Open source tool for prediction of genome wide protein-protein interaction network based on ortholog information

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions are crucially important for cellular processes. Knowledge of these interactions improves the understanding of cell cycle, metabolism, signaling, transport, and secretion. Information about interactions can hint at molecular causes of diseases, and can provide clues for new therapeutic approaches. Several (usually expensive and time consuming) experimental methods can probe protein - protein interactions. Data sets, derived from such experiments make the development of prediction methods feasible, and make the creation of protein-protein interaction network predicting tools possible.</p> <p>Methods</p> <p>Here we report the development of a simple open source program module (<it>OpenPPI_predictor</it>) that can generate a putative protein-protein interaction network for target genomes. This tool uses the orthologous interactome network data from a related, experimentally studied organism.</p> <p>Results</p> <p>Results from our predictions can be visualized using the <it>Cytoscape </it>visualization software, and can be piped to downstream processing algorithms. We have employed our program to predict protein-protein interaction network for the human parasite roundworm <it>Brugia malayi</it>, using interactome data from the free living nematode <it>Caenorhabditis elegans</it>.</p> <p>Availability</p> <p>The <it>OpenPPI_predictor </it>source code is available from <url>http://tools.neb.com/~posfai/</url>.</p

Accurate Reconstruction of Molecular Phylogenies for Proteins Using Codon and Amino Acid Unified Sequence Alignments (CAUSA)

Based on molecular clock hypothesis, and neutral theory of molecular evolution, molecular phylogenies have been widely used for inferring evolutionary history of organisms and individual genes. Traditionally, alignments and phylogeny trees of proteins and their coding DNA sequences are constructed separately, thus often different conclusions were drawn. Here we present a new strategy for sequence alignment and phylogenetic tree reconstruction, codon and amino acid unified sequence alignment (CAUSA), which aligns DNA and protein sequences and draw phylogenetic trees in a unified manner. We demonstrated that CAUSA improves both the accuracy of multiple sequence alignments and phylogenetic trees by solving a variety of molecular evolutionary problems in virus, bacteria and mammals. Our results support the hypothesis that the molecular clock for proteins has two pointers existing separately in DNA and protein sequences. It is more accurate to read the molecular clock by combination (additive) of these two pointers, since the ticking rates of them are sometimes consistent, sometimes different. CAUSA software were released as Open Source under GNU/GPL license, and are downloadable free of charge from the website www.dnapluspro.com

LSF small molecule inhibitors phenocopy LSF-targeted siRNAs causing mitotic defects and senescence in cancer cells

The oncogene LSF has been proposed as a novel target with therapeutic potential for multiple cancers. LSF overexpression correlates with poor prognosis for both liver and colorectal cancers, for which there are currently limited therapeutic treatment options. In particular, molecularly targeted therapies for hepatocellular carcinoma targeting cellular receptors and kinases have yielded disappointing clinical results, providing an urgency for targeting distinct mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple pre-clinical models of hepatocellular carcinoma, with no observable toxicity. To understand how the inhibitors impact cancer cell proliferation, we characterized the cellular phenotypes that result from loss of LSF activity. Phenotypically, inhibition of LSF activity induced a mitotic delay with condensed, but unaligned, chromosomes. This mitotic disruption resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence. The cellular phenotypes observed upon FQI1 treatment were due specifically to the loss of LSF activity, as siRNA specifically targeting LSF produced nearly identical phenotypes. Taken together, these findings confirm that LSF is a promising therapeutic target for cancer treatment.First author draf

Technology-delivered adaptations of motivational interviewing for the prevention and management of chronic diseases: Scoping review

