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People with diabetes mellitus have increased infection risk. With diabetes, urinary tract infection (UTI) is more common and has worse outcomes. Here, we investigate how diabetes and insulin resistance impact the kidney's innate defenses and urine sterility. We report that type 2 diabetic mice have increased UTI risk. Moreover, insulin-resistant prediabetic mice have increased UTI susceptibility, independent of hyperglycemia or glucosuria. To identify how insulin resistance affects renal antimicrobial defenses, we genetically deleted the insulin receptor in the kidney's collecting tubules and intercalated cells. Intercalated cells, located within collecting tubules, contribute to epithelial defenses by acidifying the urine and secreting antimicrobial peptides (AMPs) into the urinary stream. Collecting duct and intercalated cell- specific insulin receptor deletion did not impact urine acidification, suppressed downstream insulin-mediated targets and AMP expression, and increased UTI susceptibility. Specifically, insulin receptor-mediated signaling regulates AMPs, including lipocalin 2 and ribonuclease 4, via phosphatidylinositol-3-kinase signaling. These data suggest that insulin signaling plays a critical role in renal antibacterial defenses., IntroductionDiabetes mellitus (DM) has become a global epidemic. According to the International Diabetes Federation, more than 415 million people worldwide have DM, and this number is expected to increase to [...]

An exploratory study of the emotional intelligence (EI) of student leaders participating in a Supplemental Instruction (SI) program was conducted to determine whether a significant relationship exists between leadership effectiveness and EI as measured by the Bar-On Emotional Quotient Inventory (EQ-i) and to assess the impact of the leadership experience on EI scores through pre- and post-testing. The results revealed a statistically significant difference in the Total EQ-i of the more effective leaders as compared to the others. The more effective leaders also scored higher on all the EQ-i subscales, with the differences on Social Responsibility, Impulse Control, and Reality Testing being statistically significant. As for changes in EI, only the scores on the EQ-i Problem Solving subscale increased significantly between the pre- to post-testing sessions. Implications for practice and future research are addressed.

A substantial number of university students are placed on academic probation each year, many of whom never succeed in academia. Hence, it is critical to identify who these students are, why they end up on academic probation, and most importantly how best to intervene. To determine this, an empirical study of students on academic probation for the first time was conducted at a Canadian university. The results revealed that on average these students tended to be younger than the general population and included a disproportionate number of males, international, and First Nations students with the majority enrolled in first-year, general arts/sciences, or academic upgrading programs. The reasons cited by the students for being on academic probation tended to be of a more personal than academic nature, and although not statistically significant, an intervention involving personal contact via the telephone increased the retention rates for students in an experimental group. (Contains 5 tables.)

The EAP placement procedure at Thompson Rivers University (TRU) involves multiple measures to assess the language skills of incoming students, some of which are facilitated and all of which are assessed by ESL faculty. In order to determine the effectiveness of this comprehensive EAP placement process and the effect of the faculty factor, a placement validity study was conducted at TRU. The results revealed that with faculty involvement, the accuracy of course placement ranged from 81% to 84; without it the accuracy of the placement would have decreased to between 44% and 66%, depending on the skill area.

The scoring of student essays by computer has generated much debate and subsequent research. The majority of the research thus far has focused on validating the automated scoring tools by comparing the electronic scores to human scores of writing or other measures of writing skills, and exploring the predictive validity of the automated scores. However, very little research has investigated possible effects of the essay prompts. This study endeavoured to do so by exploring test scores for three different prompts for the "ACCUPLACER"[R] "WritePlacer"[R] "Plus" test which is scored by the "IntelliMetric"[R] automated scoring system. The results indicated that there was no significant difference among the prompts overall; among males, between males and females, by native language or in comparison to scores generated by human raters. However, there was a significant difference in mean scores by topic for females. (Contains 7 tables.)

How do scores from writing samples generated by computerized essay scorers compare to those generated by ''untrained'' human scorers and what combination of scores, if any, is more accurate at placing students in composition courses? This study endeavored to answer this two-part question by evaluating the correspondence between writing sample scores generated by the IntelliMetric[TM] automated scoring system and scores generated by University Preparation English faculty, as well as examining the predictive validity of both the automated and human scores. The results revealed significant correlations between the faculty scores and the IntelliMetric[TM] scores of the ACCUPLACER(TM)OnLine WritePlacer Plus test. Moreover, logistic regression models that utilized the IntelliMetric[TM] scores and average faculty scores were more accurate at placing students (77% overall correct placement rate) than were models incorporating only the average faculty score or the IntelliMetric[TM] scores. (Contains 5 tables.)

The channeling of the substrate beta-aspartyl phosphate between aspartokinase and aspartate semialdehyde dehydrogenase in Escherichia coli is descrbed. Data suggest that aspartate semialdehyde dehydrogenase may facilitate the channeling of the intermediates between the nonconsecutive reactions of the enzyme.

