Miracle-dz/UniFAR-FTUs huggingface dataset:
Solution Structure of the Phosphotyrosine Binding (PTB) Domain of Human Tensin2 Protein in Complex with Deleted in Liver Cancer 1 (DLC1) Peptide Reveals a Novel Peptide Binding Mode*

Background: DLC1 interacts with tensin2 PTB, playing a role as a tumor suppressor in many human cancers. Results: We solved the tensin2 PTB-DLC1 complex structure and showed its importance for co-localization of DLC1 and tensin2 in cells. Conclusion: The novel PTB-peptide binding mode provides a molecular basis for understanding the tumor suppression of DLC1 and tensin2. Significance: A novel PTB-peptide binding mode was observed. The protein deleted in liver cancer 1 (DLC1) interacts with the tensin family of focal adhesion proteins to play a role as a tumor suppressor in a wide spectrum of human cancers. This interaction has been proven to be crucial to the oncogenic inhibitory capacity and focal adhesion localization of DLC1. The phosphotyrosine binding (PTB) domain of tensin2 predominantly interacts with a novel site on DLC1, not the canonical NPXY motif. In this study, we characterized this interaction biochemically and determined the complex structure of tensin2 PTB domain with DLC1 peptide by NMR spectroscopy. Our HADDOCK-derived complex structure model elucidates the molecular mechanism by which tensin2 PTB domain recognizes DLC1 peptide and reveals a PTB-peptide binding mode that is unique in that peptide occupies the binding site opposite to the canonical NPXY motif interaction site with the peptide utilizing a non-canonical binding motif to bind in an extended conformation and that the N-terminal helix, which is unique to some Shc- and Dab-like PTB domains, is required for binding. Mutations of crucial residues defined for the PTB-DLC1 interaction affected the co-localization of DLC1 and tensin2 in cells and abolished DLC1-mediated growth suppression of hepatocellular carcinoma cells. This tensin2 PTB-DLC1 peptide complex with a novel binding mode extends the versatile binding repertoire of the PTB domains in mediating diverse cellular signaling pathways as well as provides a molecular and structural basis for better understanding the tumor-suppressive activity of DLC1 and tensin2.
PREVALENCE SURVEY OF SEXUAL DYSFUNCTION AMONG WOMEN IN THE REPRODUCTIVE AGE GROUP REFERRED TO THE ISLAMIC AZAD UNIVERSITY HOSPITAL DURING 2011-2012

Background: Sexual dysfunctions are common and are regarded as important health problems for women of all ages with related quality of life issues. The purpose of this cross-sectional study was to explore the frequency of sexual dysfunction among women in reproductive age group referred to the Islamic Azad University hospitals. Materials and Methods: This study was performed on married women selected by simple random sampling, aged 15-45 years who referred to Boo–Ali, Amir-Al-Momenin and Javaheri hospitals in Tehran, Iran from August 2011 to August 2012. Data were collected by face-to-face interview and completion of self-report questionnaires that assessed sexual functions among women in six separate dimensions. Analysis was done using Pearson correlation coefficient by SPSS 14.0; significant difference was set at 0.05. Results: A total of 384 women with mean age of 28.6±7.1 years were enrolled. The mean Body Mass Index (BMI) was 27.4±2.6 kg/m2. Ninety-seven subjects (25.2%) had never attained an orgasm, 31 (8%) had a low level satisfactory relationship with their husband, 55(14.3%) had painful intercourse, 42(10.9%) had arousal disorder, all of which increased significantly with age (P=0.003). Female Sexual dysfunctions had a significant negative correlation with BMI (P=0.004). The emotional relationship (P=0.003) and educational level (P=0.08) were significantly associated with the Female Sexual Function (FSF) score. No significant difference was detected in marriage duration (P=0.081) and used contraception methods (P=0.081). Conclusion: The prevalence of female sexual dysfunction including desire, arousal, lubrication, orgasm, satisfaction and pain problems increased with age and BMI. In addition, lower educational level is an associated factor that may cause sexual dysfunction. Also, emotional relationship had positive association with FSF score, while it was not associated with the use of contraceptive methods. [GMJ. 2014;3(1):14-19]
Munc18-1 Regulates First-phase Insulin Release by Promoting Granule Docking to Multiple Syntaxin Isoforms*

