Elastase-2, a tissue alternative pathway for angiotensin II generation, plays a role in circulatory sympathovagal balance in mice

In vitro and ex vivo experiments indicate that elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, is an alternative pathway for angiotensin II (Ang II) generation. However, the role played by ELA-2 in vivo is unclear. We examined ELA-2 knockout (ELA-2KO) mice compared to wild-type (WT) mice and determined whether ELA-2 played a role in hemodynamics [arterial pressure (AP) and heart rate (HR)], cardiocirculatory sympathovagal balance and baroreflex sensitivity. The variability of systolic arterial pressure (SAP) and pulse interval (PI) for evaluating autonomic modulation was examined for time and frequency domains (spectral analysis), whereas a symbolic analysis was also used to evaluate PI variability. In addition, baroreflex sensitivity was examined using the sequence method. Cardiac function was evaluated echocardiographically under anesthesia. The AP was normal whereas the HR was reduced in ELA-2KO mice (425 ± 17 vs. 512 ± 13 bpm from WT). SAP variability and baroreflex sensitivity were similar in both strains. The LF power from the PI spectrum (33.6 ± 5 vs. 51.8 ± 4.8 nu from WT) and the LF/HF ratio (0.60 ± 0.1 vs. 1.45 ± 0.3 from WT) were reduced, whereas the HF power was increased (66.4 ± 5 vs. 48.2 ± 4.8 nu from WT) in ELA-2KO mice, indicating a shift toward parasympathetic modulation of HR. Echocardiographic examination showed normal fractional shortening and an ejection fraction in ELA-2KO mice; however, the cardiac output, stroke volume, and ventricular size were reduced. These findings provide the first evidence that ELA-2 acts on the sympathovagal balance of the heart, as expressed by the reduced sympathetic modulation of HR in ELA-2KO mice

Acoustic Detection Of The Magnetocaloric Effect: Application To Gd And Gd5.09 Ge2.03 Si1.88

