Synaptosome-associated protein of 25 kDa (SNAP-25) is a presynaptic membrane protein that has been clearly implicated in membrane fusion in both developing and mature neurons, although its mechanisms of action are unclear. We have now identified a novel SNAP-25-interacting protein named SNIP. SNIP is a hydrophilic, 145-kDa protein that comprises two predicted coiled-coil domains, two highly charged regions, and two prolinerich domains with multiple PPXY and PXXP motifs. Membrane fusion is a fundamental process that is essential to cellular organization and function of all eukaryotic cells (1). In developing neurons, fusion of plasmalemmal precursor vesicles with the plasma membrane is thought to mediate membrane expansion at the growth cone (2). At mature nerve terminals, exocytotic fusion of synaptic vesicles with the plasma membrane releases neurotransmitters and initiates synaptic transmission (3, 4). Activity-dependent modulation of neurotransmitter release is an important mechanism underlying the processes of learning and memory, whereas dysregulated neurotransmitter release has been linked to several disorders of the nervous system such as depression and schizophrenia.Thus, elucidation of the molecular mechanisms that mediate and regulate neuronal exocytosis is crucial to our understanding of neuronal function and dysfunction as well as to the understanding of membrane trafficking in general.Synaptosome-associated protein of 25 kDa (SNAP-25) 1 was identified 10 years ago as a brain-specific protein that is localized in the plasma membrane of nerve terminal (5). SNAP-25 has been implicated in neurotransmitter release as well as neurite outgrowth by the following studies. Specific proteolysis of SNAP-25 by botulinum neurotoxins A and E inhibits neurotransmitter release (6 -9). The blockade of neurotransmitter release by botulinum neurotoxin E can be reversed using a C-terminal fragment of SNAP-25 (10). Furthermore, introduction of antibodies or synthetic peptides specific to SNAP-25 into synaptosomes or PC12 cells blocks Ca 2ϩ -dependent exocytosis (11,12). In Drosophila, SNAP-25 null mutation results in a complete loss of the evoked release, whereas the spontaneous release is unaffected, implicating a role for SNAP-25 in the stimulation-secretion coupling (13). In mice, coloboma (Cm/ϩ) mutation that deletes a fragment of chromosome 2 encompassing the SNAP-25 gene leads to impaired neurotransmitter release, profound spontaneous hyperactivity, and learning deficits (14 -18). These functional impairments can be rescued by introducing the SNAP-25 transgene into the coloboma mutant mice (15,17). During development, interfering with SNAP-25 expression using antisense oligonucleotides or botulinum neurotoxins prevents neurite elongation (19,20).Despite the overwhelming evidence linking SNAP-25 to membrane fusion in both developing and mature neurons, it is not understood how SNAP-25 actually facilitates the fusion process. SNAP-25 (a t-SNARE) interacts with syntaxin (another t-SNARE) and synaptobrevin/VAMP (a v-SN...

Syntaxin 1 is an essential component of the neurotransmitter release machinery, and regulation of syntaxin 1 expression levels is thought to contribute to the mechanism underlying learning and memory. However, the molecular events that control the degradation of syntaxin 1 remain undefined. Here we report the identification and characterization of a novel RING finger protein, Staring, that interacts with syntaxin 1. Staring is expressed throughout the brain, where it exists in both cytosolic and membrane-associated pools. Staring binds and recruits the brain-enriched E2 ubiquitin-conjugating enzyme UbcH8 to syntaxin 1 and facilitates the ubiquitination and proteasome-dependent degradation of syntaxin 1. These findings suggest that Staring is a novel E3 ubiquitin-protein ligase that targets syntaxin 1 for degradation by the ubiquitin-proteasome pathway.Modulation of protein degradation is a major mechanism by which cells regulate the expression levels of specific proteins and consequently the cellular processes that these proteins participate in (1, 2). The ubiquitin-proteasome pathway plays a crucial role in the degradation of proteins involved in a variety of cellular processes, including differentiation, proliferation, and apoptosis. However, the role of the ubiquitin-proteasome pathway in the degradation of presynaptic proteins remains poorly characterized, despite the presence of ubiquitin at nerve terminals (3-5). In the ubiquitin-proteasome pathway, substrates are marked for degradation by covalent linkage to ubiquitin. The ubiquitinated substrate proteins are then recognized and degraded by the 26 S proteasome (1, 2, 6). Ubiquitination involves a highly specific enzyme cascade in which ubiquitin is first activated by an E1 1 ubiquitin-activating enzyme and then transferred to an E2 ubiquitin-conjugating enzyme and finally ligated to the substrate by an E3 ubiquitin-protein ligase (1,7,8). The E3 ubiquitin-protein ligase plays an essential role in determining the specificity of ubiquitination and subsequent protein degradation. Consistent with this role, it is estimated that an organism such as a human contains over 100 E3 ubiquitin ligases, in contrast to a single E1 ubiquitin-activating enzyme and about a dozen E2 ubiquitin-conjugating enzymes (9). Despite the importance of E3 ubiquitin-protein ligases in specific protein degradation and the estimated presence of more than 100 E3 ligases in the human genome, only a few E3 ligases have been characterized at the molecular level.Syntaxin 1 is a neuronal membrane protein that was originally identified as a binding partner for synaptotagmin and the N-type calcium channel (10 -12). It is well established that syntaxin 1 functions as a synaptic t-SNARE to mediate synaptic vesicle exocytosis at nerve terminals (13)(14)(15). Syntaxin 1 appears early during embryonic development (16, 17), and its expression level is dramatically up-regulated during synapse formation and brain maturation (16 -19). Regulation of syntaxin 1 levels may contribute to the mechanism unde...

