Miracle-dz/UniFAR-FTUs huggingface dataset:
Structure of the human aminopeptidase XPNPEP3 and comparison of its in vitro activity with Icp55 orthologs: Insights into diverse cellular processes

The human aminopeptidase XPNPEP3 is associated with cystic kidney disease and TNF-TNFR2 cellular signaling. Its yeast and plant homolog Icp55 processes several imported mitochondrial matrix proteins leading to their stabilization. However, the molecular basis for the diverse roles of these enzymes in the cell is unknown. Here, we report the crystal structure of human XPNPEP3 with bound apstatin product at 1.65 Å resolution, and we compare its in vitro substrate specificity with those of fungal Icp55 enzymes. In contrast to the suggestions by earlier in vivo studies of mitochondrial processing, we found that these enzymes are genuine Xaa-Pro aminopeptidases, which hydrolyze peptides with proline at the second position (P1′). The mitochondrial processing activity involving cleavage of peptides lacking P1′ proline was also detected in the purified enzymes. A wide proline pocket as well as molecular complementarity and capping at the S1 substrate site of XPNPEP3 provide the necessary structural features for processing the mitochondrial substrates. However, this activity was found to be significantly lower as compared with Xaa-Pro aminopeptidase activity. Because of similar activity profiles of Icp55 and XPNPEP3, we propose that XPNPEP3 plays the same mitochondrial role in humans as Icp55 does in yeast. Both Xaa-Pro aminopeptidase and mitochondrial processing activities of XPNPEP3 have implications toward mitochondrial fitness and cystic kidney disease. Furthermore, the presence of both these activities in Icp55 elucidates the unexplained processing of the mitochondrial cysteine desulfurase Nfs1 in yeast. The enzymatic and structural analyses reported here provide a valuable molecular framework for understanding the diverse cellular roles of XPNPEP3.
Photoreceptor morphogenesis in the Drosophila compound eye: R1–R6 rhabdomeres become twisted just before eclosion

The photosensitive microvilli of Drosophila photoreceptors R1–R6 are not aligned in parallel over the entire length of the visual cells. In the distal half of each cell, the microvilli are slightly tilted toward one side and, in the proximal half, extremely toward the opposite side. This phenomenon, termed rhabdomere twisting, has been known for several decades, but the developmental and cell biological basis of rhabdomere twisting has not been studied so far. We show that rhabdomere twisting is also manifested as molecular polarization of the visual cell, because phosphotyrosine‐containing proteins are selectively partitioned to different sides of the rhabdomere stalk in the distal and proximal sections of each R1–R6 photoreceptor. Both the asymmetrical segregation of phosphotyrosine proteins and the tilting of the microvilli occur shortly before eclosion of the flies, when eye development in all other aspects is considered to be essentially complete. Establishment of rhabdomere twisting occurs in a light‐independent manner, because phosphotyrosine staining is unchanged in dark‐reared wild‐type flies and in mutants with defects in the phototransduction cascade, ninaE17 and norpAP24. We conclude that antiphosphotyrosine immunofluorescence can be used as a light microscopic probe for the analysis of rhabdomere twisting and that microvilli tilting represents a type of planar cell polarity that is established by an active process in the last phase of photoreceptor morphogenesis, just prior to eclosion of the flies. J. Comp. Neurol. 498:68–79, 2006. © 2006 Wiley‐Liss, Inc.
Lightning impulse testing of natural ester fluid gaps and insulation interfaces

A significant amount of lightning impulse breakdown and withstand testing has been accomplished in mineral oil to understand this important electrical characteristic for transformer insulation system design. To be considered as viable insulating fluids for high voltage equipment, alternative dielectric liquids should have similar lightning impulse characteristics as compared to mineral oil to provide the clearances necessary for common dielectric design. This paper reviews the testing for establishing the lightning impulse breakdown characteristics of natural ester fluids relative to mineral oil test results. The key variables of the testing included: various oil gap and solid insulation creep distances, electrode configurations, electrical stress characteristics, and solid insulation surfaces. The fluid gaps ranged from 3 mm to 55 mm. The electrode configurations included quasi-uniform in oil gaps, with some attached to pressboard, and nonhomogeneous contacts in oil gaps combined with a phenolic interface. The range in gap distance was selected to reflect the range commonly used in liquid insulated transformer core/coil designs. The electrical stresses used included 1.2 × 50 ¿s lightning impulses of both positive and negative polarity. The solid insulation materials consisted of high density pressboard, Kraft paper and a high density phenolic composite. It is concluded that the impulse breakdown voltage of the natural ester fluid is similar to mineral oil for the oil gaps and electrode configurations tested.
Aquatis and Ryujin projects: First steps to remote sensing bottom of the sea by small homemade Autonomous Underwater Vehicles

