Signal peptide peptidases and gamma-secretase: Cousins of the same protease family?

Signal peptide peptidase (SPIP) is an unusual aspartyl protease, which mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the,gamma-secretase complex, SPP contains a conserved GxGD motif in its C-terminal domain which is critical for its activity. While SPIP is known to be an aspartyl protease of the GxGD type, several presenilin homologues/SPP-like proteins (PSHs/ SPPL) of unknown function have been identified by database searches. In contrast to SPP and SPPL3, which are both restricted to the endoplasmic reticulum, SPPL2b is targeted through the secretory pathway to endosomes/lysosomes. As suggested by the differential subcellular localization of SPPL2b and SPPL3 distinct phenotypes were found upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutants of the putative C-terminal active sites of spp, sppl2, and spp13 produced phenocopies of the respective knockdown phenotypes. These data suggest that all investigated PSHs/SPPLs are members of the novel family of GxGD aspartyl proteases. More recently, it was shown that SPPL2b utilizes multiple intramembrane cleavages to liberate the TNF(x intracellular domain into the cytosol and to release the C-terminal counterpart into the lumen. These findings suggest common principles of intramembrane proteolysis by GxGD type aspartyl proteases. In this article,we will review the similarities of SPPs and gamma-secretase based on recent findings by us and others

Cloning, expression and location of RNase9 in human epididymis

<p>Abstract</p> <p>Background</p> <p>Mammalian spermatozoa become fully motile and fertile during transit through the luminal fluid of the epididymis. At least 200 proteins are present in the epididymal lumen, but the potential roles of these luminal proteins in male fertility are unknown. Investigation of the function of these proteins will elucidate the mechanism of sperm maturation, and also provide new drug targets for male contraception. We cloned RNase9 from a human epididymis cDNA library for characterization and analysis of its functions.</p> <p>Findings</p> <p>It was predicted that human <it>RNase9 </it>gene was located on chromosome 14q11.2 and encoded a 205 amino acids protein with a signal peptide of 26 amino acids at the N-terminus. The protein had eight conserved cysteine residues characteristic of the RNase A family members and several potential post-translational modification sites.</p> <p>At the transcriptional level, <it>RNase9 </it>was expressed in a wide variety of tissues, and the expression was higher in men than in boys. <it>RNase9 </it>was localized to the post-equatorial region of the sperms' head. Immunofluorescence staining showed that RNase9 protein was present mostly in the epithelium of the epididymal tubule. Recombinant RNase9 had no ribonuclease activity. In addition, RNase9 had no detectable effect on sperm motility and fertilization as demonstrated by blocking spermatozoa with anti-RNase9 polyclonal serum.</p> <p>Conclusion</p> <p><it>RNase9 </it>is expressed in a wide variety of tissues. It is located on the post-equatorial region of the sperm head and the epithelium of epididymal tubule. Although <it>RNase9 </it>belongs to the RNase A family, it has no ribonuclease activity.</p

MScMS-II: an innovative IR-based indoor coordinate measuring system for large-scale metrology applications

According to the current great interest concerning large-scale metrology applications in many different fields of manufacturing industry, technologies and techniques for dimensional measurement have recently shown a substantial improvement. Ease-of-use, logistic and economic issues, as well as metrological performance are assuming a more and more important role among system requirements. This paper describes the architecture and the working principles of a novel infrared (IR) optical-based system, designed to perform low-cost and easy indoor coordinate measurements of large-size objects. The system consists of a distributed network-based layout, whose modularity allows fitting differently sized and shaped working volumes by adequately increasing the number of sensing units. Differently from existing spatially distributed metrological instruments, the remote sensor devices are intended to provide embedded data elaboration capabilities, in order to share the overall computational load. The overall system functionalities, including distributed layout configuration, network self-calibration, 3D point localization, and measurement data elaboration, are discussed. A preliminary metrological characterization of system performance, based on experimental testing, is also presente

Tutte polynomial of pseudofractal scale-free web

The Tutte polynomial of a graph is a 2-variable polynomial which is quite important in both combinatorics and statistical physics. It contains various numerical invariants and polynomial invariants, such as the number of spanning trees, the number of spanning forests, the number of acyclic orientations, the reliability polynomial, chromatic polynomial and flow polynomial. In this paper, we study and gain recursive formulas for the Tutte polynomial of pseudofractal scale-free web (PSW) which implies logarithmic complexity algorithm is obtained to calculate the Tutte polynomial of PSW although it is NP-hard for general graph. We also obtain the rigorous solution for the the number of spanning trees of PSW by solving the recurrence relations derived from Tutte polynomial, which give an alternative approach for explicitly determining the number of spanning trees of PSW. Further more, we analysis the all-terminal reliability of PSW and compare the results with that of Sierpinski gasket which has the same number of nodes and edges with PSW. In contrast with the well-known conclusion that scale-free networks are more robust against removal of nodes than homogeneous networks (e.g., exponential networks and regular networks). Our results show that Sierpinski gasket (which is a regular network) are more robust against random edge failures than PSW (which is a scale-free network). Whether it is true for any regular networks and scale-free networks, is still a unresolved problem.Comment: 19pages,7figures. arXiv admin note: text overlap with arXiv:1006.533

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 The American Society of Gene & Cell Therapy.Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.Imperial College London, the Wellcome Trust, and Brunel University

