Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-kappa B pathway

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Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells

Sphingosine kinase 1 (SKI) converts sphingosine to the bioactive lipid sphingosine 1-phosphate (SIP). SW binds to G-protein-coupled receptors (S1PR(1-5)) to regulate cellular events, including Ca2+ signaling. The SK1/S1P axis and Ca2+ signaling both play important roles in health and disease. In this respect, Ca2+ microdomains at the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are of importance in oncogenesis. Mitofusin 2 (MFN2) modulates ER-mitochondria contacts, and dysregulation of MFN2 is associated with malignancies. We show that overexpression of SKI augments agonist-induced Ca2+ release from the ER resulting in increased mitochondria] matrix Ca2+. Also, overexpression of SK1 induces MFN2 fragmentation, likely through increased calpain activity. Further, expressing putative calpain-cleaved MFN2 N- and C-terminal fragments increases mitochondrial matrix Ca2+ during agonist stimulation, mimicking the SK1 overexpression in cells. Moreover, SK1 overexpression enhances cellular respiration and cell migration. Thus, SK1 regulates MFN2 fragmentation resulting in increased mitochondrial Ca2+ and downstream cellular effects.Peer reviewe

Prospective randomized comparison of open versus laparoscopic management of splenic artery aneurysms: a 10-year study

Abstract BACKGROUND: The literature does not support the choice between open and laparoscopic management of splenic artery aneurysms (SAA). METHODS: We designed a prospective, randomized comparison between open and laparoscopic surgery for SAA. Primary end points were types of surgical procedures performed and clinical outcomes. Analysis was developed on an intention-to-treat basis. RESULTS: Fourteen patients were allocated to laparotomy (group A) and 15 to laparoscopy (group B). Groups displayed similar patient- and aneurysm-related characteristics. The conversion rate to open surgery was 13.3 %. The type of surgical procedure performed on the splenic artery was similar in the two groups: aneurysmectomy with splenic artery ligature or direct anastomosis was performed in 51 % and 21 % of patients in group A and in 60 % and 20 % in group B, respectively. The splenectomy rate was similar (14 % vs. 20 %). Postoperative splenic infarction was observed in one case in each group. Laparoscopy was associated with shorter procedures (p = 0.0003) and lower morbidity (25 % vs. 64 %, p = 0.045). Major morbidity requiring interventional procedures and blood transfusion was observed only in group A. Laparoscopy was associated with quicker resumption of oral diet (p < 0.001), earlier drain removal (p = 0.046), and shorter hospital stay (p < 0.01). During a mean follow-up of 50 months, two patients in group A required hospital readmission. In group B, two patients developed a late thrombosis of arterial anastomoses. CONCLUSIONS: Our study demonstrates that laparoscopy permits multiple technical options, does not increase the splenectomy rate, and reduces postoperative complications. It confirms the supposed clinical benefits of laparoscopy when ablative procedures are required but laparoscopic anastomoses show poor long-term results

Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes

Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis.Peer reviewe

Midterm results on a new self-expandable covered stent combined with branched stent grafts: Insights from a multicenter Italian registry