Background: Transcatheter aortic valve implantation/replacement (TAVI/TAVR) is becoming more frequently used to treat aortic stenosis (AS), with increasing push for the procedure in lower risk patients.Numerous randomized controlled trials have demonstrated that TAVI offers a suitable alternative to the current gold standard of surgical aortic valve replacement (SAVR) in terms of short-term outcomes. The present review evaluates long-term outcomes following TAVI procedures.Methods: Literature search using three electronic databases was performed up to June 2017. Studies which included 20 or more patients undergoing TAVI procedures, either as a stand-alone or concomitant procedure and with a follow-up of at least 5 years, were included in the present review. Literature search and data extraction were performed by two independent researchers. Digitized survival data were extracted from Kaplan-Meier curves in order to re-create the original patient data using an iterative algorithm and subsequently aggregated for analysis.Results: Thirty-one studies were included in the present analysis, with a total of 13,857 patients. Two studies were national registries, eight were multi-institutional collaborations and the remainder were institutional series. Overall, 45.7% of patients were male, with mean age of 81.5±7.0 years. Where reported, the mean Logistic EuroSCORE (LES) was 22.1±13.7 and the mean Society of Thoracic Surgeons (STS) score was 9.2±6.6. The pooled analysis found 30-day mortality, cerebrovascular accidents, acute kidney injury (AKI) and requirement for permanent pacemaker (PPM) implantation to be 8.4%, 2.8%, 14.4%, and 13.4%, respectively. Aggregated survival at 1-, 2-, 3-, 5-and 7-year were 83%, 75%, 65%, 48% and 28%, respectively. Conclusions:The present systematic review identified acceptable long-term survival results for TAVI procedures in an elderly population. Extended follow-up is required to assess long-term outcomes following TAVI, particularly before its application is extended into wider population groups. Ann Cardiothorac Surg 2017;6(5):432-443 www.annalscts.com IntroductionAs Western populations age, the prevalence of aortic stenosis (AS) is gradually increasing (1). In a select population, surgical aortic valve replacement (SAVR) is precluded by patient frailty and other comorbidities (2). The availability of transcatheter aortic valve implantation/ replacement (TAVI/TAVR), pioneered in the early 2000s, has made a significant impact on survival for these patients (3-5). These early successes led to a number of trials, such as the PARTNER and US Pivotal trials, which compared TAVI, SAVR and standard treatment outcomes ( Figure 1). As a result, TAVI is increasingly being considered as a less-invasive option for treatment of AS in younger and lower surgical risk patients, where SAVR is not necessarily contraindicated (6,7), although this is not without controversy (8).While the short-term outcomes of TAVI have been well explored, limited studies have examined longer term results (9,10). Additiona...

At least 50% reversal is required to allow safe sheath removal after cardiac catheterization. REG1 appears a safe strategy to anticoagulate ACS patients managed invasively and warrants further investigation in adequately powered clinical trials of patients who require short-term high-intensity anticoagulation.

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Objective: Bioprosthetic heart valves (BHVs) are commonly used in surgical and percutaneous valve replacement. The durability of percutaneous valve replacement is unknown, but surgical valves have been shown to require reintervention after 10 to 15 years. Further, smaller-diameter surgical BHVs generally experience higher rates of prosthesis-patient mismatch, which leads to higher rates of failure. Bioprosthetic aortic valves can flutter in systole, and fluttering is associated with fatigue and failure in flexible structures. The determinants of flutter in BHVs have not been well characterized, despite their potential to influence durability. Methods:We use an experimental pulse duplicator and a computational fluidstructure interaction model of this system to study the role of device geometry on BHV dynamics. The experimental system mimics physiological conditions, and the computational model enables precise control of leaflet biomechanics and flow conditions to isolate the effects of variations in BHV geometry on leaflet dynamics.