Background: Munc18-1 is expressed in islet β-cells, but its functional requirement remains unknown. Results: Munc18-1 knock-out mice have impaired glucose tolerance and first-phase insulin release defects. Munc18-1 overexpression enhances human islet insulin release and increases SNARE complex formation. Conclusion: Munc18-1 is required in insulin exocytosis for facilitating SNARE assembly using multiple syntaxin isoforms. Significance: Increased Munc18-1 in human islets enhances β-cell function. Attenuated levels of the Sec1/Munc18 (SM) protein Munc18-1 in human islet β-cells is coincident with type 2 diabetes, although how Munc18-1 facilitates insulin secretion remains enigmatic. Herein, using conventional Munc18-1+/− and β-cell specific Munc18–1−/− knock-out mice, we establish that Munc18-1 is required for the first phase of insulin secretion. Conversely, human islets expressing elevated levels of Munc18-1 elicited significant potentiation of only first-phase insulin release. Insulin secretory changes positively correlated with insulin granule number at the plasma membrane: Munc18-1-deficient cells lacked 35% of the normal component of pre-docked insulin secretory granules, whereas cells with elevated levels of Munc18-1 exhibited a ∼20% increase in pre-docked granule number. Pre-docked syntaxin 1-based SNARE complexes bound by Munc18-1 were detected in β-cell lysates but, surprisingly, were reduced by elevation of Munc18-1 levels. Paradoxically, elevated Munc18-1 levels coincided with increased binding of syntaxin 4 to VAMP2 at the plasma membrane. Accordingly, syntaxin 4 was a requisite for Munc18-1 potentiation of insulin release. Munc18c, the cognate SM isoform for syntaxin 4, failed to bind SNARE complexes. Given that Munc18-1 does not pair with syntaxin 4, these data suggest a novel indirect role for Munc18-1 in facilitating syntaxin 4-mediated granule pre-docking to support first-phase insulin exocytosis.
The Wage Distribution in a Model of the Assignment of Skills to Jobs

This paper discusses a general equilibrium model of the assignment of heterogeneous workers to heterogeneous jobs. Both jobs and workers are measured along a continuous one-dimensional scale. The composition of labor supply is represented by a distribution function. Workers maximize their earnings. Highly skilled workers have an absolute advantage in all jobs and a comparative advantage in complex jobs. Utility is represented by a constant elasticity of substitution function defined over the output of an infinite number of jobs. Equilibrium is characterized by a mapping of skills on complexities. The model is able simultaneously to explain the remuneration of skill, the allocation of skills to jobs, and variations in labor demand per job type. Estimation results for the Netherlands for 1982 and 1988 offer support for its relevance. Wage differentials are due mainly to skill differentials in the left tail of the distribution and to differences between jobs in the right tail.
Stature estimation in a central Patagonian prehispanic population: development of new models considering specific body proportions

Stature estimation of individuals from extinct human populations is a classic topic in anthropology. The estimations, using regression formulae generated from different reference samples, display different results. This fact is related to inter-populational differences in body proportions, which is a phenotypic trait mainly correlated with climatic parameters. The aim of this paper is to address the problem of stature estimation of an archaeological skeletal sample from Patagonia – a region for which there are no specific models available – using different methods and considering differences in body proportions between reference and target populations. The sample used in this analysis is composed of 35 Late Holocene adults of both sexes recovered in central Patagonia (Argentina). The stature of each individual was first reconstructed using the anatomical method [Fully G. 1956. Une nouvelle me´thode de de´termination de la taille. Annales Medicine Legale35: 266–273], which has no assumptions on body proportions. The results were compared with estimations based on 32 different regression formulae [Trotter M, Gleser G. 1958. A re-evaluation of estimation of stature based on measurements taken during life and the long bones after death. American Journal of Physical Anthropology16: 79–124. 10.1002/ajpa.1330160106] and three femur/stature ratios [Feldesman MR, Fountain RL. 1996. Race specificity and the femur/stature ratio. American Journal of Physical Anthropology100: 207–224. 10.1002/(SICI)1096-8644(199606)]. The average reconstructed stature was 160.8 cm for females (95% confidence band = 155.6–166.2 cm), and 170.5 cm for males (95% confidence band = 168.8–172.2 cm). Most of the comparisons of the regression formulae and femur/stature ratios showed significant differences, which are explained by differences in body proportions between the Patagonian sample and the ones chosen as reference. Finally, a set of new equations was developed using simple regression techniques. It is suggested that whenever possible, population-specific formulae should be used in archaeological studies. In any other situation, the choice of a reference population should be made by taking into account its geographic (latitudinal) provenance. Copyright © 2009 John Wiley & Sons, Ltd.
Tau Isoform Composition Influences Rate and Extent of Filament Formation*