In this paper we present a simple method for the determination of the total magnetocaloric effect based on the acoustic detection of the adiabatic temperature rise caused by the application of an ac magnetic field of small amplitude. The continuous scanning of a superimposed dc magnetic field allows, by numerical integration, the determination of large temperature variations caused by magnetic field steps from zero to tens of kOe. Absolute values of temperature rise are easily acquired after the calibration of the microphone signal using an appropriate reference sample. Once the calibration is done, no further information about the sample's thermal properties is necessary since the measured signal is directly proportional to the temperature variation. Measurements were made in Gd and Gd5.09 Ge2.03 Si1.88 samples in the temperature range from 240 to 320 K. The technique shows to be suitable for the investigation of materials undergoing both purely magnetic phase transitions, as in the case of Gd, and magnetic-crystallographic first-order ones, as observed for Gd5.09 Ge2.03 Si1.88. Besides the ability to determine the temperature variation due to a large magnetic field step through the continuous scanning of the magnetic field, the technique is also very suitable for measuring the magnetocaloric effect under very small magnetic field steps since it has sensitivity below millikelvin. Moreover, it is able to detect temperature variations in very small amount of sample, leading to its potential application in magnetocaloric thin films. © 2009 The American Physical Society.8013Foldeaki, M., Schnelle, W., Gmelin, E., Benard, P., Koszegi, B., Giguere, A., Chahine, R., Bose, T.K., (1997) J. Appl. Phys., 82, p. 309. , 10.1063/1.365813Pecharsky, V.K., Gschneidner, Jr.K.A., (1999) J. Appl. Phys., 86, p. 565. , 10.1063/1.370767Gopal, B.R., Chahine, R., Bose, T.K., (1997) Rev. Sci. Instrum., 68, p. 1818. , 10.1063/1.1147999Pecharsky, V.K., Gschneidner, Jr.K.A., (1999) J. Magn. Magn. Mater., 200, p. 44. , 10.1016/S0304-8853(99)00397-2Pecharsky, V.K., Gschneidner, Jr.K.A., (1997) Phys. Rev. Lett., 78, p. 4494. , 10.1103/PhysRevLett.78.4494Otowski, W., Glorieux, C., Hofman, R., Thoen, J., (1993) Thermochim. Acta, 218, p. 123. , 10.1016/0040-6031(93)80416-8Gopal, B.R., Chahine, R., Földeàki, M., Bose, T.K., (1995) Rev. Sci. Instrum., 66, p. 232. , 10.1063/1.1145264Rosencwaig, A., Gersho, A., (1976) J. Appl. Phys., 47, p. 64. , 10.1063/1.322296Pecharsky, V.K., Gschneidner, Jr.K.A., (2001) Adv. Mater., 13, p. 683. , 10.1002/1521-4095(200105)13:93.0.CO;2-OVon Ranke, P.J., De Oliveira, N.A., Gama, S., (2004) J. Magn. Magn. Mater., 277, p. 78. , 10.1016/j.jmmm.2003.10.013Carvalho, A.M.G., Alves, C.S., Campos, A., Coelho, A.A., Gama, S., Gandra, F.C.G., Von Ranke, P.J., Oliveira, N.A., (2005) J. Appl. Phys., 97, pp. 10M320. , 10.1063/1.1860932Pecharsky, A.O., Gschneidner, Jr.K.A., Pecharsky, V.K., (2003) J. Magn. Magn. Mater., 267, p. 60. , 10.1016/S0304-8853(03)00305-6Gama, S., Alves, C.S., Coelho, A.A., Ribeiro, C.A., Persiano, A.I.C., Silva, D., (2004) J. Magn. Magn. Mater., 272-276, p. 848. , 10.1016/j.jmmm.2003.12.1260Pires, M.J.M., Carvalho, A.M.G., Gama, S., Da Silva, E.C., Coelho, A.A., Mansanares, A.M., (2005) Phys. Rev. B, 72, p. 224435. , 10.1103/PhysRevB.72.224435Glorieux, C., Thoen, J., Bednarz, G., White, M.A., Geldart, D.J.W., (1995) Phys. Rev. B, 52, p. 12770. , 10.1103/PhysRevB.52.12770Bednarz, G., Geldart, D.J.W., White, M.A., (1993) Phys. Rev. B, 47, p. 14247. , 10.1103/PhysRevB.47.14247Yu. Dan'Kov, S., Tishin, A.M., Pecharsky, V.K., Gschneidner, Jr.K.A., (1998) Phys. Rev. B, 57, p. 3478. , 10.1103/PhysRevB.57.3478Glorieux, C., Caerels, J., Thoen, J., (1996) J. Appl. Phys., 80, p. 3412. , 10.1063/1.363208Pecharsky, V.K., Gschneidner, Jr.K.A., (1999) J. Appl. Phys., 86, p. 6315. , 10.1063/1.371734Giguere, A., Foldeaki, M., Ravi Gopal, B., Chahine, R., Bose, T.K., Frydman, A., Barclay, J.A., (1999) Phys. Rev. Lett., 83, p. 2262. , 10.1103/PhysRevLett.83.2262Yue, M., Zhang, J., Zeng, H., Chen, H., Liu, X.B., (2006) J. Appl. Phys., 99, pp. 08Q104. , 10.1063/1.2158971Tocado, L., Palacios, E., Burriel, R., (2006) J. Therm Anal. Calorim., 84, p. 213. , 10.1007/s10973-005-7180-zGschneidner, Jr.K.A., Pecharsky, V.K., Brück, E., Duijn, H.G.M., Levin, E.M., (2000) Phys. Rev. Lett., 85, p. 4190. , 10.1103/PhysRevLett.85.419

Thimet oligopeptidase (EC 3.4.24.15) key functions suggested by knockout mice phenotype characterization

Thimet oligopeptidase (THOP1) is thought to be involved in neuropeptide metabolism, antigen presentation, neurodegeneration, and cancer. Herein, the generation of THOP1 C57BL/6 knockout mice (THOP1(-/-)) is described showing that they are viable, have estrus cycle, fertility, and a number of puppies per litter similar to C57BL/6 wild type mice (WT). In specific brain regions, THOP1(-/-) exhibit altered mRNA expression of proteasome beta5, serotonin 5HT2a receptor and dopamine D2 receptor, but not of neurolysin (NLN). Peptidomic analysis identifies differences in intracellular peptide ratios between THOP1(-/-) and WT mice, which may affect normal cellular functioning. In an experimental model of multiple sclerosis THOP1(-/-) mice present worse clinical behavior scores compared to WT mice, corroborating its possible involvement in neurodegenerative diseases. THOP1(-/-) mice also exhibit better survival and improved behavior in a sepsis model, but also a greater peripheral pain sensitivity measured in the hot plate test after bradykinin administration in the paw. THOP1(-/-) mice show depressive-like behavior, as well as attention and memory retention deficits. Altogether, these results reveal a role of THOP1 on specific behaviors, immune-stimulated neurodegeneration, and infection-induced inflammation

