Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2

Mutations are introduced into rearranged Ig variable genes at a frequency of 10⁻² mutations per base pair by an unknown mechanism. Assuming that DNA repair pathways generate or remove mutations, the frequency and pattern of mutation will be different in variable genes from mice defective in repair. Therefore, hypermutation was studied in mice deficient for either the DNA nucleotide excision repair gene Xpa or the mismatch repair gene Pms2. High levels of mutation were found in variable genes from XPA-deficient and PMS2-deficient mice, indicating that neither nucleotide excision repair nor mismatch repair pathways generate hypermutation. However, variable genes from PMS2-deficient mice had significantly more adjacent base substitutions than genes from wild-type or XPA-deficient mice. By using a biochemical assay, we confirmed that tandem mispairs were repaired by wild-type cells but not by Pms2^−/− human or murine cells. The data indicate that tandem substitutions are produced by the hypermutation mechanism and then processed by a PMS2-dependent pathway.     

The effect of bitter melon (Mormordica charantia) in patients with diabetes mellitus: a systematic review and meta-analysis

Background:

Mormordica charantia (bitter melon) has been investigated for lowering plasma glucose in patients with diabetes mellitus (DM). Previous data has offered inconclusive and inconsistent results about the benefits of bitter melon in patients with DM. Our current project aims to determine whether bitter melon has a favorable effect in lowering plasma glucose in patients with DM.

Methods:

We searched PubMed, EMBASE and the Cochrane Library from inception to July 2013 without any language restrictions for randomized controlled trials (RCTs) evaluating bitter melon to no treatment in patients with type 1 or type 2 diabetes. Study selection, data extraction and validity of each article were independently assessed by two investigators. Articles were appraised for proper random sequence generation, allocation concealment, blinding, selective reporting and completeness of outcomes reporting to assess the risk for biases. The glycemic results of each RCT were analyzed to yield weighted mean differences (WMDs) and 95% confidence intervals (CIs).

Results:

A total of four RCTs, each with 40–66 participants, followed between 4 and 12 weeks were identified in this meta-analysis. Overall risk of bias for each article included was determined to be unclear. In total, 208 participants with type 2 DM (mean age of 56.5 years) were evaluated. Compared with no treatment, bitter melon did not significantly lower A1C (WMD −0.13%, 95% CI −0.41 to 0.16) nor fasting plasma glucose (FPG) 47 (WMD 2.23 mg dl⁻¹, 95% CI −14.91 to 19.37).

Conclusions:

Bitter melon supplementation compared with no treatment did not show significant glycemic improvements on either A1c or FPG.     

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptor-mediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phosphorylated and unphosphorylated human TBK1 kinase and ubiquitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKKβ, but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events.     

Trends for genetic variation of Hepatitis C Virus quasispecies in Human Immunodeficiency virus-1 coinfected patients

Chronic infection by Hepatitis C Virus (HCV) causes liver fibrosis, which is accelerated by unknown mechanisms in patients with HIV-1 coinfection. The evolution of HCV quasispecies in this setting of coinfection is not fully understood. To compare HCV quasispecies between HIV–HCV coinfection and HCV monoinfection, we sequenced 340 HCV clones from the HVR-1 and NS3 regions at two different time points in two groups of treatment-naïve patients with HCV-1a infection: (1) HIV–HCV positive (n = 6); and (2) HIV negative–HCV positive (n = 3). In HCV/HIV coinfection, we found a trend for reduced HCV genetic complexity and diversity, and a trend towards reduced dN/dS ratios in the HVR-1 region, especially in those patients with CD4 < 200 cells/mm³, who lost positive selective immune pressure in the HVR-1 region. Differences in immune regulation of HCV quasispecies in HIV coinfected individuals deserve further exploration to clarify the different outcomes of chronic hepatitis C noted between the immunocompromised and the immunocompetent host.     

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

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