Background: Convergent evidence implicates gut microbiota in human health and disease. Hitherto, relatively few studies have evaluated the gut microbiota profile in individuals with bipolar disorder (BD) relative to healthy controls (HC). Methods: Fecal samples were collected from subjects (aged 18–65) meeting DSM-5-defined criteria for BD and age- and sex-matched HC without current or past history of mental or major medical disorders. Samples were sequenced using Illumina sequencing and association of specific taxa and co-occurrence of taxa with sample groups including the effect of diet was assessed using cluster analysis and analysis of communities of microorganisms (ANCOM). Nutritional composition was evaluated using the Dietary Questionnaire for Epidemiological Studies (DQES v2) Food Frequency Questionnaire. Results: Forty-six subjects were enrolled (n=23 BD, n=23 HC). Cluster analyses did not identify any significant differences between BD and HC (p=0.38). Lower microbiota diversity was observed among BD subjects relative to HC (p=0.04). A greater abundance of a Clostridiaceae OTU was observed among BD subjects when compared to HC and of Collinsella among BD-II subjects relative to BD-I. Cluster analysis revealed that neither diagnosis (p=0.38) nor diet (p=0.43) had a significant effect on overall gut microbiota composition. Limitations: This study has a small sample size and insufficient control for some potential moderating factors (e.g. psychotropic medication and smoking). Conclusion: This study suggests that individuals with BD may have a distinct gut microbiota profile compared to healthy controls, with a greater abundance of Clostridiaceae and Collinsella. These findings need to be replicated in future studies with larger sample sizes. [ABSTRACT FROM AUTHOR]

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Describes the production and characterization of bifunctional enzymes. Allosteric regulation of kinase activity; Accounts on the pathway of amino acid biosynthesis; Creation of hybrid bifunctional enzymes.

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa. [ABSTRACT FROM AUTHOR]

Abstract: Archaeal RNA polymerases (RNAPs) are most similar to eukaryotic RNAP II (Pol II) but require the support of only two archaeal general transcription factors, TBP (TATA-box binding protein) and TFB (archaeal homologue of the eukaryotic general transcription factor TFIIB) to initiate basal transcription. However, many archaeal genomes encode more than one TFB and/or TBP leading to the hypothesis that different TFB/TBP combinations may be employed to direct initiation from different promoters in Archaea. As a first test of this hypothesis, we have determined the ability of RNAP purified from Thermococcus kodakaraensis (T.k.) to initiate transcription from a variety of T.k. promoters in vitro when provided with T.k. TBP and either TFB1 or TFB2, the two TFBs encoded in the T.k. genome. With every promoter active in vitro, transcription initiation occurred with either TFB1 or TFB2 although the optimum salt concentration for initiation was generally higher for TFB2 (∼250 mM K+) than for TFB1 (∼200 mM K+). Consistent with this functional redundancy in vitro, T.k. strains have been constructed with the TFB1- (tfb1; TK1280) or TFB2- (tfb2; TK2287) encoding gene deleted. These mutants exhibit no detectable growth defects under laboratory conditions. Domain swapping between TFB1 and TFB2 has identified a central region that contributes to the salt sensitivity of TFB activity, and deleting residues predicted to form the tip of the B-finger region of TFB2 had no detectable effects on promoter recognition or transcription initiation but did eliminate the production of very short (≤5 nt) abortive transcripts. [Copyright &y& Elsevier]

Recent evidence suggests antimicrobial peptides protect the urinary tract from infection. Ribonuclease 7 (RNase 7), a member of the RNase A superfamily, is a potent epithelial-derived protein that maintains human urinary tract sterility. RNase 7 expression is restricted to primates, limiting evaluation of its antimicrobial activity in vivo. Here we identified ribonuclease 6 (RNase 6) as the RNase A superfamily member present in humans and mice that is most conserved at the amino acid level relative to RNase 7. Like RNase 7, recombinant human and murine RNase 6 has potent antimicrobial activity against uropathogens. Quantitative real-time PCR and immunoblot analysis indicate that RNase 6 mRNA and protein are upregulated in the human and murine urinary tract during infection. Immunostaining located RNase 6 to resident and infiltrating monocytes, macrophages, and neutrophils. Uropathogenic E. coli induces RNase 6 peptide expression in human CD14+ monocytes and murine bone marrow-derived macrophages. Thus, RNase 6 is an inducible, myeloid-derived protein with markedly different expression from the epithelial-derived RNase 7 but with equally potent antimicrobial activity. Our studies suggest RNase 6 serves as an evolutionarily conserved antimicrobial peptide that participates in the maintenance of urinary tract sterility. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women worldwide. A new promising anti-cancer therapy involves the use of monoclonal antibodies specific for target tumor-associated antigens (TAAs). A TAA of interest for immunotherapy of Triple Negative Breast Cancer (TNBC) is nucleolin (NCL), a multifunctional protein, selectively expressed on the surface of cancer cells, which regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and drug-resistance. We previously isolated a novel human anti-NCL scFv, called 4LB5, that is endowed with selective anti-tumor effects. Here we report the construction and characterization of a novel immunoRNase constituted by 4LB5 and a human pancreatic RNase (HP-RNase) called "4LB5-HP-RNase". This immunoRNase retains both the enzymatic activity of human pancreatic RNase and the specific binding of the parental scFv to a panel of surface NCL-positive breast cancer cells. Notably, 4LB5-HP-RNase dramatically and selectively reduced the viability and proliferation of NCL-positive tumor cells in vitro and in vivo. Specifically, it induced apoptosis and reduced the levels of the tumorigenic miRNAs miR-21, -221 and -222. Thus, this novel immunoagent could be a valuable tool for the treatment of TNBC patients ineligible for currently available targeted treatments.