Identification of gene-oriented exon orthology between human and mouse

<p>Abstract</p> <p>Background</p> <p>Gene orthology has been well studied in the evolutionary area and is thought to be an important implication to functional genome annotations. As the accumulation of transcriptomic data, alternative splicing is taken into account in the assignments of gene orthologs and the orthology is suggested to be further considered at transcript level. Whether gene or transcript orthology, exons are the basic units that represent the whole gene structure; however, there is no any reported study on how to build exon level orthology in a whole genome scale. Therefore, it is essential to establish a gene-oriented exon orthology dataset.</p> <p>Results</p> <p>Using a customized pipeline, we first build exon orthologous relationships from assigned gene orthologs pairs in two well-annotated genomes: human and mouse. More than 92% of non-overlapping exons have at least one ortholog between human and mouse and only a small portion of them own more than one ortholog. The exons located in the coding region are more conserved in terms of finding their ortholog counterparts. Within the untranslated region, the 5' UTR seems to have more diversity than the 3' UTR according to exon orthology designations. Interestingly, most exons located in the coding region are also conserved in length but this conservation phenomenon dramatically drops down in untranslated regions. In addition, we allowed multiple assignments in exon orthologs and a subset of exons with possible fusion/split events were defined here after a thorough analysis procedure.</p> <p>Conclusions</p> <p>Identification of orthologs at the exon level is essential to provide a detailed way to interrogate gene orthology and splicing analysis. It could be used to extend the genome annotation as well. Besides examining the one-to-one orthologous relationship, we manage the one-to-multi exon pairs to represent complicated exon generation behavior. Our results can be further applied in many research fields studying intron-exon structure and alternative/constitutive exons in functional genomic areas.</p

Differential and Joint Effects of Metformin and Statins on Overall Survival of Elderly Patients with Pancreatic Adenocarcinoma: A Large Population-Based Study.

Background: Published evidence indicates that individual use of metformin and statin is associated with reduced cancer mortality. However, their differential and joint effects on pancreatic cancer survival are inconclusive.Methods: We identified a large population-based cohort of 12,572 patients ages 65 years or older with primary pancreatic ductal adenocarcinoma (PDAC) diagnosed between 2008 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. Cox proportional hazards models with time-varying covariates adjusted for propensity scores were used to assess the association while controlling for potential confounders.Results: Of 12,572 PDAC patients, 950 (7.56%) had used metformin alone, 4,506 (35.84%) had used statin alone, and 2,445 (19.45%) were dual users. Statin use was significantly associated with improved overall survival [HR, 0.94; 95% confidence interval (CI), 0.90-0.98], and survival was more pronounced in postdiagnosis statin users (HR, 0.69; 95% CI, 0.56-0.86). Metformin use was not significantly associated with overall survival (HR, 1.01; 95% CI, 0.94-1.09). No beneficial effect was observed for dual users (HR, 1.00; 95% CI, 0.95-1.05).Conclusions: Our findings suggest potential benefits of statins on improving survival among elderly PDAC patients; further prospective studies are warranted to corroborate the putative benefit of statin therapy in pancreatic cancer.Impact: Although more studies are needed to confirm our findings, our data add to the body of evidence on potential anticancer effects of statins. Cancer Epidemiol Biomarkers Prev; 26(8); 1225-32. ©2017 AACR

Kawm Ntawv Qib Siab Understanding the psychosociocultural educational experiences of Hmong American undergraduates

Using a psychosociocultural framework, this study examined the educational experiences of 85 Hmong American undergraduates attending a predominantly-White university. Differences in class standing indicated that upper-division students reported higher confidence in college-related tasks than their lower-division counterparts, yet the upper-division students perceived a less-welcoming university environment that was incongruent with their cultural values than the lower-division undergraduates. Peer support, college self-efficacy and cultural congruity were salient variables in understanding Hmong American undergraduate’s educational experiences. The study’s limitations, future research directions, and implications for college administrators and faculty are discussed

