SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD.

Maternal prenatal plasma oxytocin is positively associated with prenatal psychological symptoms, but method of immunoassay extraction may affect results.

We examined associations between prenatal plasma oxytocin levels and depressive symptoms, state anxiety, and pregnancy anxiety in 75 women who visited the laboratory with their partners during mid-to-late pregnancy and engaged in relationship discussion tasks prior to a blood draw. Given controversy in the literature regarding oxytocin measurement, we compared two widely-used immunoassay approaches (with and without extraction prior to immunoassay). Levels of immunoreactive oxytocin measured with and without extraction were not correlated with each other. However, both extracted and unextracted oxytocin were positively associated with women's prenatal depressive symptoms in a model that controlled for pregnancy stage and body mass index. Only unextracted oxytocin was associated with state anxiety and pregnancy-specific anxiety. In summary, elevated plasma oxytocin levels in expectant mothers might indicate risk for mental health symptoms during the prenatal period, but results for anxiety are mixed and appear to depend on the immunoassay approach employed.

Metabolomic changes in human adipose tissue derived products following non-enzymatic microfacturing.

OBJECTIVE: In this study, we evaluated the metabolomic profiling of cryopreserved Lipogems® tissue products and the initial lipoaspirates before microfracturing, to determine altered metabolites that could result from the non-enzymatic processing or the cryopreservation method. MATERIALS AND METHODS: Human Lipoaspirate samples (n=10) were divided in two aliquots, of which one was non-processed and the other was processed by Lipogems® device. Non-processed lipoaspirates and Lipogems® processed tissues were stored at -80°C fresh frozen (N=3 per group) or in the presence of 0.5 M dimethyl sulfoxide (DMSO) (N=7 per group). A global non-targeted metabolic profile on these samples was performed. RESULTS: Differences were observed in carbohydrate and nucleotide metabolism. These alterations translated in long chain and polyunsaturated fatty acid levels and amino acid metabolites showed divergent trends. When Lipogems® and Lipoaspirate tissue products were cryopreserved with DMSO, amino acids tended to increase in Lipogems® product. However, in the absence of DMSO aminoacids and their catabolites, tended to decrease in Lipogems® fat tissue product. CONCLUSIONS: Microfractured human adipose tissue has been shown to provide a more effective source of adult stromal cells compared to the initial lipoaspirated tissue material. These could be, according to our findings, due to the changes in the metabolic profile of lipoaspirate tissues products.

Evidence for Gamow-Teller Decay of

The ß-delayed neutron emission of ^{83,84}Ga isotopes was studied using the neutron time-of-flight technique. The measured neutron energy spectra showed emission from states at excitation energies high above the neutron separation energy and previously not observed in the ß decay of midmass nuclei. The large decay strength deduced from the observed intense neutron emission is a signature of Gamow-Teller transformation. This observation was interpreted as evidence for allowed ß decay to ^{78}Ni core-excited states in ^{83,84}Ge favored by shell effects. We developed shell model calculations in the proton fpg_{9/2} and neutron extended fpg_{9/2}+d_{5/2} valence space using realistic interactions that were used to understand measured ß-decay lifetimes. We conclude that enhanced, concentrated ß-decay strength for neutron-unbound states may be common for very neutron-rich nuclei. This leads to intense ß-delayed high-energy neutron and strong multineutron emission probabilities that in turn affect astrophysical nucleosynthesis models.

gVARVI: A graphical software tool for the acquisition of the heart rate in response to external stimuli.

BACKGROUND AND OBJECTIVE: At present, tools capable of acquiring heart rate data can be found both in commercial and research fields. However, these tools do not allow users to manage experiments comprising sequences of activities or to store the information needed to perform heart rate variability analysis across different activities. One exception is VARVI, a simple software tool developed previously in our research group that does not have a graphical user interface and it works only with visual stimuli. In this paper, we present gVARVI, a software tool aimed at obtaining heart rate data signals while the user is either receiving a sequence of external stimuli or performing a sequence of actions (an activity). METHODS: gVARVI is an open source application developed in Python programming language. It can acquire heart rate data by means of a wireless chest strap using either Bluetooth or ANT+ protocols. Users can define activities of different types (video, sounds, pictures or keyboard controlled actions) which will associate contextual information to the heart rate data. gVARVI allows users to preview this data or to store it to be used for heart rate variability studies. Our tool was validated by 15 researchers, who worked with the application and filled in a usability questionnaire. RESULTS: The outcome of the usability test was satisfactory, giving a mean score of 4.75 in a 1-5 scale (1 - strongly disagree, 5 - strongly agree). Participants also contributed with valuable comments, which we used to include new features in the last version of our tool. CONCLUSIONS: gVARVI is an open source tool that offers new possibilities to both physicians and clinicians to perform heart rate variability studies. It allows users to acquire heart rate data including information on the activity performed by subjects while recording. In this paper, we describe all the functionalities included in gVARVI, and a complete example of use is provided.