Background: As transcatheter aortic valve replacement (TAVR) extends its reach to lower surgical risk patients, the differences between resource utilization for TAVR and surgical AVR (SAVR) will become increasingly important. Methods and Results: AVR procedures between January 2012 and September 2015 at hospitals performing TAVR were identified using the National Inpatient Sample databases. Adults aged ≥50 years with aortic stenosis who underwent isolated TAVR or SAVR were eligible for inclusion. Standardized morbidity ratio weights were calculated using patient demographics, comorbidities, and hospital characteristics. Weighted linear and generalized logistic regression models were used to estimate the effect of undergoing TAVR, compared with undergoing SAVR, on length of stay (LOS) and discharge disposition. In TAVR-performing hospitals, 7266 (40%) patients underwent TAVR (6107 endovascular approach and 1159 transapical approach), while 10 833 (60%) underwent isolated SAVR. Patients undergoing TAVR were older, more likely to be female, and had more comorbidities. From 2012 to 2015, average LOS declined for both TAVR (6.3 days to 4.6 days; P <0.0001) and SAVR (7.5 days to 6.8 days; P <0.0001), with greater reduction in the TAVR group ( P <0.0001). An increase in home/home health discharge was noted with TAVR (67.7%–77.4%; P <0.0001) but not with SAVR (76.8%–79.5%; P =0.25). After standardizing, patients undergoing TAVR had significantly shorter LOS (change in estimate, −2.93, 95% CI, −3.26 to −2.60) and lower incidence of transfer to skilled nursing facility (odds ratio, 0.45; 95% CI, 0.40–0.51) but no difference in in-hospital mortality (odds ratio, 0.85; 95% CI, 0.61–1.20) compared with if they had undergone SAVR. As compared with SAVR, patients who had TAVR performed via an endovascular approach had shorter LOS and lower rates of skilled nursing facility transfer, whereas in the transapical cohort, LOS, and skilled nursing facility transfer were similar to SAVR. Conclusions: As compared with if they undergo SAVR, patients undergoing TAVR (by a nontransapical approach) had a shorter LOS and higher likelihood of home discharge, as opposed to skilled nursing facility. From 2012 to 2015, there was a greater trend towards a reduction of LOS and more home discharges among TAVR, as opposed to SAVR. These data have important implications in the era of constrained resources with a growing emphasis on reducing health care costs.

We aimed to determine the frequency of aortic valve surgery (AVR) with or without coronary artery bypass grafting (CABG), among patients with moderate/severe aortic stenosis (AS) and left ventricular systolic dysfunction (LVSD), and its relationship with survival. Methods and resultsThe Duke Echocardiographic Database (N ¼ 132 804) was queried for patients with mean gradient ≥25 mmHg and/or peak velocity ≥3 m/s and LVSD (left ventricular ejection fraction ≤50%) from 1 January 1995-28 February 2014. For analyses purposes, AS was defined both by mean gradient and calculated aortic valve area (AVA) criteria. Time-dependent indicators of AVR in multivariable Cox models were used to assess the relationship of AVR and all-cause mortality. A total of 1634 patients had moderate (N ¼ 1090, 67%) or severe (N ¼ 544, 33%) AS by mean gradient criteria. Overall, 287 (26%) patients with moderate AS and 263 (48%) patients with severe AS underwent AVR within 5 years of the qualifying echo. There were 863 (53%) deaths observed up to 5 years following index echo. After multivariable adjustment in an inverse probability weighted regression model, AVR was associated with higher 5-year survival amongst patients with moderate AS and severe AS whether classified by AVA or mean gradient criteria. Over all, AVR + CABG compared with medical therapy was associated with significantly lower mortality [hazard ratio, HR ¼ 0.49 (0.38, 0.62), P , 0.0001]. Compared with CABG alone, CABG + AVR was associated with better survival [HR ¼ 0.18 (0.12, 0.27), P , 0.0001]. ConclusionsIn patients with moderate/severe AS and LVSD, mortality is substantial and amongst those selected for surgery, AVR with or without CABG is associated with higher survival. Research is required to understand factors contributing to current practice patterns and the possible utility of transcatheter approaches in this high-risk cohort.