Evaluation of viable dynamic treatment regimes in a sequentially randomized trial of advanced prostate cancer

We present new statistical analyses of data arising from a clinical trial designed to compare two-stage dynamic treatment regimes (DTRs) for advanced prostate cancer. The trial protocol mandated that patients be initially randomized among four chemotherapies, and that those who responded poorly be re-randomized to one of the remaining candidate therapies. The primary aim was to compare the DTRs' overall success rates, with success defined by the occurrence of successful responses in each of two consecutive courses of the patient's therapy. Of the 150 study participants, 47 did not complete their therapy as per the algorithm. However, 35 of them did so for reasons that precluded further chemotherapy, that is, toxicity and/or progressive disease. Consequently, rather than comparing the overall success rates of the DTRs in the unrealistic event that these patients had remained on their assigned chemotherapies, we conducted an analysis that compared viable switch rules defined by the per-protocol rules but with the additional provision that patients who developed toxicity or progressive disease switch to a non-prespecified therapeutic or palliative strategy. This modification involved consideration of bivariate per-course outcomes encoding both efficacy and toxicity.We used numerical scores elicited from the trial's principal investigator to quantify the clinical desirability of each bivariate per-course outcome, and defined one endpoint as their average over all courses of treatment. Two other simpler sets of scores as well as log survival time were also used as endpoints. Estimation of each DTR-specific mean score was conducted using inverse probability weighted methods that assumed that missingness in the 12 remaining dropouts was informative but explainable in that it only depended on past recorded data.We conducted additional worst-and best-case analyses to evaluate sensitivity of our findings to extreme departures from the explainable dropout assumption.Fil: Wang, Lu. University of Michigan; Estados UnidosFil: Rotnitzky, Andrea Gloria. Universidad Torcuato Di Tella. Departamento de Economía; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lin, Xihong. Harvard University; Estados UnidosFil: Millikan, Randall. University of Texas; Estados UnidosFil: Thall, Peter. University of Texas; Estados Unido

Recurrence-Free Survival Prediction for Anal Squamous Cell Carcinoma Chemoradiotherapy using Planning CT-based Radiomics Model

Objectives: Approximately 30% of non-metastatic anal squamous cell carcinoma (ASCC) patients will experience recurrence after chemoradiotherapy (CRT), and currently available clinical variables are poor predictors of treatment response. We aimed to develop a model leveraging information extracted from radiation pretreatment planning CT to predict recurrence-free survival (RFS) in ASCC patients after CRT. Methods: Radiomics features were extracted from planning CT images of 96 ASCC patients. Following pre-feature selection, the optimal feature set was selected via step-forward feature selection with a multivariate Cox proportional hazard model. The RFS prediction was generated from a radiomics-clinical combined model based on an optimal feature set with five repeats of five-fold cross validation. The risk stratification ability of the proposed model was evaluated with Kaplan-Meier analysis. Results: Shape- and texture-based radiomics features significantly predicted RFS. Compared to a clinical-only model, radiomics-clinical combined model achieves better performance in the testing cohort with higher C-index (0.80 vs 0.73) and AUC (0.84 vs 0.79 for 1-year RFS, 0.84 vs 0.78 for 2-year RFS, and 0.86 vs 0.83 for 3-year RFS), leading to distinctive high- and low-risk of recurrence groups (p<0.001). Conclusions: A treatment planning CT based radiomics and clinical combined model had improved prognostic performance in predicting RFS for ASCC patients treated with CRT as compared to a model using clinical features only

Modeling the Mistakes of Boundedly Rational Agents Within a Bayesian Theory of Mind