A radio jet from the optical and x-ray bright stellar tidal disruption flare ASASSN-14li.

The tidal disruption of a star by a supermassive black hole leads to a short-lived thermal flare. Despite extensive searches, radio follow-up observations of known thermal stellar tidal disruption flares (TDFs) have not yet produced a conclusive detection. We present a detection of variable radio emission from a thermal TDF, which we interpret as originating from a newly launched jet. The multiwavelength properties of the source present a natural analogy with accretion-state changes of stellar mass black holes, which suggests that all TDFs could be accompanied by a jet. In the rest frame of the TDF, our radio observations are an order of magnitude more sensitive than nearly all previous upper limits, explaining how these jets, if common, could thus far have escaped detection.

gHRV: Heart rate variability analysis made easy.

In this paper, the gHRV software tool is presented. It is a simple, free and portable tool developed in python for analysing heart rate variability. It includes a graphical user interface and it can import files in multiple formats, analyse time intervals in the signal, test statistical significance and export the results. This paper also contains, as an example of use, a clinical analysis performed with the gHRV tool, namely to determine whether the heart rate variability indexes change across different stages of sleep. Results from tests completed by researchers who have tried gHRV are also explained: in general the application was positively valued and results reflect a high level of satisfaction. gHRV is in continuous development and new versions will include suggestions made by testers.

Depressive symptoms linked to 1-h plasma glucose concentrations during the oral glucose tolerance test in men and women with the metabolic syndrome.

AIMS: The addition of the 1-h plasma glucose concentration measure from an oral glucose tolerance test to prediction models of future Type 2 diabetes has shown to significantly strengthen their predictive power. The present study examined the relationship between severity of depressive symptoms and hyperglycaemia, focusing on the 1-h glucose concentration vs. fasting and 2-h glucose measures from the oral glucose tolerance test. METHODS: Participants included 140 adults with the metabolic syndrome and without diabetes who completed a baseline psychobiological assessment and a 2-h oral glucose tolerance test, with measurements taken every 30 min. Depressive symptoms were assessed using the Beck Depression Inventory. RESULTS: Multivariate linear regression revealed that higher levels of depressive symptoms were associated with higher levels of 1-h plasma glucose concentrations after adjusting for age, gender, ethnicity, BMI, antidepressant use and high-sensitivity C-reactive protein. Results were maintained after controlling for fasting glucose as well as for indices of insulin resistance and secretion. Neither fasting nor 2-h plasma glucose concentrations were significantly associated with depressive symptoms. CONCLUSIONS: Elevated depressive symptoms in persons with the metabolic syndrome were associated with greater glycaemic excursion 1-h following a glucose load that was not accounted for by differences in insulin secretory function or insulin sensitivity. Consistent with previous findings, this study highlights the value of the 1-h plasma glucose measurement from the oral glucose tolerance test in the relation between depressive symptoms and glucose metabolism as an indicator of metabolic abnormalities not visible when focusing on fasting and 2-h post-oral glucose tolerance test measurements alone.

Large ß-delayed one and two neutron emission rates in the decay of 86Ga.

Beta decay of 86Ga was studied by means of ß-neutron-γ spectroscopy. An isotopically pure ^{86}Ga beam was produced at the Holifield Radioactive Ion Beam Facility using a resonance ionization laser ion source and high-resolution electromagnetic separation. The decay of 86Ga revealed a half-life of 43(-15)(+21) ms and large ß-delayed one-neutron and two-neutron branching ratios of P1n=60(10)% and P2n=20(10)%. The ßγ decay of 86Ga populated a 527 keV transition that is interpreted as the deexcitation of the first 2+ state in the N=54 isotone 86Ge and suggests a quick onset of deformation in Ge isotopes beyond N=50.

