Palliative care in the older adult Veteran.

The United States military Veteran population is aging, thus leading to a group of Veterans who have functional disabilities, sensory impairments, and geriatric syndromes such as frailty and dementia. As they age, Veterans are also at risk of being diagnosed with a variety of serious illnesses, such as neurologic conditions and cancers, some of which are a consequence of prior military service or toxic exposures. In addition to frailty and multicomplexity, Veterans have higher rates of mental health disorders than civilians.

Genome-wide association study in patients with pulmonary complex disease.

Rationale: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear.

Objectives: We aimed to identify host susceptibility loci for complex (MAC), the most common NTM pathogen.

Whole-Exome Sequencing Identifies the 6q12-q16 Linkage Region and a Candidate Gene, TTK, for Pulmonary Nontuberculous Mycobacterial Disease.

Rationale: Pulmonary nontuberculous mycobacterial disease (PNTM) often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism.

Objectives: To map the genes associated with PNTM, whole-exome sequencing was conducted in 12 PNTM families and 57 sporadic cases recruited at the National Institutes of Health Clinical Center during 2001-2013.

MPEG1/perforin-2 mutations in human pulmonary nontuberculous mycobacterial infections.

Perforin-2 is a highly conserved pore-forming protein encoded by macrophage expressed gene 1 (MPEG1). A number of studies have shown that Perforin-2-deficient mice are unable to survive following a bacterial challenge that is nonlethal in WT mice. There is also recent evidence that Mpeg1+/- heterozygous mice display an intermediate killing ability compared with Mpeg1 WT and Mpeg1-/- mice.

Biallelic mutations in IRF8 impair human NK cell maturation and function.

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease.

Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease.

Rationale: The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not.

Objectives: To examine genetic variants in patients with PNTM, their unaffected family members, and a control group.

Methods: Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members.

Budding yeast protein extraction and purification for the study of function, interactions, and post-translational modifications.

Homogenization by bead beating is a fast and efficient way to release DNA, RNA, proteins, and metabolites from budding yeast cells, which are notoriously hard to disrupt. Here we describe the use of a bead mill homogenizer for the extraction of proteins into buffers optimized to maintain the functions, interactions and post-translational modifications of proteins. Logarithmically growing cells expressing the protein of interest are grown in a liquid growth media of choice.

A SUMO-targeted ubiquitin ligase is involved in the degradation of the nuclear pool of the SUMO E3 ligase Siz1.

The Slx5/Slx8 heterodimer constitutes a SUMO-targeted ubiquitin ligase (STUbL) with an important role in SUMO-targeted degradation and SUMO-dependent signaling. This STUbL relies on SUMO-interacting motifs in Slx5 to aid in substrate targeting and carboxy-terminal RING domains in both Slx5 and Slx8 for substrate ubiquitylation. In budding yeast cells, Slx5 resides in the nucleus, forms distinct foci, and can associate with double-stranded DNA breaks.