Stock Market Analysis of 10 Different Countries in the Period of Disease COVID-19

Our effort is to analyze the effect of the rampant over the economies of 10 affected nations by studying their stock market values during the COVID-19 episode. We have endowed the nations with their respective stock markets stated in brackets - Brazil(Ibovespa), Canada (S&P/TSX Composite), France (AEX), Germany (DAX 30), India (NIFTY 50), Italy (FTSE MIB), Russia (IMOEX), Spain (IBEX 35), U.K. (FTSE 100), U.S.A. (DOW JONES INDUSTRIAL AVERAGE). We have gathered the indices of stock per country from 2 March to 23rd June, collected from official website of respective stocks. In order to collect data, we had to inculcate the fundamental lessons of Statistics. R-software aided us to plot the curves of stock values providing an ease to master our project. We also formulated a Python 3.7 language program code to solidify analysis on various aspects of economy of the countries and comparison between these aspects

Human transcription factor protein interaction networks

Transcription factors (TFs) interact with several other proteins in the process of transcriptional regulation. Here the authors identify 6703 and 1536 protein-protein interactions for 109 different human TFs through BioID and AP-MS analyses, respectively. Transcription factors (TFs) interact with several other proteins in the process of transcriptional regulation. Here, we identify 6703 and 1536 protein-protein interactions for 109 different human TFs through proximity-dependent biotinylation (BioID) and affinity purification mass spectrometry (AP-MS), respectively. The BioID analysis identifies more high-confidence interactions, highlighting the transient and dynamic nature of many of the TF interactions. By performing clustering and correlation analyses, we identify subgroups of TFs associated with specific biological functions, such as RNA splicing or chromatin remodeling. We also observe 202 TF-TF interactions, of which 118 are interactions with nuclear factor 1 (NFI) family members, indicating uncharacterized cross-talk between NFI signaling and other TF signaling pathways. Moreover, TF interactions with basal transcription machinery are mainly observed through TFIID and SAGA complexes. This study provides a rich resource of human TF interactions and also act as a starting point for future studies aimed at understanding TF-mediated transcription.Peer reviewe

Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells

Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines. Method: The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses. Results: Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor dactolisib, showed synthetic lethality in several mTOR-addicted cell lines. Conclusions: Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.Peer reviewe

Ileocolonic-Targeted JAK Inhibitor: A Safer and More Effective Treatment for Inflammatory Bowel Disease

Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD

Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malig- nancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epi- genetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.Aggressiivinen NK-soluleukemia (ANKL) on elimistön luonnolliseen puolustusjärjestelmään kuuluvien luonnollisten tappajasolujen eli natural killer (NK) –solujen verisyöpä eli leukemia. ANKL:aan sairastuneet potilaat säilyvät käytössä olevilla solunsalpaaja- ja kantasolusiirtohoidoilla elossa keskimäärin vain joitakin kuukausia. Erityisesti aasialaisväestössä esiintyvän ANKL:n lisäksi NK-soluisiin syöpiin kuuluu Suomessakin harvinaisina tavattavia NK/T-soluisia lymfoomia. ANKL:n taustalla olevia hankittuja geenimuutoksia eli mutaatioita ei ole aiemmin selvitetty laajamittaisesti. Tutkimuksessa selvitimme ANKL:n tautimekanismeja kartoittamalla 14 potilaan syöpäsolujen geenimuutokset perimän proteiineja koodaavien geenien osalta ja tutkimalla pahanlaatuisten NK-solujen herkkyyttä yli 400 lääkeaineelle. Löysimme ANKL-potilaiden soluista geenimuutoksia etenkin STAT3- ja DDX3X-geeneissä, joita kumpiakin oli yli viidenneksellä potilaista. STAT3-mutaatioita on aiemmin todettu suurten granulaaristen lymfosyyttien (LGL) leukemiassa, sekä useissa muissakin T- ja NK-soluista lähtöisin olevissa syövissä. STAT3-mutaatiot ANKL:ssa viittaavat osin yhteisiin tautimekanismeihin näiden sukulaistautien kanssa. Kun yhdistimme ANKL-potilaiden geenitietoa aiemmin julkaistujen NK//T-solulymfoomapotilaista tuotettujen aineistojen kanssa, havaitsimme NK-soluisille syöville yhteisiä JAK-STAT-signalointigeenien monistumia. Etsimme myös potentiaalisia lääkeaineita NK-soluisten syöpien hoitoon testaamalla pahanlaatuisten NK-solujen herkkyyttä yli 400 lääkeaineelle. Havaitsimme NK-solujen olevan poikkeuksellisen herkkiä JAK-tyrosiinikinaasin ja BCL-perheen solukuolemaa säätelevien proteiinien estäjille. JAK-estäjillä pyritään hiljentämään samaa JAK-STAT-signalointireittiä, josta löysimme geneettisiä muutoksia ANKL-potilailla. Myeloproliferatiivisten sairauksien ja nivelreuman hoidossa käytettävillä JAK-estäjillä voitaisiin mahdollisesti tehostaa NK-soluisten syöpien hoitoa hyödyntämällä kyseisen solutyypin voimakasta riippuvuutta JAK-STAT-signaloinnin aktiivisuudesta. Tutkimuksemme valottaa geenitason muutoksia aiemmin tautimekanismeiltaan tuntemattomassa ANKL:ssa. Lääkeherkkyysseulonnan avulla pystyimme tunnistamaan potentiaalisia lääkeaineita ajatellen hoitokokeiluja harvinaisessa ANKL:ssa, jossa kliinisiä lääketutkimuksia pystytään harvoin toteuttamaan