Objective: To investigate the technical periprocedural and midterm outcomes of endovascular repairs with multibranched endovascular repair or iliac branch devices combined with a new self-expanding covered stent. Methods: The COvera in BRAnch registry is a physician-initiated, multicenter, ambispective, observational registry (ClinicalTrials.gov Identifier: NCT04598802) enrolling patients receiving a multibranched endovascular repair or iliac branch devices procedure mated with Bard Covera Plus (Tempe, AZ) covered stent, designed to evaluate the outcomes of the covered stent mated with patient-specific and off-the-shelf branched stent graft. Primary end points were technical success, branch instability, and freedom from aortic and branch-related reintervention within 30 days and at follow-up. Preoperative characteristics, comorbidities, and outcomes definitions were graded according to the Society for Vascular Surgery reporting standards. Results: Two hundred eighty-four patients (76 years; range, 70-80 years; 79% males) in 24 centers were enrolled for a total of 708 target vessels treated. The covered stents were mated with an off-the-shelf graft in 556 vessels (79%) and a custom-made graft in 152 (21%). Three hundred seven adjunctive relining stents in 277 vessels (39%) were deployed, of which 116 (38%) were proximal, 66 (21%) intrastent, and 125 (41%) distal. Adjunctive relining stent placement was more frequent when landing in a vessel branch instead of the main trunk (59% vs 39%; P = .031), performing a percutaneous access (49% vs 35%; P < .001), using a stent with a diameter of 8 mm or greater (44% vs 36%; P = .032) and a length of 80 mm or greater (65% vs 55%; P = .005), when a post-dilatation was not performed (45% vs 29%; P < .001) and when an inner branch configuration was used (55% vs 35%; P < .001). Perioperative technical bridging success was 98%. Eight patients (3%) died in the perioperative period. Two deaths (1%) were associated with renal branch occlusion followed by acute kidney injury and paraplegia. Follow-up data were available for 638 vessels (90%) at a median of 32 months (Q1, Q3, 21, 46). Branch instability was reported in 1% of branches. Forty-six patients (17%) died during follow-up, nine (3%) of them owing to aortic-related causes. Primary patency rates at 1, 2, and 3 years were 99% (581/587), 99% (404/411), and 97% (272/279), respectively. Branch instability was associated with patient-specific devices (9% vs 4%; P = .014) and intrastent adjunctive stent placement (12% vs 2%; P = .003), especially when a bare metal balloon-expandable stent was used (25% vs 3%; P < .001). Conclusions: The use of this new self-expanding covered stent mated with branched endografts proved to be safe and feasible with high technical procedural success rates. Low rates of branch instability were observed at midterm follow-up. Comparative studies with other commercially available covered stents are warranted

Maternal sensitivity at the age of 8 months associates with local connectivity of the medial prefrontal cortex in children at 5 years of age

The quality of mother-child interaction, especially maternal sensitivity in caregiving behavior, plays an important role in a child's later socioemotional development. Numerous studies have indicated associations between poor mother-child interaction and offspring brain structure and function, but more knowledge on how variation in the characteristics of early caregiving is associated with children's brain structure and function is needed. We investigated whether maternal sensitivity at 8 or 30 months is associated with functional connectivity in a child's brain at 5 years of age based on the FinnBrain Birth Cohort Study (17 and 39 mother-child dyads at 8 and 30 months, respectively, with an overlap of 13 dyads). Maternal sensitivity was assessed during a free play interaction using the Emotional Availability Scales at 8 and 30 months of the children's age. Task-free functional magnetic resonance imaging (fMRI) was acquired at the age of 5 years in 7-min scans while watching the Inscapes movie. Regional homogeneity (ReHo) maps were created from the fMRI data, and multiple regression analysis was performed to assess the relation between maternal sensitivity and ReHo. Maternal sensitivity at the age of 8 months was positively associated with children's ReHo values within the medial prefrontal cortex. Distal connectivity of this region showed no significant association with maternal sensitivity in a seed-based connectivity analysis. No associations were found between maternal sensitivity during toddlerhood and brain functional connectivity. Together, these results suggest that maternal sensitivity, especially in infancy, may influence offspring brain functional connectivity. However, studies with larger sample sizes are warranted

Fin whale density and distribution estimation using acoustic bearings derived from sparse arrays

D.V.H. and L.T. were funded by the Office of Naval Research (Grant Nos. N00014-14-1-0394 and N00014-16-1-2364). J.L.M.O. and J.A.V. were funded under Grant Nos. N00014-14-1-0397 and N00014-16-1-2860 also from the Office of Naval Research.Passive acoustic monitoring of marine mammals is common, and it is now possible to estimate absolute animal density from acoustic recordings. The most appropriate density estimation method depends on how much detail about animals' locations can be derived from the recordings. Here, a method for estimating cetacean density using acoustic data is presented, where only horizontal bearings to calling animals are estimable. This method also requires knowledge of call signal-to-noise ratios, as well as auxiliary information about call source levels, sound propagation, and call production rates. Results are presented from simulations, and from a pilot study using recordings of fin whale (Balaenoptera physalus) calls from Comprehensive Nuclear-Test-Ban Treaty Organization (CTBTO) hydrophones at Wake Island in the Pacific Ocean. Simulations replicating different animal distributions showed median biases in estimated call density of less than 2%. The estimated average call density during the pilot study period (December 2007-February 2008) was 0.02 calls hr-1 km2 (coefficient of variation, CV: 15%). Using a tentative call production rate, estimated average animal density was 0.54 animals/1000 km2 (CV: 52%). Calling animals showed a varied spatial distribution around the northern hydrophone array, with most detections occurring at bearings between 90 and 180 degrees.PostprintPeer reviewe