When inferring the goals that others are trying to achieve, people intuitively understand that others might make mistakes along the way. This is crucial for activities such as teaching, offering assistance, and deciding between blame or forgiveness. However, Bayesian models of theory of mind have generally not accounted for these mistakes, instead modeling agents as mostly optimal in achieving their goals. As a result, they are unable to explain phenomena like locking oneself out of one's house, or losing a game of chess. Here, we extend the Bayesian Theory of Mind framework to model boundedly rational agents who may have mistaken goals, plans, and actions. We formalize this by modeling agents as probabilistic programs, where goals may be confused with semantically similar states, plans may be misguided due to resource-bounded planning, and actions may be unintended due to execution errors. We present experiments eliciting human goal inferences in two domains: (i) a gridworld puzzle with gems locked behind doors, and (ii) a block-stacking domain. Our model better explains human inferences than alternatives, while generalizing across domains. These findings indicate the importance of modeling others as bounded agents, in order to account for the full richness of human intuitive psychology.Comment: Accepted to CogSci 2021. 6 pages, 5 figures. (Appendix: 1 page, 1 figure

Txoj Kev Ntshiab: Hmong American undergraduates’ perceptions of intellectual phoniness and psychosociocultural persistence decisions

Examining the educational experiences of 103 Hmong American undergraduates, gender and class standing differences emerged using a psychosociocultural approach. Females reported increased perceptions of family and friend support and greater cultural congruity in the university environment than males. Lower-division students indicated greater perceptions of social support from family, greater cultural congruity, and lower self-esteem than upper-division students. Feelings of phoniness emerged as the most significant negative predictor of academic persistence decisions. Implications, limitations, and future research are discussed

Potvrđivanje učinkovitosti testa identifikacije poremećaja uzrokovanih alkoholom (AUDIT) – verzija na Dusun jeziku u konzumenata alkohola u Sabahu, Borneo

Introduction: The Alcohol Use Disorder Identification Test (AUDIT) developed by WHO is instrumental in identifying individuals on the alcohol misuse spectrum. However there is no culturally appropriate Dusun language version in Sabahan Borneo. This study aims to develop and validate a Dusun language version of AUDIT (AUDIT-D). Methods: AUDIT was translated to Dusun and back translated to English and Malay. The first version was pilot tested in 20 participants and harmonised. The harmonised version was administered to 50 Dusun first language speakers fluent in Malay from villages in rural Sabah. Participants filled in socio-demographic questionnaires, Dusun (AUDIT-D) and Bahasa Malaysia (AUDIT-M) versions of AUDIT, and validated Bahasa Malaysia versions of the M.I.N.I. alcohol dependence subscale and CAGE. Results: ROC curves calculated AUDIT-D dependence cut-off of 9 and more, with prevalence of dependence at 46%. Factor analysis of AUDIT-D yielded a one - or three-factor solution, distinct from the AUDIT-M factor structure. Cronbach alpha coefficients for the total AUDIT-D was 0.83. Significant Spearman’s correlations existed between AUDIT-D and AUDIT-M scores (Spearman’s rho=0.999, p<.001). AUDIT-D and AUDIT-M were both significantly correlated with M.I.N.I. alcohol dependence subscales (rho=0.624 and 0.617 respectively, with p<0.0001). Both were not significantly correlated with CAGE. Conclusion: The AUDIT-D questionnaire has acceptable psychometric properties, properties and demonstrates similar factor structures to other areas with high alcohol dependence prevalence. It is suitable for the assessment and identification of alcohol use disorders in the unique Sabahan Borneo cultural landscape.Uvod: Test identifikacije poremećaja uzrokovanih alkoholom (AUDIT eng. The Alcohol Use Disorder Identification Test) kojeg je razvila Svjetska zdravstvena organizacija (WHO), od iznimne je koristi u identifikaciji pojedinaca koji boluju od poremećaja ponašanja uzrokovanih alkoholom. Doduše, ne postoji kulturološki primjerena verzija testa na Dusun jeziku u saveznoj državi Sabah na otoku Borneu, Malezija. Cilj ovog istraživanja je razviti i potvrditi verziju AUDIT test na Dusun jeziku. Metode: AUDIT test je preveden na Dusun jezik, zatim s Dusun jezika na engleski i malezijski. Prva verzija je bila pilot test koji je uključio 20 ispitanika, te je bio usklađen. Usklađena verzija testa je provedena na 50 ispitanika čiji je prvi jezik bio Dusun, te su također bili tečni u malezijskom jeziku, a bili su žitelji ruralnih sela Sabaha. Ispitanici su ispunili socio-demografske upitnike, Dusun (AUDIT-D) i Bahasa malezijske (AUDIT-M) verzije testa, usklađene verzije M.I.N.I. testa alkoholne ovisnosti na Bahasa malezijskom jeziku, te CAGE upitnik. Rezultati: ROC krivulje izračunale su graničnu ovisnost AUDIT-D od 9 i više, s prevalencijom ovisnosti od 46%. Faktorska analiza AUDIT-D dala je jedno- ili trofaktorsko rješenje, za razliku od strukture faktora u AUDIT-M testu. Cronbach alfa koeficijenti za ukupni AUDIT-D bili su 0,83. Značajne Spearmanove korelacije postojale su između AUDIT-D i AUDIT-M rezultata (Spearmanov rho = 0,999, p <0,001). AUDIT-D i AUDIT-M bili su značajno povezani s M.I.N.I. podskupinama za ovisnosti o alkoholu (rho = 0,624 i 0,617, s p <0,0001). Oba nisu pokazala značajnu povezanost s CAGE upitnikom. Zaključak: AUDIT-D upitnik ima prihvatljiva psihometrijska svojstva i pokazuje slične faktorske strukture u odnosu na druga područja s visokom prevalencijom ovisnosti o alkoholu. Prikladan je za procjenu i utvrđivanje poremećaja ponašanja uzrokovanih konzumacijom alkohola u jedinstvenom kulturnom krajoliku Sabaha