New half-lives of r-process Zn and Ga isotopes measured with electromagnetic separation.

The ß decays of neutron-rich nuclei near the doubly magic (78)Ni were studied at the Holifield Radioactive Ion Beam Facility using an electromagnetic isobar separator. The half-lives of (82)Zn (228±10 ms), (83)Zn (117±20 ms), and (85)Ga (93±7 ms) were determined for the first time. These half-lives were found to be very different from the predictions of the global model used in astrophysical simulations. A new calculation was developed using the density functional model, which properly reproduced the new experimental values. The robustness of the new model in the (78)Ni region allowed us to extrapolate data for more neutron-rich isotopes. The revised analysis of the rapid neutron capture process in low entropy environments with our new set of measured and calculated half-lives shows a significant redistribution of predicted isobaric abundances strengthening the yield of A>140 nuclei.

Aerobic training does not alter CRP in apparently healthy, untrained men.

AIM: Regular aerobic exercise may reduce cardiovascular disease (CVD) risk by lowering the concentration of inflammatory markers, such as C-reactive protein (CRP). While studies in diseased populations have shown significant decreases in CRP concentrations with regular aerobic training, little has been conclusively determined regarding the effects of aerobic training on CRP concentrations in apparently healthy, untrained populations. Aim of the study was to examine the effects of a 17-wk half marathon training program (TP) on CRP concentrations, aerobic fitness, and body composition in apparently healthy, untrained men. METHODS: Twenty men (29.3±1.0 y) enrolled as training subjects (TRN) in a 17-wk half marathon TP. An additional 22 men (27.8±1.4 y) served as controls (CON). Fasting blood samples were taken at four time points over the TP and were analyzed for CRP and interleukin-6 (IL-6) concentrations. Aerobic capacity (VO2max) and body fat percent (BF%) were measured before and after the TP. RESULTS: No significant post-training changes in CRP (P=0.70) or IL-6 concentrations (P=0.67) were seen in TRN as a result of the TP, despite significant improvements in VO2max (42.2±1.9 ml∙kg-1∙min⁻¹, P<0.0001) and significant reductions in resting heart rate (P=0.004), BF% (P=0.03), and body mass index (BMI, P=0.05). No significant changes in CRP, VO2max, BMI, or BF% were detected in CON over time. CONCLUSION: Regular aerobic training does not appear to affect CRP concentrations in apparently healthy, untrained men despite significant improvements in bodyweight, BF%, BMI, and VO2max.

Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

OBJECTIVES: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. METHODS: A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. RESULTS: The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). CONCLUSIONS: HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.

Expression, cellular distribution, and heterogeneity of growth hormone in the chicken cerebellum during development.

Although growth hormone (GH) is mainly synthesized and secreted by pituitary somatotrophs, it is now well established that the GH gene can be expressed in many extrapituitary tissues, including the central nervous system (CNS). Here we studied the expression of GH in the chicken cerebellum. Cerebellar GH expression was analyzed by in situ hybridization and cDNA sequencing, as well as by immunohistochemistry and confocal microscopy. GH heterogeneity was studied by Western blotting. We demonstrated that the GH gene was expressed in the chicken cerebellum and that its nucleotide sequence is closely homologous to pituitary GH cDNA. Within the cerebellum, GH mRNA is mainly expressed in Purkinje cells and in cells of the granular layer. GH-immunoreactivity (IR) is also widespread in the cerebellum and is similarly most abundant in the Purkinje and granular cells as identified by specific neuronal markers and histochemical techniques. The GH concentration in the cerebellum is age-related and higher in adult birds than in embryos and juveniles. Cerebellar GH-IR, as determined by Western blot under reducing conditions, is associated with several size variants (of 15, 23, 26, 29, 35, 45, 50, 55, 80 kDa), of which the 15 kDa isoform predominates (>30% among all developmental stages). GH receptor (GHR) mRNA and protein are also present in the cerebellum and are similarly mainly present in Purkinje and granular cells. Together, these data suggest that GH and GHR are locally expressed within the cerebellum and that this hormone may act as a local autocrine/paracrine factor during development of this neural tissue.

An open source tool for heart rate variability spectral analysis.