Acquiring 3D very high resolution data in operational conditions is a real challenge in marine coastal areas exploration for environmental, archaeological and defense and security applications. In order to achieve these goals the use of small autonomous robots can be seen as an efficient solution. Because of the complexity of the development of that kind of vehicles, the main contribution are due today to large research laboratories. But because of the democratization of information and communication technologies, such works begin to be affordable and as participating to these developments could be also a very interesting and innovative pedagogical experience, we have chosen to open some of our research projects to undergraduate students. In this paper, we present two research projects in the development of Autonomous Underwater Vehicle involving undergraduate students, projects that have won awards in the international student contest SAUCE.
Non-Coding RNAs in Mammalian Sexual Development

The present decade is witnessing a paradigm shift in our understanding of gene regulation. RNA, once relegated to an intermediary between DNA and protein, has emerged as a key contributor in the coordination of complex developmental pathways. For sexually reproducing organisms, propagation of the species is accomplished via an elaborate sexual phenotype. In mammals this consists of a highly complex cell lineage that has the capacity for intricate self-differentiation whilst maintaining the potential to generate all cell types upon fertilization. In addition, mammals possess a diverse range of somatic reproductive tissues and organs that often undergo dynamic morphological changes in response to a variety of external and internal cues. Although the protein component required to mediate these processes continues to be vigorously investigated, it is becoming increasingly apparent that an understanding of the non-coding RNA (ncRNA) component is required to develop a comprehensive picture of mammalian sexual development.
Functional Interaction of Human Cdc37 with the Androgen Receptor but Not with the Glucocorticoid Receptor*

Cdc37 is a molecular chaperone closely associated with the folding of protein kinases. Results from studies using a yeast model system showed that it was also important for activation of the human androgen receptor (AR). Based on results from the yeast model system (Fliss, A. E., Fang, Y., Boschelli, F., and Caplan, A. J. (1997) Mol. Biol. Cell 8, 2501–2509), we initiated studies to address whether AR and Cdc37 interact with each other in animal cell systems. Our results show that Cdc37 binds to AR but not to glucocorticoid receptors (GR) synthesized in rabbit reticulocyte lysates. This binding occurs via the ligand-binding domain of the AR in a manner that is partially dependent on Hsp90 and the presence of hormone. Further studies using the yeast system showed that Cdc37 is not interchangeable with Hsp90, suggesting that it functions at a distinct step in the activation pathway. Expression of a dominant negative form of Cdc37 in animal cells down-regulates full-length AR but has very little effect on an AR truncation lacking the ligand-binding domain or full-length GR. These results reveal differences in the mechanisms by which AR and GR become active transcription factors and strengthen the notion that Cdc37 has a wider range of polypeptide clients than was realized previously.
Fluorescence lifetime images and correlation spectra obtained by multidimensional time‐correlated single photon counting

Multidimensional time‐correlated single photon counting (TCSPC) is based on the excitation of the sample by a high‐repetition rate laser and the detection of single photons of the fluorescence signal in several detection channels. Each photon is characterized by its arrival time in the laser period, its detection channel number, and several additional variables such as the coordinates of an image area, or the time from the start of the experiment. Combined with a confocal or two‐photon laser scanning microscope and a pulsed laser, multidimensional TCSPC makes a fluorescence lifetime technique with multiwavelength capability, near‐ideal counting efficiency, and the capability to resolve multiexponential decay functions. We show that the same technique and the same hardware can be used for precision fluorescence decay analysis and fluorescence correlation spectroscopy (FCS) in selected spots of a sample. Microsc. Res. Tech. 69:186–195, 2006. © 2006 Wiley‐Liss, Inc.
Bullying and HIV Risk Among High School Teenagers: The Mediating Role of Teen Dating Violence.

