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Competing Interests: All the authors declare no conflict of interest.

DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD + (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD + to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate-ribose) polymerase], a critical DNA repair protein. As mice age and NAD + concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD + Thus, NAD + directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging., (Copyright © 2017, American Association for the Advancement of Science.)

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution., (© 2015 by The American Society of Hematology.)

Mitochondrial defects underlie a multitude of human diseases. Genetic manipulation of mitochondrial regulatory pathways represents a potential therapeutic approach. We have carried out a high-throughput overexpression screen for genes that affect mitochondrial abundance or activity using flow-cytometry-based enrichment of a cell population expressing a high-complexity, concentration-normalized pool of human ORFs. The screen identified 94 candidate mitochondrial regulators including the nuclear protein GLTSCR2, also known as PICT1. GLTSCR2 enhances mitochondrial function and is required for the maintenance of oxygen consumption, consistent with a pivotal role in the control of cellular respiration. RNAi inactivation of the Caenorhabditis elegans ortholog of GLTSCR2 reduces respiration in worms, indicating functional conservation across species. GLTSCR2 controls cellular proliferation and metabolism via the transcription factor Myc, and is induced by mitochondrial stress, suggesting it may constitute a significant component of the mitochondrial signaling pathway.

Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.

Resveratrol induces mitochondrial biogenesis and protects against metabolic decline, but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of germline SIRT1 knockouts, we have developed an inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD(+) levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. A mouse overexpressing SIRT1 mimicked these effects. A high dose of resveratrol activated AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Importantly, at both doses of resveratrol no improvements in mitochondrial function were observed in animals lacking SIRT1. Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Carotid artery stenting is a relatively new intervention for the treatment of carotid artery stenosis, and the long-term outcomes and complications are therefore yet to be determined. In one surgeon's practice, it was found that a stent fracture was the etiological factor for recurrent stenosis. A retrospective study was therefore performed with the hypothesis that carotid stent fractures are common. The aims were to determine prevalence of fractures in this surgeon's series, risk factors, and most importantly, clinical relevance., Methods: Patients from one surgeon's private practice who had carotid stenosis deemed suitable for intervention (>80% asymptomatic, >70% symptomatic, 50% to 70% if an ulcerated lesion) and had suitable aortic and carotid morphology for carotid stenting between March 2004 and December 2006 were included. To enhance the quality of the measurement, two vascular surgeons and one radiologist examined the films independently to determine if there was a fracture present. Given that this was a retrospective study, there was no preconceived sample size determined., Results: Fracture prevalence was found to be 29.2% or 14 out of 48 stents. Restenosis occurred in 21% of those stents with a detected fracture, after an average follow-up of 15 months. Several anetiological factors are proposed, with a finding in this series, of a strong and significant association between the presence of calcified vessels and the presence of fractures (odds ratio 7.7; standard error 5.6; 95% confidence interval 1.9-32.0, P =.003)., Conclusions: Although this is a small study, it demonstrates that carotid stent fractures do exist, and importantly, not all of them are benign. Therefore, the authors recommend regular surveillance with plain radiography in addition to duplex ultrasonography to enable early detection of fracturing. Following detection, institution of increased surveillance frequency and/or any appropriate intervention can be implemented, to aid in the prevention of complications resulting from restenosis should it become apparent.

Objective: To report the clinical results of scalp defect using V-Y-S rotation flap., Methods: From March 2003 to October 2005, 5 cases scalp defect (4 male, 1 female) were reconstructed with the technique. The age ranged from 26 to 52 years (mean 32 years). The scalp defect ranged from 3 cmx3.5 cm to 4 cmx5 cm. Four cases were reconstructed with bilateral flap and one case was reconstructed with unilateral flaps., Results: All patients were followed-up from 10 to 42 months (mean, 28 months). All the flaps survived completely and showed good hair growth and had satisfactory clinical results., Conclusion: Repair of scalp defect using V-Y-S rotation flap technique is simple with no need for a skin graft and can be performed quickly, there is minimal morbidity and the outcome is highly successful.

Objective: To summarize clinical application of the sural medial gastrocnemius island muscle flap to cover wound of infection on upper region of the tibial., Methods: Nine patients (7 men, 2 women) with soft tissue defects on the upper region of the tibial underwent reconstruction with the sural medial gastrocnemius island muscle flap. The age ranged from 21 to 60 years old (mean, 34 years). The immediate coverage of the muscle flaps were performed by a meshed split-thickness skin graft. The donor site was closed directly. The donor leg was ipsilateral in all cases., Results: Only one case sustained superficial infection postoperative and the gradual wound healed by daily wound dressings. All the muscle flaps and skin graft had survived completely without major complication with satisfactory clinical results. All patients were followed-up for 13 months to 4 years (mean 21 months), the donor site was healing, there was no remarkable donor site morbidity., Conclusion: The sural medial gastrocnemius island muscle flap is nourished by the medial sural artery. The muscle flaps seem to have highly vascularize, a constant vascular anatomy and a long vascular pedicle. The muscle flap is thin and suitable for repairing soft tissue defect on the upper region of the tibial.

Type II endoleak is defined as persistent blood flow and pressure within an aneurysmal sac after endovascular deployment of a stent graft from patent aortic branches. This paper describes the simultaneous deployment of an endoluminal graft, with limited extraperitoneal dissection of a collateral vessel and use of an ethylene vinyl alcohol copolymer, Onyx, to obliterate a large type II endoleak.