Territory-Wide Chinese Cohort of Long QT Syndrome: Random Survival Forest and Cox Analyses

Introduction: Congenital long QT syndrome (LQTS) is a cardiac ion channelopathy that predisposes affected individuals to spontaneous ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD). The main aims of the study were to: (1) provide a description of the local epidemiology of LQTS, (2) identify significant risk factors of ventricular arrhythmias in this cohort, and (3) compare the performance of traditional Cox regression with that of random survival forests. / Methods: This was a territory-wide retrospective cohort study of patients diagnosed with congenital LQTS between 1997 and 2019. The primary outcome was spontaneous VT/VF. / Results: This study included 121 patients [median age of initial presentation: 20 (interquartile range: 8–44) years, 62% female] with a median follow-up of 88 (51–143) months. Genetic analysis identified novel mutations in KCNQ1, KCNH2, SCN5A, ANK2, CACNA1C, CAV3, and AKAP9. During follow-up, 23 patients developed VT/VF. Univariate Cox regression analysis revealed that age [hazard ratio (HR): 1.02 (1.01–1.04), P = 0.007; optimum cut-off: 19 years], presentation with syncope [HR: 3.86 (1.43–10.42), P = 0.008] or VT/VF [HR: 3.68 (1.62–8.37), P = 0.002] and the presence of PVCs [HR: 2.89 (1.22–6.83), P = 0.015] were significant predictors of spontaneous VT/VF. Only initial presentation with syncope remained significant after multivariate adjustment [HR: 3.58 (1.32–9.71), P = 0.011]. Random survival forest (RSF) model provided significant improvement in prediction performance over Cox regression (precision: 0.80 vs. 0.69; recall: 0.79 vs. 0.68; AUC: 0.77 vs. 0.68; c-statistic: 0.79 vs. 0.67). Decision rules were generated by RSF model to predict VT/VF post-diagnosis. / Conclusions: Effective risk stratification in congenital LQTS can be achieved by clinical history, electrocardiographic indices, and different investigation results, irrespective of underlying genetic defects. A machine learning approach using RSF can improve risk prediction over traditional Cox regression models

Arrhythmic Outcomes in Catecholaminergic Polymorphic Ventricular Tachycardia

Introduction Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. The aim of this study is to examine the genetic basis and identify pre-dictive factors for arrhythmic outcomes in CPVT patients from Hong Kong. Methods This was a territory-wide retrospective cohort study of consecutive patients diagnosed with CPVT at public hospitals or clinics in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF). Results A total of 16 (mean presentation age=11±4 years old) patients were included. All patients presented at or before 19 years of age. Fifteen patients (93.8%) were initially symptomatic. Ten patients had both premature ventricular complexes (PVCs) and VT/VF, whereas one patient had PVCs without VT/VF. Genetic tests were performed in 14 patients (87.5%). Eight (57.1%) tested positive for the RyR2 gene. Seven variants have been described else-where (c.14848G>A, c.12475C>A, c.7420A>G, c.11836G>A, c.14159T>C, c.10046C>T and c.7202G>A). c.14861C>G is a novel RyR2 variant that has not been reported outside this cohort. All patients were treated with beta-blockers, three patients received amiodarone and two received verapamil. Sympathectomy (n=8), ablation (n=1) and implantable-cardioverter defibrillator implantation (n=3) were performed. Over a median follow-up of 127 (IQR: 97-143) months, six patients suffered from incident VT/VF. No significant predictors were identified on Cox regression. Nevertheless, a random survival forest model identified initial VT/VF/sudden cardiac death, palpitations, QTc, initially symptomatic and heart rate as important variables for estimating the probability of developing incident VT/VF. Conclusion All CPVT patients who are from Hong Kong presented at or before 19 years of age. Clinical and electrocardiographic findings can be used to predict arrhythmic outcomes. A nonparametric machine learning survival analysis achieved high accuracy for predicting the probability of incident VT/VF

Relationship between angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and COVID-19 incidence or severe disease

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may be associated with higher susceptibility of COVID-19 infection and adverse outcomes. We compared ACEI/ARB use and COVID-19 positivity in a case-control design, and severity in COVID-19 positive patients. METHODS: Consecutive patients who attended Hong Kong's public hospitals or outpatient clinics between 1 January and 28 July 2020 for COVID-19 real time-PCR (RT-PCR) tests were included. Baseline demographics, past comorbidities, laboratory tests and use of different medications were compared between COVID-19 positive and negative patients. Severe endpoints for COVID-19 positive patients were 28-day mortality, need for intensive care admission or intubation. RESULTS: This study included 213 788 patients (COVID-19 positive: n = 2774 patients; negative: n = 211 014). In total, 162 COVID-19 positive patients (5.83%) met the severity outcome. The use of ACEI/ARB was significantly higher amongst cases than controls (n = 156/2774, 5.62 vs. n = 6708/211014, 3.17%; P 1, P  0.05). CONCLUSION: There was a significant relationship between ACEI/ARB use and COVID-19 positivity and severe disease after adjusting for significant confounders

Effect of Heat Treatment on Fracture Toughness ( K IC ) and Microstructure of a Fluorcanasite-Based Glass-Ceramic

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73358/1/j.1532-849X.2007.00233.x.pd