Novel imidazoline antimicrobial scaffold that inhibits DNA replication with activity against mycobacteria and drug resistant Gram-positive cocci.

Bacterial antimicrobial resistance is an escalating public health threat, yet the current antimicrobial pipeline remains alarmingly depleted, making the development of new antimicrobials an urgent need. Here, we identify a novel, potent, imidazoline antimicrobial compound, SKI-356313, with bactericidal activity against Mycobacterium tuberculosis and Gram-positive cocci, including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). SKI-356313 is active in murine models of Streptococcus pneumoniae and MRSA infection and is potently bactericidal for both replicating and nonreplicating M.

Characterization of Mycobacterium smegmatis PolD2 and PolD1 as RNA/DNA polymerases homologous to the POL domain of bacterial DNA ligase D.

Mycobacteria exploit nonhomologous end-joining (NHEJ) to repair DNA double-strand breaks. The core NHEJ machinery comprises the homodimeric DNA end-binding protein Ku and DNA ligase D (LigD), a modular enzyme composed of a C-terminal ATP-dependent ligase domain (LIG), a central 3'-phosphoesterase domain (PE), and an N-terminal polymerase domain (POL). LigD POL is proficient at adding templated and nontemplated deoxynucleotides and ribonucleotides to DNA ends in vitro and is the catalyst in vivo of unfaithful NHEJ events involving nontemplated single-nucleotide additions to blunt DSB ends.

Mycobacterium tuberculosis lacking all mycolic acid cyclopropanation is viable but highly attenuated and hyperinflammatory in mice.

Mycolic acids, the major lipid of the Mycobacterium tuberculosis cell wall, are modified by cyclopropane rings, methyl branches, and oxygenation through the action of eight S-adenosylmethionine (SAM)-dependent mycolic acid methyltransferases (MAMTs), encoded at four genetic loci. Mycolic acid modification has been shown to be important for M. tuberculosis pathogenesis, in part through effects on the inflammatory activity of trehalose dimycolate (cord factor).

Clinical evaluation of Soothing Gan and invigorating Pi acupuncture treatment on diarrhea-predominant irritable bowel syndrome.

Objective: To explore the effect of Soothing Gan and invigorating Pi (SGIP) acupuncture treatment on the clinical symptoms and quality of life (QOL) in patients with diarrhea-predominant irritable bowel syndrome (IBS-D).

Methods: With a single-blinded randomized control study adopted, 63 patients who met the inclusion criteria were assigned by a random number table to two groups, 31 in the treatment group and 32 in the drug control group. The treatment group received SGIP acupuncture therapy; while the control group was treated orally with pinaverium bromide.

Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression.

Lung cancer is a genetically heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of the rat sarcoma viral oncogene homolog (RAS) and AKT signaling cascades. These pathways intersect at various points, rendering this network highly redundant and suggesting that combined mitogen-activated protein/extracellular signal-regulated kinase (MEK) and mammalian target of rapamycin (mTOR) inhibition may be a promising drug combination that can overcome its intrinsic plasticity. The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor, rapamycin, or its analogue AP23573, exhibited dose-dependent synergism in human lung cancer cell lines that was associated with suppression of proliferation rather than enhancement of cell death.

Persistence of partially functional double-stranded (ds) DNA binding B cells in mice transgenic for the IgM heavy chain of an anti-dsDNA antibody.

One mechanism by which anti-double stranded (ds) DNA B cells are regulated is anergy. Multiple phenotypes have been attributed to anergic B cells in various transgenic models. Differences in the nature of the antigen and in the avidity of antigen-antibody interactions may account for these variations in phenotype.