The Prehistoric Indian Ayurvedic Rice Shashtika Is an Extant Early Domesticate With a Distinct Selection History

Fully domesticated rice is considered to have emerged in India at approximately 2000 B.C., although its origin in India remains a contentious issue. The fast-growing 60-days rice strain described in the Vedic literature (1900–500 B.C.) and termed Shashtika (Sanskrit) or Njavara (Dravidian etymology) in Ayurveda texts including the seminal texts Charaka Samhita and Sushruta Samhita (circa 660–1000 B.C.) is a reliable extant strain among the numerous strains described in the Ayurveda literature. We here report the results of the phylogenetic analysis of Njavara accessions in relation to the cultivars belonging to the known ancestral sub-groups indica, japonica, aromatic, and aus in rice gene pool and the populations of the progenitor species Oryza rufipogon using genetic and gene genealogical methods. Based on neutral microsatellite markers, Njavara produced a major clade, which comprised of minor clades corresponding to the genotypic classes reported in Njavara germplasm, and was distinct from that were produced by the ancestral sub-groups. Further we performed a phylogenetic analysis using the combined sequence of 19 unlinked EST-based sequence tagged site (STS) loci with proven potential in inferring rice phylogeny. In the phylogenetic tree also the Njavara genotypic classes were clearly separated from the ancestral sub-groups. For most loci the genealogical analysis produced a high frequency central haplotype shared among most of the rice samples analyzed in the study including Njavara and a set of O. rufipogon accessions. The haplotypes sharing pattern with the progenitor O. rufipogon suggests a Central India–Southeast Asia origin for Njavara. Results signify that Njavara is genetically distinct in relation to the known ancestral sub-groups in rice. Further, from the phylogenetic features together with the reported morphological characteristics, it is likely that Njavara is an extant early domesticate in Indian rice gene pool, preserved in pure form over millennia by the traditional prudence in on-farm selection using 60-days maturity, because of its medicinal applications

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Human Protein Phosphatase Interactions and Dynamics : Proteomic and Functional Perspective