BACKGROUND: Motivational interviewing (MI) can increase health-promoting behaviors and decrease health-damaging behaviors. However, MI is often resource intensive, precluding its use with people with limited financial or time resources. Mobile health-based versions of MI interventions or technology-delivered adaptations of MI (TAMIs) might increase reach. OBJECTIVE: We aimed to understand the characteristics of existing TAMIs. We were particularly interested in the inclusion of people from marginalized sociodemographic groups, whether the TAMI addressed sociocontextual factors, and how behavioral and health outcomes were reported. METHODS: We employed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for scoping reviews to conduct our scoping review. We searched PubMed, CINAHL, and PsycInfo from January 1, 1996, to April 6, 2022, to identify studies that described interventions incorporating MI into a mobile or electronic health platform. For inclusion, the study was required to (1) describe methods/outcomes of an MI intervention, (2) feature an intervention delivered automatically via a mobile or electronic health platform, and (3) report a behavioral or health outcome. The exclusion criteria were (1) publication in a language other than English and (2) description of only in-person intervention delivery (ie, no TAMI). We charted results using Excel (Microsoft Corp). RESULTS: Thirty-four studies reported the use of TAMIs. Sample sizes ranged from 10 to 2069 participants aged 13 to 70 years. Most studies (n=27) directed interventions toward individuals engaging in behaviors that increased chronic disease risk. Most studies (n=22) oversampled individuals from marginalized sociodemographic groups, but few (n=3) were designed specifically with marginalized groups in mind. TAMIs used text messaging (n=8), web-based intervention (n=22), app + text messaging (n=1), and web-based intervention + text messaging (n=3) as delivery platforms. Of the 34 studies, 30 (88%) were randomized controlled trials reporting behavioral and health-related outcomes, 23 of which reported statistically significant improvements in targeted behaviors with TAMI use. TAMIs improved targeted health behaviors in the remaining 4 studies. Moreover, 11 (32%) studies assessed TAMI feasibility, acceptability, or satisfaction, and all rated TAMIs highly in this regard. Among 20 studies with a disproportionately high number of people from marginalized racial or ethnic groups compared with the general US population, 16 (80%) reported increased engagement in health behaviors or better health outcomes. However, no TAMIs included elements that addressed sociocontextual influences on behavior or health outcomes. CONCLUSIONS: Our findings suggest that TAMIs may improve some health promotion and disease management behaviors. However, few TAMIs were designed specifically for people from marginalized sociodemographic groups, and none included elements to help address sociocontextual challenges. Research is needed to determine how TAMIs affect individual health outcomes and how to incorporate elements that address sociocontextual factors, and to identify the best practices for implementing TAMIs into clinical practice

Increasing Referral of LBJ Patients to the Active Living After Cancer (ALAC) Program

https://openworks.mdanderson.org/sumexp21/1032/thumbnail.jp

Employment loss and food insecurity - race and sex disparities in the context of COVID-19

INTRODUCTION: Applying an intersectional framework, we examined sex and racial inequality in COVID-19-related employment loss (ie, job furlough, layoff, and reduced pay) and food insecurity (ie, quality and quantity of food eaten, food worry, and receipt of free meals or groceries) among residents in Saint Louis County, Missouri. METHODS: We used cross-sectional data from adults aged 18 or older (N = 2,146), surveyed by using landlines or cellular phones between August 12, 2020, and October 27, 2020. We calculated survey-weighted prevalence of employment loss and food insecurity for each group (Black female, Black male, White female, White male). Odds ratios for each group were estimated by using survey-weighted binary and multinomial logistic regression models. RESULTS: Black female residents had higher odds of being laid off, as compared with White male residents (OR = 2.61, 95% CI, 1.24-5.46). Both Black female residents (OR = 4.13, 95% CI, 2.29-7.45) and Black male residents (OR = 2.41, 95% CI, 1.15-5.07) were more likely to receive free groceries, compared with White male residents. Black female (OR = 4.25, 95% CI, 2.28-7.94) and White female residents (OR = 1.93, 95% CI, 1.04-3.60) had higher odds of sometimes worrying about food compared with White male residents. Black women also had higher odds of always or nearly always worrying about food, compared with White men (OR = 2.99, 95% CI, 1.52-5.87). CONCLUSION: Black women faced the highest odds of employment loss and food insecurity, highlighting the disproportionate impact of COVID-19 among people with intersectional disadvantages of being both Black and female. Interventions to reduce employment loss and food insecurity can help reduce the disproportionately negative social effects among Black women

Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer.

Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency1-5. Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies6-8. MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-β receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer9, is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion

Validation and calibration of next-generation sequencing to identify Epstein-Barr virus-positive gastric cancer in The Cancer Genome Atlas

The Epstein-Barr virus (EBV)-positive subtype of gastric adenocarcinoma is conventionally identified by in situ hybridization (ISH) for viral nucleic acids, but next-generation sequencing represents a potential alternative. We therefore determined normalized EBV read counts by whole genome, whole exome, mRNA and miRNA sequencing for 295 fresh-frozen gastric tumor samples. Formalin-fixed, paraffin-embedded tissue sections were retrieved for ISH confirmation of 13 high-EBV and 11 low-EBV cases. In pairwise comparisons, individual samples were either concordantly high or concordantly low by all genomic methods for which data were available. Empiric cut-offs of sequencing counts identified 26 (9%) tumors as EBV-positive. EBV-positivity or negativity by molecular testing was confirmed by EBER-ISH in all but one tumor evaluated by both approaches (kappa=0.91). EBV-positive gastric tumors may be accurately identified by quantifying viral sequences in genomic data. Simultaneous analyses of human and viral DNA, mRNA and miRNA could streamline tumor profiling for clinical care and research

A novel totivirus and piscine reovirus (PRV) in Atlantic salmon (Salmo salar) with cardiomyopathy syndrome (CMS)

<p>Abstract</p> <p>Background</p> <p>Cardiomyopathy syndrome (CMS) is a severe disease affecting large farmed Atlantic salmon. Mortality often appears without prior clinical signs, typically shortly prior to slaughter. We recently reported the finding and the complete genomic sequence of a novel piscine reovirus (PRV), which is associated with another cardiac disease in Atlantic salmon; heart and skeletal muscle inflammation (HSMI). In the present work we have studied whether PRV or other infectious agents may be involved in the etiology of CMS.</p> <p>Results</p> <p>Using high throughput sequencing on heart samples from natural outbreaks of CMS and from fish experimentally challenged with material from fish diagnosed with CMS a high number of sequence reads identical to the PRV genome were identified. In addition, a sequence contig from a novel totivirus could also be constructed. Using RT-qPCR, levels of PRV in tissue samples were quantified and the totivirus was detected in all samples tested from CMS fish but not in controls. <it>In situ </it>hybridization supported this pattern indicating a possible association between CMS and the novel piscine totivirus.</p> <p>Conclusions</p> <p>Although causality for CMS in Atlantic salmon could not be proven for either of the two viruses, our results are compatible with a hypothesis where, in the experimental challenge studied, PRV behaves as an opportunist whereas the totivirus might be more directly linked with the development of CMS.</p

Genomic alterations associated with mutational signatures, DNA damage repair and chromatin remodeling pathways in cervical carcinoma

Despite recent advances in the prevention of cervical cancer, the disease remains a leading cause of cancer-related deaths in women worldwide. By applying the GISTIC2.0 and/or the MutSig2CV algorithms on 430 whole-exome-sequenced cervical carcinomas, we identified previously unreported significantly mutated genes (SMGs) (including MSN, GPX1, SPRED3, FAS, and KRT8), amplifications (including NFIA, GNL1, TGIF1, and WDR87) and deletions (including MIR562, PVRL1, and NTM). Subset analyses of 327 squamous cell carcinomas and 86 non-squamous cell carcinomas revealed previously unreported SMGs in BAP1 and IL28A, respectively. Distinctive copy number alterations related to tumors predominantly enriched for *CpG- and Tp*C mutations were observed. CD274, GRB2, KRAS, and EGFR were uniquely significantly amplified within the Tp*C-enriched tumors. A high frequency of aberrations within DNA damage repair and chromatin remodeling genes were detected. Facilitated by the large sample size derived from combining multiple datasets, this study reveals potential targets and prognostic markers for cervical cancer.publishedVersio