BACKGROUND Teen dating violence (TDV), bullying, and HIV risk behaviors are public health concerns that impact adolescents in the United States. National estimates reveal high rates of these risk behaviors among high school students. Based on theoretical and empirical evidence, we hypothesized that experiencing teen dating violence (sexual and physical) would mediate the impact of bullying on HIV risk. METHODS Data were from the 2013 National Youth Behavior Risk Surveillance Survey (YRBSS) among students who answered questions on bullying, TDV, and HIV risk (N = 13,571). The YRBSS is conducted biennially among 9th- to 12th-grade students nationally. We used multiple regression analysis and Hayes' SPSS process macro to examine the 2 study hypotheses. RESULTS Findings from bivariate analysis suggest an association between bullying and HIV risk. The study also found associations between physical, sexual teen dating violence and HIV risk. Results also indicate that both physical and sexual teen dating violence mediate the association between bullying and HIV risk. CONCLUSION Our findings suggest that multidimensional interventions should be developed to reduce the rate of teen dating violence and combat bullying as a preventative method for HIV risk among high school students.
Soluble urokinase‐type plasminogen activator receptor as a putative marker of male accessory gland inflammation

The association between male accessory gland infection/inflammation (MAGI) and infertility is well‐known in clinical practice. Standard semen analysis, leukocytospermia, and microbiological tests are often not enough accurate for a diagnosis. A large amount of biochemical parameters in seminal plasma have been suggested as inflammation markers, however, there is not yet a sensitive and specific biomarker that accurately identifies MAGI. We investigated the presence of soluble urokinase‐type plasminogen activator receptor (suPAR), known marker of systemic inflammation, in the seminal plasma to evaluate its possible involvement in urogenital tract inflammation. On the basis of andrological evaluation, including spermiogram and ultrasound findings, we selected 76 patients with MAGI and 30 healthy men as control group. Patients were classified according to the results of the semen culture in group A (n = 28) presenting a bacterial MAGI and group B (n = 48) with abacterial MAGI. C‐reactive protein (CRP), total protein (TP), procalcitonin (PCT), leukocytes peroxidase (LP), and suPAR concentrations were assayed on seminal plasma. Spermiogram parameters were significantly lower in the patients with MAGI than in controls. CRP, TP, PCT, and LP did not differ in MAGI vs. controls. suPAR was detectable in all semen samples; it was significantly increased in A and B groups (86.6 ± 30.7 ng/mL vs. 39.7 ± 17.2 ng/mL) with an inverse correlation with sperm parameters. We selected by receiver operating characteristic curve a suPAR cut‐off value of 55.3 ng/mL as a diagnostic threshold for the diagnosis of MAGI. We report in this study the first evidence of suPAR presence in seminal plasma, focusing on its interesting role as reliable and sensitive marker of inflammation for the differential diagnosis of MAGI.
Ezetimibe ameliorates early diabetic nephropathy in db/db mice.

AIM Lipid-lowering medications have been suggested to have a potential benefit in the treatment of chronic kidney disease (CKD) such as diabetic nephropathy. Although ezetimibe has been widely used to lower serum cholesterol levels, the effect of this drug on diabetic nephropathy remains unclear. In the present study, therefore, we examined the protective effect of ezetimibe on diabetic nephropathy in db/db mice. METHOD Db/db mice were fed a standard diet with 0.01% (w/w) of ezetimibe for 8 weeks from 8 weeks of age. RESULTS Treatment with ezetimibe did not affect food intake, body weight gain, adiposity, or blood pressure in db/db mice. Ezetimibe also had no effect on glucose metabolism such as fasting plasma glucose and insulin; however, it markedly reduced plasma lipid levels and hepatic lipid contents and reduced the urinary excretion of albumin by 50% in db/db mice, suggesting the effect of ezetimibe on diabetic nephropathy. Furthermore, ezetimibe improved glomerular hypertrophy. Although ezetimibe had no effect on oxidative stress measured by urinary 8-OHdG in db/db mice, the plasma adiponectin level was normalized, and the expression of adiponectin receptor 1 in the kidney was increased by ezetimibe treatment. CONCLUSION Our data suggest that ezetimibe can improve early diabetic nephropathy through its hypolipidemic effect, and the amelioration of adiponectin resistance may also be responsible for the renoprotective effect of ezetimibe as its underlying mechanism.
Molecular Changes Associated with Acquired Resistance to Crizotinib in ROS1-Rearranged Non–Small Cell Lung Cancer