In this paper we describe a software package for developing heart rate variability analysis. This package, called RHRV, is a third party extension for the open source statistical environment R, and can be freely downloaded from the R-CRAN repository. We review the state of the art of software related to the analysis of heart rate variability (HRV). Based upon this review, we motivate the development of an open source software platform which can be used for developing new algorithms for studying HRV or for performing clinical experiments. In particular, we show how the RHRV package greatly simplifies and accelerates the work of the computer scientist or medical specialist in the HRV field. We illustrate the utility of our package with practical examples.

Extraction simulations and emittance measurements of a Holifield Radioactive Ion Beam Facility electron beam plasma source for radioactive ion beams.

The Holifield Radioactive Ion Beam Facility (HRIBF) at Oak Ridge National Laboratory has a variety of ion sources used to produce radioactive ion beams (RIBs). Of these, the workhorse is an electron beam plasma (EBP) ion source. The recent addition of a second RIB injector, the Injector for Radioactive Ion Species 2 (IRIS2), for the HRIBF tandem accelerator prompted new studies of the optics of the beam extraction from the EBP source. The source was modeled using SIMION V8.0, and results will be presented, including comparison of the emittances as predicted by simulation and as measured at the HRIBF offline ion source test facilities. Also presented will be the impact on phase space shape resulting from extraction optics modifications implemented at IRIS2.

Growth hormone expression in stromal and non-stromal cells in the bursa of Fabricius during bursal development and involution: Causal relationships?

Growth hormone (GH) is expressed in the chicken bursa of Fabricius (BF), an organ that undergoes three distinct developmental stages: rapid growth (late embryogenesis until 6-8 weeks of age [w]), plateaued growth (between 10 and 15w), and involution (after 18-20w). The distribution and abundance of GH-immunoreactivity (GH-IR) and GH mRNA expression in stromal and non-stromal bursal cells during development, as well as the potential anti-apoptotic effect of GH in bursal cell survival were the focus of this study. GH mRNA expression was mainly in the epithelial layer and in epithelial buds at embryonic day (ED) 15; at 2w it was widely distributed within the follicle and in the interfollicular epithelium (IFE); at 10w it clearly diminished in the epithelium; whereas at 20w it occurred in only a few cortical cells and in the connective tissue. Parallel changes in the relative proportion of GH mRNA expression (12, 21, 13, 1%) and GH-IR (19, 18, 11, <3%) were observed at ED 15, 2w, 10w, and 20w, respectively. During embryogenesis, GH-IR co-localized considerably with IgM-IR, but scarcely with IgG-IR, whereas the opposite was observed after hatching. Significant differences in bursal cell death occurred during development, with 9.3% of cells being apoptotic at ED 15, 0.4% at 2w, 0.23% at 10w, and 21.1% at 20w. Addition of GH increased cultured cell survival by a mechanism that involved suppression (up to 41%) of caspase-3 activity. Results suggest that autocrine/paracrine actions of bursal GH are involved in the differentiation and proliferation of B lymphocytes and in BF growth and cell survival in embryonic and neonatal chicks, whereas diminished GH expression in adults may result in bursal involution.

Immune growth hormone (GH): localization of GH and GH mRNA in the bursa of Fabricius.

Expression of growth hormone (GH) and GH receptor (GHR) genes in the bursa of Fabricius of chickens suggests that it is an autocrine/paracrine site of GH production and action. The cellular localization of GH and GH mRNA within the bursa was the focus of this study. GH mRNA was expressed mainly in the cortex, comprised of lymphocyte progenitor cells, but was lacking in the medulla where lymphocytes mature. In contrast, more GH immunoreactivity (GH-IR) was present in the medulla than in the cortex. In non-stromal tissues, GH-IR and GH mRNA were primarily in lymphocytes, and also in macrophage-like cells and secretory dendritic cells. In stromal tissues, GH mRNA, GH and GHR were expressed in cells near the connective tissue (CT) between follicles and below the outer serosa. In contrast, GH (but not GH mRNA or GHR), was present in cells of the interfollicular epithelium (IFE), the follicle-associated epithelium (FAE) and the interstitial corticoepithelium. This mismatch may reflect dynamic temporal changes in GH translation. Co-expression of GHR-IR, GH-IR, GH mRNA and IgG was found in immature lymphoid cells near the cortex and in IgG-IR CT cells, suggesting an autocrine/paracrine role for bursal GH in B-cell differentiation.

ABCA1 and amphipathic apolipoproteins form high-affinity molecular complexes required for cholesterol efflux.

