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This Week in PNAS: Oct 25, 2011

In PNAS this week, a team of US researchers present a study on the conformational trapping of mismatch recognition complex MSH2/MSH3 on repair-resistant DNA loops. MSH2/MSH3 discriminates between repair-competent and repair-resistant loops by "sensing the conformational dynamics of their junctions," the authors write. MSH2/MSH3 dissociates from repair-competent loops, but repair-resistant CAG loops trap nucleotide-bound MSH2/MSH3 and don't allow it to dissociate from DNA. "We envision that junction dynamics is an active participant and a conformational regulator of repair signaling, and governs whether a loop is removed by MSH2/MSH3 or escapes to become a precursor for mutation," the team adds.

Also in PNAS, researchers in Switzerland say that PI3Kγ negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance, within a non-hematopoietic cell type. In this study, the team shows that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3Kγ is largely due to their leaner phenotype. "Furthermore," the team adds, "our data show that PI3Kγ action on diet-induced obesity depends on PI3Kγ activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain." These results suggest that PI3Kγ could be a drug target for treating obesity.

In the PNAS Early Edition , researchers in Japan report the main auxin biosynthesis pathway in Arabidopsis. The team writes that the tryptophan aminotransferase of Arabidopsis protein family produces indole-3-pyruvic acid, and that the yucca flavin monooxygenase-like proteins function to convert indole-3-pyruvic acid into indole-3-acetic acid in Arabidopsis. "We further show that YUC protein expressed in Escherichia coli directly converts IPA to IAA. Indole-3-acetaldehyde is probably not a precursor of IAA in the IPA pathway," the authors write. "Our results indicate that YUC proteins catalyze a rate-limiting step of the IPA pathway, which is the main IAA biosynthesis pathway in Arabidopsis."

Also in the online edition, a team of researchers from the US and Canada reports the molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus. The team sequenced the genomes of eight S. aureus clinical isolates representative of the phage-type 80/81 clone, an MRSA clone, and contemporary S. aureus clones, and found that there was "coincident divergence of these clones from a recent common ancestor, a finding that resolves controversy about the evolutionary history of the lineage." The researchers also found nonsynonymous SNPs in genes encoding accessory gene regulator C and α-hemolysin. "We conclude that agr and hla (along with penicillin resistance) were essential for world dominance of phage-type 80/81 S. aureus, whereas key SNPs in contemporary CC30 clones restrict these pathogens to hospital settings in which the host is typically compromised," the authors add.

The Scan

Drug Response Variants May Be Distinct in Somatic, Germline Samples

Based on variants from across 21 drug response genes, researchers in The Pharmacogenomics Journal suspect that tumor-only DNA sequences may miss drug response clues found in the germline.

Breast Cancer Risk Gene Candidates Found by Multi-Ancestry Low-Frequency Variant Analysis

Researchers narrowed in on new and known risk gene candidates with variant profiles for almost 83,500 individuals with breast cancer and 59,199 unaffected controls in Genome Medicine.

Health-Related Quality of Life Gets Boost After Microbiome-Based Treatment for Recurrent C. Diff

A secondary analysis of Phase 3 clinical trial data in JAMA Network Open suggests an investigational oral microbiome-based drug may lead to enhanced quality of life measures.

Study Follows Consequences of Early Confirmatory Trials for Accelerated Approval Indications

Time to traditional approval or withdrawal was shorter when confirmatory trials started prior to accelerated approval, though overall regulatory outcomes remained similar, a JAMA study finds.