Purpose: Although ROS1-rearranged non–small cell lung cancer (NSCLC) is sensitive to crizotinib, development of resistance is inevitable. Here, we identified molecular alterations in crizotinib-resistant tumors from two NSCLC patients with the CD74–ROS1 rearrangement, and in HCC78 cells harboring SLC34A2–ROS1 that showed resistance to crizotinib (HCC78CR cells). Experimental Design: ROS1 kinase domain mutations were examined in fresh tumor tissues from two NSCLC patients and HCC78CR1-3 cells by direct sequencing. Ba/F3 cells expressing ROS1 secondary mutations were constructed to evaluate resistance to crizotinib. An upregulated pathway was identified using phospho-receptor tyrosine kinase array, EGFR signaling antibody array, and RNA sequencing (RNA-seq). Cell proliferation and ROS1 downstream signaling pathways were compared between HCC78 and HCC78CR1-3 cells. Results: The ROS1 G2032R mutation was identified in crizotinib-resistant tumors from one patient. Furthermore, HCC78CR1 and CR2 cells harbored a novel ROS1 L2155S mutation (73.3% and 76.2%, respectively). ROS1 G2032R and L2155S mutations conferred resistance to crizotinib in Ba/F3 cells. Evidence of epithelial-to-mesenchymal transition with downregulated E-cadherin and upregulated vimentin was observed in HCC78CR1-2 cells and in the other patient. RNA-seq and EGFR signaling antibody array revealed that the EGFR pathway was significantly upregulated in HCC78CR3 versus HCC78 cells. Cells with the ROS1 mutation and upregulated EGFR were sensitive to foretinib, an inhibitor of c-MET, VEGFR2, and ROS1 and irreversible EGFR tyrosine kinase inhibitors plus crizotinib, respectively. Conclusions: Molecular changes associated with acquired crizotinib resistance in ROS1-rearranged NSCLC are heterogeneous, including ROS1 tyrosine kinase mutations, EGFR activation, and epithelial-to-mesenchymal transition. Clin Cancer Res; 21(10); 2379–87. ©2015 AACR.
Cognitive Impairment in Schizophrenia, Neurotransmitters and the New Atypical Antipsychotic Aripiprazole

Abstract Cognition is a group of mental processes that includes the capacity to perceive, think, learn and to study, and the capacity of the brain to analyze information and program adaptive behaviour. Although there has been an appreciable evolution in the therapy of psychoses in the last twenty-five years, cognitive disturbances still persist in spite of antipsychotic treatment. The cognitive decay disrupts the ability of clinically diagnosed patients with psychoses, mainly schizophrenia, to learn and to memorize skills that are useful for their family and social relationships. Moreover, cognitive deficiency is often considered to be crucial for further rehabilitation. In atypical antipsychotics there are big differences in the effects on cognitive functions. Some clinical studies demonstrate the benefits of a third generation of antipsychotics on cognitive functions in patients treated for mental illnesses. In the present study we have reviewed many articles investigating the influence of aripiprazole on cognition in human and animal subjects. Aripiprazole is a third generation antipsychotic drug that possesses a unique pharmacodynamic profile, which in conjunction with recently published scientific data on the drugs’ influence on antidepressant, anxiolytic and cognitive functions, suggests a highly positive future potential for restorative cognitive treatment and ongoing healthy function. The data included in the review will contribute to determining the potential benefits of aripiprazole on memory and training processes.
Threshold switching selector and 1S1R integration development for 3D cross-point STT-MRAM