The development of meibomian glands in mice

PurposeThe purpose of this study was to characterize the natural history of meibomian gland morphogenesis in the mouse.MethodsEmbryonic (E) and post natal (P) C57Bl/6 mouse pups were obtained at E18.5, P0, P1, P3, P5, P8, P15, and P60. Eyelids were fixed and processed for en bloc staining with Phalloidin/DAPI to identify gland morphogenesis, or frozen for immunohistochemistry staining with Oil red O (ORO) to identify lipid and antibodies specific against peroxisome proliferator-activated receptor gamma (PPARγ) to identify meibocyte differentiation. Samples were then evaluated using a Zeiss 510 Meta laser scanning confocal microscope or Nikon epi-fluorescent microscope. Tissues from adult mice (2 month-old) were also collected for western blotting.ResultsMeibomian gland morphogenesis was first detected at E18.5 with the formation of an epithelial placode within the fused eyelid margin. Invagination of the epithelium into the eyelid was detected at P0. From P1 to P3 there was continued extension of the epithelium into the eyelid. ORO and PPARγ staining was first detected at P3, localized to the central core of the epithelial cord thus forming the presumptive ductal lumen. Ductal branching was first detected at P5 associated with acinar differentiation identified by ORO and PPARγ staining. Adult meibomian glands were observed by P15. Western blotting of meibomian gland proteins identified a 50 kDa and a 72 kDa band that stained with antibodies specific to PPARγ.ConclusionsWe have demonstrated that meibomian gland development bears distinct similarities to hair development with the formation of an epithelial placode and expression of PPARγ co-incident with lipid synthesis and meibocyte differentiation

The Aromatase Gene (CYP19A1) Variants and Circulating Hepatocyte Growth Factor in Postmenopausal Women

Background: Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations. Design We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations. Results: We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ≤0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′≥97%, r2≥56%), constituted a block with 2 common haplotypes accounting for 82% frequency. The most common haplotype, TCCCA, was associated with lower ranked- or normal score-transformed HGF levels (corrected p values ≤0.001), whereas the second most common haplotype, CTTCA, was associated with higher ranked- or normal score-transformed HGF levels (corrected p values ≤0.02). Conclusion: Our findings of a potential association between the CYP19A1 variants and circulating HGF levels warrant confirmation in studies with larger sample size