qualitative study using focus group discussions and in-depth interviews. SETTING: Two contrasting village clusters in South 24 Parganas district, West Bengal, India. Fieldwork was conducted between November 2019 and January 2020. PARTICIPANTS: 98 adult community members (42 men and 56 women) were selected purposively for 8 focus group discussions. In-depth interviews were conducted with 16 community key informants (7 teachers, 4 elected village representatives, 2 doctors and 3 social workers) and 14 community health workers. RESULTS: Significant themes at the individual level included sociodemographics (age, gender, education), cognitive factors (knowledge and perceptions of modern antibiotics within non-biomedical belief systems), affective influences (emotive interpretations of appropriate medicine consumption) and economic constraints (affordability of antibiotic courses and overall costs of care). Antibiotics were viewed as essential fever remedies, akin to antipyretics, with decisions to halt mid-course influenced by non-biomedical beliefs associating prolonged use with toxicity. Themes at the community and health system levels included the health stewardship roles of village leaders and knowledge brokering by informal providers, pharmacists and public sector accredited social health activists. However, these community resources lacked sufficient knowledge to address people's doubts and concerns. Qualified doctors were physically and socially inaccessible, creating a barrier to seeking their expertise. CONCLUSIONS: The interplay of sociodemographic, cognitive and affective factors, and economic constraints at the individual level, underscores the complexity of antibiotic usage. Additionally, community leaders and health workers emerge as crucial players, yet their knowledge gaps and lack of empowerment pose challenges in addressing public concerns. This comprehensive analysis highlights the need for targeted interventions that address both individual beliefs and community health dynamics to promote judicious antibiotic use

Genomic characterization of Plasmodium falciparum genes associated with anti-folate drug resistance and treatment outcomes in eastern India: A molecular surveillance study from 2008 to 2017

IntroductionAfter being used vigorously for the previous two decades to treat P. falciparum, chloroquine and sulfadoxine-pyrimethamine were replaced in 2009 with an artemisinin-based combination therapy (artesunate-sulfadoxine-pyrimethamine) in an effort to combat multidrug-resistant parasites.MethodsWe set out to assess the genetic variants of sulfadoxine-pyrimethamine resistance and the effectiveness of its treatment in eastern India prior to, during, and 6 to 8 years following the introduction of the new pharmacological regime. In 2008-2009, 318 P. falciparum–positive patients got the recommended doses of sulfadoxine-pyrimethamine. We used 379 additional isolates from 2015 to 2017 in addition to the 106 isolates from 2010. All 803 isolates from two study sites underwent in vitro sulfadoxine-pyrimethamine sensitivity testing and genomic characterisation of sulfadoxine-pyrimethamine resistance (pfdhfr and pfdhps).ResultsIn Kolkata and Purulia, we observed early treatment failure in 30.7 and 14.4% of patients, respectively, whereas recrudescence was found in 8.1 and 13.4% of patients, respectively, in 2008–2009. In 2017, the proportion of in vitro pyrimethamine and sulfadoxine resistance steadily grew in Kolkata and Purulia despite a single use of sulfadoxine-pyrimethamine. Treatment failures with sulfadoxine-pyrimethamine were linked to quintuple or quadruple pfdhfr- pfdhps mutations (AICII-AGKAT, AICII-AGKAA, AICII-SGKGT, AICII-AGKAA, AICNI-AGKAA) in 2008–2009 (p < 0.001). The subsequent spread of mutant-haplotypes with higher in vitro sulfadoxine-pyrimethamine resistance (p < 0.001), such as the sextuple (dhfr-AIRNI+dhps-AGEAA, dhfr-ANRNL+dhps-AGEAA) and septuple (dhfr-AIRNI+dhps-AGEAT), mutations were observed in 2015-2017.DiscussionThis successive spread of mutations with high in vitro sulfadoxine-pyrimethamine resistance confirmed the progressive increase in antifolate resistance even after an 8-year withdrawal of sulfadoxine-pyrimethamine

Immune Differentiation Regulator p100 Tunes NF-κB Responses to TNF

Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings

Summary of the Activities of the Working Group I on High Energy and Collider Physics

This is a summary of the projects undertaken by the Working Group I on High Energy Collider Physics at the Eighth Workshop on High Energy Physics Phenomenology (WHEPP8) held at the Indian Institute of Technology, Mumbai, January 5-16, 2004. The topics covered are (i) Higgs searches (ii) supersymmetry searches (iii) extra dimensions and (iv) linear collider.Comment: summary of Working Group I at the Eighth Workshop on High Energy Physics Phenomenology (WHEPP8), I.I.T., Mumbai, January 5-16, 200

Changes in hypertension prevalence, awareness, treatment and control rates over 20 years in National Capital Region of India: results from a repeat cross-sectional study.

BACKGROUND AND OBJECTIVES: Despite being one of the leading risk factors of cardiovascular mortality, there are limited data on changes in hypertension burden and management from India. This study evaluates trend in the prevalence, awareness, treatment and control of hypertension in the urban and rural areas of India's National Capital Region (NCR). DESIGN AND SETTING: Two representative cross-sectional surveys were conducted in urban and rural areas (survey 1 (1991-1994); survey 2 (2010-2012)) of NCR using similar methodologies. PARTICIPANTS: A total of 3048 (mean age: 46.8±9.0 years; 52.3% women) and 2052 (mean age: 46.5±8.4 years; 54.2% women) subjects of urban areas and 2487 (mean age: 46.6±8.8 years; 57.0% women) and 1917 (mean age: 46.5±8.5 years; 51.3% women) subjects of rural areas were included in survey 1 and survey 2, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: Hypertension was defined as per Joint National Committee VII guidelines. Structured questionnaire was used to measure the awareness and treatment status of hypertension. A mean systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg was defined as control of hypertension among the participants with hypertension. RESULTS: The age and sex standardised prevalence of hypertension increased from 23.0% to 42.2% (p<0.001) and 11.2% to 28.9% (p<0.001) in urban and rural NCR, respectively. In both surveys, those with high education, alcohol use, obesity and high fasting blood glucose were at a higher risk for hypertension. However, the change in hypertension prevalence between the surveys was independent of these risk factors (adjusted OR (95% CI): urban (2.3 (2.0 to 2.7)) rural (3.1 (2.4 to 4.0))). Overall, there was no improvement in awareness, treatment and control rates of hypertension in the population. CONCLUSION: There was marked increase in prevalence of hypertension over two decades with no improvement in management