Background: Human brain Tau isoforms differ by the presence or absence of inserts derived from alternative splicing of MAPT transcripts. Results: Tau inserts modulate Tau aggregation propensity through differing kinetic mechanisms that synergize or compete depending on sequence context. Conclusion: MAPT splicing patterns associated with tauopathies correlate with aggregation propensity. Significance: Tau aggregation propensity may contribute to disease pathogenesis. The risk of developing tauopathic neurodegenerative disease depends in part on the levels and composition of six naturally occurring Tau isoforms in human brain. These proteins, which form filamentous aggregates in disease, vary only by the presence or absence of three inserts encoded by alternatively spliced exons 2, 3, and 10 of the Tau gene (MAPT). To determine the contribution of alternatively spliced segments to Tau aggregation propensity, the aggregation kinetics of six unmodified, recombinant human Tau isoforms were examined in vitro using electron microscopy assay methods. Aggregation propensity was then compared at the level of elementary rate constants for nucleation and extension phases. We found that all three alternatively spliced segments modulated Tau aggregation but through differing kinetic mechanisms that could synergize or compete depending on sequence context. Overall, segments encoded by exons 2 and 10 promoted aggregation, whereas the segment encoded by exon 3 depressed it with its efficacy dependent on the presence or absence of a fourth microtubule binding repeat. In general, aggregation propensity correlated with genetic risk reported for multiple tauopathies, implicating aggregation as one candidate mechanism rationalizing the correlation between Tau expression patterns and disease.
Role of Deleted in Breast Cancer 1 (DBC1) Protein in SIRT1 Deacetylase Activation Induced by Protein Kinase A and AMP-activated Protein Kinase*

Background: DBC1 is a key regulator of SIRT1 activity, although it is unknown how the SIRT1-DBC1 interaction is regulated. Results: PKA and AMPK activate SIRT1 by disrupting the interaction between SIRT1 and DBC1. Conclusion: We provide mechanistic evidence on how the SIRT1-DBC1 complex is regulated. Significance: The SIRT1-DBC1 complex constitutes a target for the development of drugs to activate SIRT1. The NAD+-dependent deacetylase SIRT1 is a key regulator of several aspects of metabolism and aging. SIRT1 activation is beneficial for several human diseases, including metabolic syndrome, diabetes, obesity, liver steatosis, and Alzheimer disease. We have recently shown that the protein deleted in breast cancer 1 (DBC1) is a key regulator of SIRT1 activity in vivo. Furthermore, SIRT1 and DBC1 form a dynamic complex that is regulated by the energetic state of the organism. Understanding how the interaction between SIRT1 and DBC1 is regulated is therefore essential to design strategies aimed to activate SIRT1. Here, we investigated which pathways can lead to the dissociation of SIRT1 and DBC1 and consequently to SIRT1 activation. We observed that PKA activation leads to a fast and transient activation of SIRT1 that is DBC1-dependent. In fact, an increase in cAMP/PKA activity resulted in the dissociation of SIRT1 and DBC1 in an AMP-activated protein kinase (AMPK)-dependent manner. Pharmacological AMPK activation led to SIRT1 activation by a DBC1-dependent mechanism. Indeed, we found that AMPK activators promote SIRT1-DBC1 dissociation in cells, resulting in an increase in SIRT1 activity. In addition, we observed that the SIRT1 activation promoted by PKA and AMPK occurs without changes in the intracellular levels of NAD+. We propose that PKA and AMPK can acutely activate SIRT1 by inducing dissociation of SIRT1 from its endogenous inhibitor DBC1. Our experiments provide new insight on the in vivo mechanism of SIRT1 regulation and a new avenue for the development of pharmacological SIRT1 activators targeted at the dissociation of the SIRT1-DBC1 complex.
Do patients with tuberous sclerosis complex have an increased risk for malignancies?