Apolipoproteins, such as apolipoprotein A-I (apoA-I), can stimulate cholesterol efflux from cells expressing the ATP binding cassette transporter A1 (ABCA1). The nature of the molecular interaction between these cholesterol acceptors and ABCA1 is controversial, and models suggesting a direct protein-protein interaction or indirect association have been proposed. To explore this issue, we performed competition binding and chemical cross-linking assays using six amphipathic plasma proteins and an 18 amino acid amphipathic helical peptide. All seven proteins stimulated lipid efflux and inhibited the cross-linking of apoA-I to ABCA1. Cross-linking of apoA-I to ABCA1 was saturable and occurred at high affinity (Kd of 7.0 +/- 1.9 nM), as was cross-linking of apoA-II. After binding to ABCA1, apoA-I rapidly dissociated (half-life of 25 min) from the complex and was released back into the medium. A mutant form of ABCA1 (W590S) that avidly binds apoA-I but fails to promote cholesterol efflux released apoA-I with similar kinetics but without transfer of cholesterol to apoA-I. Thus, a high-affinity, saturable, protein-protein interaction occurs between ABCA1 and all of its amphipathic protein ligands. Dissociation of the complex leads to the cellular release of cholesterol and the apolipoprotein. However, dissociation is not dependent on cholesterol transfer, which is a clearly separable event, distinguishable by ABCA1 mutants.

Evaluation of an automated wavelet-based system dedicated to the detection of clustered microcalcifications in digital mammograms.

Mammographic screening programs are delivering reductions in breast cancer mortality. However, breast cancer screening will be cost effective and will provide a real profit only when both high sensitivity and specificity levels are reached. To date, due to human or technical factors, a significant number of breast cancers are still missed or misinterpreted on the mammograms. Computer methodologies, developed to assist radiologists, could represent further amelioration by increasing diagnostic accuracy in the screening programs. We have tested a computerized scheme to detect clustered microcalcifications in digital mammograms, employing 360 mammograms that were randomly selected from the mammographic screening program, currently undergoing at the Galicia Community (Spain). After the digitization process, the breast border was initially determined. A wavelet-based algorithm was employed to detect the clusters of microcalcifications. The performance of the automated system over the test set was evaluated employing Free-response Receiver Operating Characteristic (FROC) methodology. The sensitivity achieved was 74% at a false positive detection rate of 1.83. The corresponding area under the Alternative FROC (AFROC) curve was A1=0.667 +/-0.09.

Circuit resistance training improves the atherogenic lipid profiles of persons with chronic paraplegia.

BACKGROUND: People with chronic paraplegia frequently experience dyslipidemias characterized by depressed levels of high-density lipoprotein cholesterol (HDL-C) and elevated levels of low-density lipoprotein cholesterol (LDL-C). These abnormal lipid profiles and poor fitness levels increase their risk for cardiovascular disease. METHODS: To test the hypothesis that circuit resistance exercise training improves both upper-extremity fitness and the atherogenic lipid profile in persons with chronic paraplegia, a homogeneous cohort of 5 men with neurologically complete spinal cord injuries at T6 to L1 underwent 3 months of exercise training using uninterrupted resistance and endurance exercises of the upper extremities. Training was performed 3 times a week on alternating days. RESULTS: Results of graded arm exercise testing showed a 30.3% improvement in peak oxygen consumption (P < .01), a 33.5% increase in time to fatigue (P < .01) and a 30.4% increase in peak power output (P < .05). Pretraining total cholesterol levels (TC) were in the low-risk category and were nonsignificantly lowered following training. Similar nonsignificant reductions of plasma triglycerides averaging 12 mg/dL were attained. Conversely, a 25.9% lowering of LDL-C (P < .05) and 9.8% elevation of HDL-C (P < .05) were observed after training. These changes reduced the average LDL-C-to-HDL-C ratio by 1 unit (P < .05) and the TC-to-HDL-C ratio from 5.0 +/- 1.1 (mean +/- SD) to 3.9 +/- 0.7 (P < .05). CONCLUSIONS: This change reflects a cardiovascular risk reduction of almost 25%; the TC/HDL-C declined from the high-risk score of 5.0 to near the desired score of 3.5. These findings support the beneficial effects of circuit exercise resistance training on fitness and atherogenic lipid profiles in persons with chronic paraplegia.