Nearly all eukaryotic processes are regulated by cyclic phosphorylation-dephosphorylation of cellular signaling proteins, catalyzed by protein kinases and phosphatases, respectively. Until now, the kinases dominated the scientific research, however, in recent years only, the protein phosphatases have emerged as crucial regulators for setting up the levels and amplitude of phosphorylation-driven signaling events. Nevertheless, our molecular and biological awareness of these enzymes is still poor. This thesis aims to gather information on these vital aspects of phosphatase biology. Through our high-throughput systematic affinity-purification coupled to mass spectrometry (AP-MS) approach, we provide the first glimpse on the cellular protein protein interactions and functional networks of human protein phosphatases from three broad families: phosphoprotein phosphatase, metal-dependent phosphatase, and protein tyrosine phosphatase. Next, we obtained the comprehensive view on their enzymatic structure-activity relationship by utilizing inhibitor Okadaic acid, revealing the effect of catalytic disruption on the phosphatase interaction profile and on the phosphorylation status of their various sub-complex components. From here, we expanded the thesis by investigating the functional relevance of unique phosphates-kinase interaction in the context of specific signaling. From dephosphorylation and luciferase assays we established the role of PTPRA phosphatase in negatively regulating RET kinase activities and its down-stream Ras-MAPK pathway, showing RET as novel PTPRA substrate. By including RET cancer mutants- MEN2A and MEN2B, we, further, shed light on the tumor suppressor functions of PTPRA in human cancers. Taken together, this thesis not only provides a global landscape of human protein phosphatase complexes and their functions but also furnish a reliable resource for futuristic investigations.Lähes kaikkia eukaryoottisia prosesseja säätelee proteiinikinaasien ja fosfataasien katalysoimien solusignalointiproteiinien syklinen fosforylaatio-defosforylaatio. Tähän saakka kinaasit hallitsivat tieteellistä tutkimusta, mutta vain viime vuosina proteiinifosfataasit ovat kehittyneet keskeisinä säätäjinä fosforylaation ohjaamien signalointitapahtumien tasojen ja amplitudin määrittämiseksi. Näiden entsyymien molekyyli- ja biologinen tietoisuus on kuitenkin edelleen huono. Opinnäytetyön tavoitteena on kerätä tietoa näistä tärkeistä fosfataasibiologian näkökohdista. Suuritehoisen systemaattisen affiniteettipuhdistuksemme, joka on yhdistetty massaspektrometriaan (AP-MS), avulla tarjoamme ensimmäisen katseemme soluvalkuaisproteiinien vuorovaikutuksiin ja ihmisen proteiinifosfataasien toiminnallisiin verkkoihin kolmesta laajasta perheestä: fosfoproteiinifosfataasi, metallipohjainen fosfataasi ja proteiinityrosiinifosfataasi. Seuraavaksi saimme kattavan kuvan niiden entsymaattisesta rakenteen ja aktiivisuuden suhteesta käyttämällä inhibiittoria Okadaic-happoa, paljastamalla katalyyttisen häiriön vaikutuksen fosfataasi-vuorovaikutuksen profiiliin ja niiden eri kompleksikomponenttien fosforylaatiotilaan. Tästä lähtien laajensimme opinnäytetyötä tutkimalla ainutlaatuisen fosfaatti-kinaasivuorovaikutuksen toiminnallista merkitystä tietyn signaloinnin yhteydessä. Defosforylaatio- ja lusiferaasimäärityksistä totesimme PTPRA-fosfataasin roolin RET-kinaasiaktiivisuuden negatiivisessa säätelyssä ja sen alaspäin virtaavassa Ras-MAPK-reitissä, mikä osoittaa RET: n uutena PTPRA-substraattina. Mukaan lukien RET-syöpämutantit - MEN2A ja MEN2B, valaisimme lisäksi PTPRA: n tuumorisuppressorifunktioita ihmisen syövissä. Yhteenvetona tämä väitöskirja tarjoaa paitsi ihmisen proteiinifosfataasikompleksien globaalin maiseman ja niiden toiminnot, myös tarjoaa luotettavan resurssin futuristisille tutkimuksille

An institution-based assessment of health care worker on handwashing knowledge and behavior in a tertiary care hospital central India

Patients, governments, and regulatory agencies are increasingly concerned about infections associated with health care. This is not only due to the severity of the problem in terms of associated morbidity, mortality, and treatment costs, but also because it is becoming increasingly apparent that the majority of these are preventable. The medical community is witnessing unprecedented advances in both the understanding of the pathophysiology of infectious diseases and the global spread of multidrug-resistant infections in health care facilities. These factors, coupled with the scarcity of new antimicrobials, have necessitated a reevaluation of the role of fundamental infection prevention practises in contemporary health care. There is now irrefutable evidence that strict hand hygiene practises reduce the risk of infection transmission. With "Clean Care is Safer Care" as a top priority of the WHO's global initiative on patient safety programmes, the time has come for developing countries to formulate policies for the implementation of fundamental infection prevention practises in health care settings. This study focuses on hand hygiene, one of the simplest, least expensive, and least accepted forms of infection prevention

<span style="font-size:11.0pt;mso-bidi-font-size: 10.0pt;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA" lang="EN-US">Efficacy of different extraction procedures on antibacterial activity of stem bark of <i style="mso-bidi-font-style:normal">Butea monosperma</i> (Lam.) Kuntze</span>

551-556The search for new antimicrobials of natural origin derived from plants is still very important at present. Over the decades it has been observed that selection of solvents is critical for the extraction of active compounds from plants. In this study, three solvents namely, hexane, chloroform and methanol were employed to extract the active constituents from the stem bark of Butea monosperma (Lam.) Kuntze. High performance thin layer chromatography (HPTLC) was used to separate and establish the active constituents from the bark of the plant. Active constituent were tested for their antibacterial activity against five Gram positive bacteria (Bacillus subtilis, <i style="mso-bidi-font-style: normal">Enterococcus faecalis, Micrococcus luteus, Staphylococcus aureus and S. epidermidis) and seven Gram negative (Aeromonas hydrophila, Alcaligenes faecalis, Enterobacter aerogenes, Escherichia coli, <i style="mso-bidi-font-style: normal">Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella typhimurium) bacteria using agar well diffusion assay. Relatively low minimum inhibitory concentrations (MIC) were obtained for hexane and methanol extracts compared to chloroform extracts. Our findings revealed that hexane and methanol could be used as best solvents for extraction of antimicrobial compounds from <i style="mso-bidi-font-style: normal">B. monosperma bark. </span