Tuberous Sclerosis Complex (TSC) is generally characterized by the presence of benign tumors, but some patients with malignancies have been reported in the literature. We examined a large Italian TSC population (240 individuals followed from 2001 to 2015, aged 3 months–74 years), assessing the frequency of malignancies to determine whether there is an increased risk for cancer in this disorder, and looking for possible features associated with the development of neoplasia. Fifteen patients had malignancies (6.25%); median age at diagnosis was 37.5 years (range of 1.6–58). Five of seven renal tumors were renal cell carcinomas. Eight patients had a non‐renal malignancy (3.3%), but we did not find a more prevalent type of cancer. No patient developed more than one malignancy. The prevalence of all malignant tumors was compatible with the prevalence in the general population (5.6%, 95%CI 2.99−9.31%, vs. 4.4% in Italy). Median age at cancer diagnosis was lower (37.5 years, 95%CI 28.6−44.7, vs. 66.0 years). Two patients (13.3%) died of their cancer, while outcome was favorable in the remaining individuals. Malignant tumors were more frequently diagnosed in patients with mutations in TSC1 when compared to TSC2 and patients with no mutation identified (P = 0.032). Our study demonstrated that TSC patients do not seem to have an increased risk for malignancies besides renal cell carcinoma. However, when cancer develops, age at diagnosis is lower than in the general population, and malignant tumors are more frequently diagnosed in patients with mutations in TSC1. Further studies are needed to confirm these data. ©2016 Wiley Periodicals, Inc.
Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: Two proof‐of‐concept examples

Whole exome sequencing (WES) is a powerful tool to identify clinically undefined forms of intellectual disability/developmental delay (ID/DD), especially in consanguineous families. Here we report the genetic definition of two sporadic cases, with syndromic ID/DD for whom array—Comparative Genomic Hybridization (aCGH) identified a de novo copy number variant (CNV) of uncertain significance. The phenotypes included microcephaly with brachycephaly and a distinctive facies in one proband, and hypotonia in the legs and mild ataxia in the other. WES allowed identification of a functionally relevant homozygous variant affecting a known disease gene for rare syndromic ID/DD in each proband, that is, c.1423C>T (p.Arg377*) in the Trafficking Protein Particle Complex 9 (TRAPPC9), and c.154T>C (p.Cys52Arg) in the Very Low Density Lipoprotein Receptor (VLDLR). Four mutations affecting TRAPPC9 have been previously reported, and the present finding further depicts this syndromic form of ID, which includes microcephaly with brachycephaly, corpus callosum hypoplasia, facial dysmorphism, and overweight. VLDLR‐associated cerebellar hypoplasia (VLDLR‐CH) is characterized by non‐progressive congenital ataxia and moderate‐to‐profound intellectual disability. The c.154T>C (p.Cys52Arg) mutation was associated with a very mild form of ataxia, mild intellectual disability, and cerebellar hypoplasia without cortical gyri simplification. In conclusion, we report two novel cases with rare causes of autosomal recessive ID, which document how interpreting de novo array‐CGH variants represents a challenge in consanguineous families; as such, clinical WES should be considered in diagnostic testing. © 2016 Wiley Periodicals, Inc.
Ca2+-independent Activation of Ca2+/Calmodulin-dependent Protein Kinase II Bound to the C-terminal Domain of CaV2.1 Calcium Channels*