To develop very high density STT-MRAM, 3D cross-point architecture is desirable, which requires a selector integrated with a pMTJ memory element. We present a two terminal bi-directional threshold switching selector based on doped-HfOx materials and integrated one selector/one perpendicular MTJ (1S1R) cross-point device. The selector shows sharp turn-on slope of around 2.8 mV/dec, high On/Off ratio (above 107), low on-resistance (∼1 kΩ), low threshold voltage (0.3 V), low holding voltage (0.02 V), fast turn on speed (10 ns), and good thermal stability (400°C). Switching operations between “AP” and “P” state have been demonstrated for the 1S1R STT-MRAM device. This integrated 1S1R enables implementation of the 3D STT-MRAM array for high density memory application.
Fat utilization during exercise: adaptation to a fat‐rich diet increases utilization of plasma fatty acids and very low density lipoprotein‐triacylglycerol in humans

1 This study was carried out to test the hypothesis that the greater fat oxidation observed during exercise after adaptation to a high‐fat diet is due to an increased uptake of fat originating from the bloodstream. 2 Of 13 male untrained subjects, seven consumed a fat‐rich diet (62% fat, 21% carbohydrate) and six consumed a carbohydrate‐rich diet (20% fat, 65% carbohydrate). After 7 weeks of training and diet, 60 min of bicycle exercise was performed at 68 ± 1% of maximum oxygen uptake. During exercise [1‐13C]palmitate was infused, arterial and venous femoral blood samples were collected, and blood flow was determined by the thermodilution technique. Muscle biopsy samples were taken from the vastus lateralis muscle before and after exercise. 3 During exercise, the respiratory exchange ratio was significantly lower in subjects consuming the fat‐rich diet (0.86 ± 0.01, mean ±s.e.m.) than in those consuming the carbohydrate‐rich diet (0.93 ± 0.02). The leg fatty acid (FA) uptake (183 ± 37 vs. 105 ± 28 μmol min−1) and very low density lipoprotein‐triacylglycerol (VLDL‐TG) uptake (132 ± 26 vs. 16 ± 21 μmol min−1) were both higher (each P < 0.05) in the subjects consuming the fat‐rich diet. Whole‐body plasma FA oxidation (determined by comparison of 13CO2 production and blood palmitate labelling) was 55‐65% of total lipid oxidation, and was higher after the fat‐rich diet than after the carbohydrate‐rich diet (13.5 ± 1.2 vs. 8.9 ± 1.1 μmol min−1 kg−1; P < 0.05). Muscle glycogen breakdown was significantly lower in the subjects taking the fat‐rich diet than those taking the carbohydrate‐rich diet (2.6 ± 0.5 vs. 4.8 ± 0.5 mmol (kg dry weight)−1 min−1, respectively; P < 0.05), whereas leg glucose uptake was similar (1.07 ± 0.13 vs. 1.15 ± 0.13 mmol min−1). 4 In conclusion, plasma VLDL‐TG appears to be an important substrate source during aerobic exercise, and in combination with the higher plasma FA uptake it accounts for the increased fat oxidation observed during exercise after fat diet adaptation. The decreased carbohydrate oxidation was apparently due to muscle glycogen sparing and not to diminished plasma glucose uptake.
Changes of Membrane Fluidity in Erythrocytes of Obese Children: A Spin Label Study

ABSTRACT. Red blood cells depend on circulating lipoproteins for the turnover of membrane phospholipids. Thus abnormalities in lipid and lipoprotein metabolism are frequently associated with changes in composition and fluidity of erythrocyte membranes. Using the electron spin resonance technique we studied the physical state of erythrocyte membranes from 15 obese children with a body mass index ranging from 22.8 to 34 kg · m-2 and slight alterations of plasma lipids. The spin labels used, 5-doxylstearate and 16-doxylstearate, have shown an increase of the order parameter and of the correlation time, respectively. These observations indicate a decrease of fluidity at the surface and in the hydrophobic core of erythrocyte membranes from obese subjects. The results are statistically significant and they are discussed in relation to clinical aspects of childhood obesity. Studies on erythrocyte membrane molecular organization could represent a sensitive way to find out small metabolic alterations hardly detectable with compositional studies.