Background: Calmodulin regulation of Ca2+ channels mediates short term synaptic plasticity. Results: Binding of CaMKII to CaV2.1 channels induces Ca2+-independent kinase activity. Conclusion: A complex of CaMKII and CaV2.1 channels is required for short term synaptic plasticity. Significance: CaMKII bound to CaV2.1 may regulate synaptic plasticity. Ca2+/calmodulin-dependent protein kinase II (CaMKII) forms a major component of the postsynaptic density where its functions in synaptic plasticity are well established, but its presynaptic actions are poorly defined. Here we show that CaMKII binds directly to the C-terminal domain of CaV2.1 channels. Binding is enhanced by autophosphorylation, and the kinase-channel signaling complex persists after dephosphorylation and removal of the Ca2+/CaM stimulus. Autophosphorylated CaMKII can bind the CaV2.1 channel and synapsin-1 simultaneously. CaMKII binding to CaV2.1 channels induces Ca2+-independent activity of the kinase, which phosphorylates the enzyme itself as well as the neuronal substrate synapsin-1. Facilitation and inactivation of CaV2.1 channels by binding of Ca2+/CaM mediates short term synaptic plasticity in transfected superior cervical ganglion neurons, and these regulatory effects are prevented by a competing peptide and the endogenous brain inhibitor CaMKIIN, which blocks binding of CaMKII to CaV2.1 channels. These results define the functional properties of a signaling complex of CaMKII and CaV2.1 channels in which both binding partners are persistently activated by their association, and they further suggest that this complex is important in presynaptic terminals in regulating protein phosphorylation and short term synaptic plasticity.
The Interaction between Polynucleotide Kinase Phosphatase and the DNA Repair Protein XRCC1 Is Critical for Repair of DNA Alkylation Damage and Stable Association at DNA Damage Sites*

Background: XRCC1 interacts with multiple DNA repair proteins. Results: Identification of mutant versions of XRCC1 that are defective in binding with a different single partner. Conclusion: Interaction between XRCC1 and polynucleotide kinase 3′-phosphatase is critical for the retention of XRCC1 at DNA damage sites and DNA damage repair. Significance: Insights into function of one of three DNA end processing factors that bind to the same region of XRCC1. XRCC1 plays a key role in the repair of DNA base damage and single-strand breaks. Although it has no known enzymatic activity, XRCC1 interacts with multiple DNA repair proteins and is a subunit of distinct DNA repair protein complexes. Here we used the yeast two-hybrid genetic assay to identify mutant versions of XRCC1 that are selectively defective in interacting with a single protein partner. One XRCC1 mutant, A482T, that was defective in binding to polynucleotide kinase phosphatase (PNKP) not only retained the ability to interact with partner proteins that bind to different regions of XRCC1 but also with aprataxin and aprataxin-like factor whose binding sites overlap with that of PNKP. Disruption of the interaction between PNKP and XRCC1 did not impact their initial recruitment to localized DNA damage sites but dramatically reduced their retention there. Furthermore, the interaction between PNKP and the DNA ligase IIIα-XRCC1 complex significantly increased the efficiency of reconstituted repair reactions and was required for complementation of the DNA damage sensitivity to DNA alkylation agents of xrcc1 mutant cells. Together our results reveal novel roles for the interaction between PNKP and XRCC1 in the retention of XRCC1 at DNA damage sites and in DNA alkylation damage repair.
Molecular typing of clinical Candida strains using random amplified polymorphic DNA and contour‐clamped homogenous electric fields electrophoresis

Aims: This report describes an investigation into the genetic profiles of 38 Candida albicans and 19 Candida glabrata strains collected from a dental hospital of Monastir (Tunisia) and the Laboratory of Parasitology, Farhat Hached Hospital of Sousse (Tunisia), using two typing methods: random amplified polymorphic DNA (RAPD) and contour‐clamped homogenous electric fields (CHEF).
Metalworking fluids biodiversity characterization

Aims: Hypersensitivity pneumonitis of machinists associated with metalworking fluids (MWF) was recently linked to Mycobacterium immunogenum. In addition to Mycobacterium, impacts of continuous and massive contact to other micro‐organisms, such as Pseudomonas, were little studied. This report intended to quantify and characterize the microbial load of 44 in‐use MWF.
Cloning, characterization and heterologous expression of the first Penicillium echinulatum cellulase gene

Aims: Penicillium echinulatum is effective for bioconversion processes. However, nothing is known about the molecular biology of its cellulolytic system. We describe for the first time the isolation, cloning and expression of a P. echinulatum cellulase cDNA (Pe‐egl1) encoding a putative endoglucanase.