KCNV2-associated retinopathy: detailed retinal phenotype and structural endpoints-KCNV2 study group report 2

PURPOSE: To describe the detailed retinal phenotype of KCNV2-associated retinopathy.STUDY DESIGN: Multicenter international retrospective case series.METHODS: Review of retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), including qualitative and quantitative analyses.RESULTS: Three distinct macular FAF features were identified: (1) centrally increased signal (n = 35, 41.7%), (2) decreased autofluorescence (n = 27, 31.1%), and (3) ring of increased signal (n = 37, 44.0%). Five distinct FAF groups were identified based on combinations of those features, with 23.5% of patients changing the FAF group over a mean (range) follow-up of 5.9 years (1.9-13.1 years). Qualitative assessment was performed by grading OCT into 5 grades: (1) continuous ellipsoid zone (EZ) (20.5%); (2) EZ disruption (26.1%); (3) EZ absence, without optical gap and with preserved retinal pigment epithelium complex (21.6%); (4) loss of EZ and a hyporeflective zone at the foveola (6.8%); and (5) outer retina and retinal pigment epithelium complex loss (25.0%). Eighty-six patients had scans available from both eyes, with 83 (96.5%) having the same grade in both eyes, and 36.1% changed OCT grade over a mean follow-up of 5.5 years. The annual rate of outer nuclear layer thickness change was similar for right and left eyes.CONCLUSIONS: KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. The identification of a single OCT or FAF measurement as an endpoint to determine progression that applies to all patients may be challenging, although outer nuclear layer thickness is a potential biomarker. Findings suggest a potential window for intervention until 40 years of age. (C) 2021 The Authors. Published by Elsevier Inc.Ophthalmic researc

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950–2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2•72 (95% uncertainty interval [UI] 2•66–2•79) in 2000 to 2•31 (2•17–2•46) in 2019. Global annual livebirths increased from 134•5 million (131•5–137•8) in 2000 to a peak of 139•6 million (133•0–146•9) in 2016. Global livebirths then declined to 135•3 million (127•2–144•1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2•1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27•1% (95% UI 26•4–27•8) of global livebirths. Global life expectancy at birth increased from 67•2 years (95% UI 66•8–67•6) in 2000 to 73•5 years (72•8–74•3) in 2019. The total number of deaths increased from 50•7 million (49•5–51•9) in 2000 to 56•5 million (53•7–59•2) in 2019. Under-5 deaths declined from 9•6 million (9•1–10•3) in 2000 to 5•0 million (4•3–6•0) in 2019. Global population increased by 25•7%, from 6•2 billion (6•0–6•3) in 2000 to 7•7 billion (7•5–8•0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58•6 years (56•1–60•8) in 2000 to 63•5 years (60•8–66•1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation: Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global burden of 87 risk factors in 204 countries and territories, 1990�2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. Methods: GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk�outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk�outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk�outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. Findings: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95 uncertainty interval UI 9·51�12·1) deaths (19·2% 16·9�21·3 of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12�9·31) deaths (15·4% 14·6�16·2 of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253�350) DALYs (11·6% 10·3�13·1 of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0�9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10�24 years, alcohol use for those aged 25�49 years, and high systolic blood pressure for those aged 50�74 years and 75 years and older. Interpretation: Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980�2015: the Global Burden of Disease Study 2015

Background Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015. Methods For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification. Findings Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95 uncertainty interval UI 3·1�3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5�2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6�40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7�1·9 million) in 2005, to 1·2 million deaths (1·1�1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections. Interpretation Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030. Funding Bill & Melinda Gates Foundation, and National Institute of Mental Health and National Institute on Aging, National Institutes of Health. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Assessment Of The Thermal Expansion Mismatch In Lanthanum Strontium Cobalt Ferrite-yttria Stabilized Zirconia Two-layers Systems Using Photoacoustic Methodology

In this letter we investigate the thermo-elastic mismatch in lanthanum strontium cobalt ferrite (La0.6Sr0.4Co 0.2Fe0.8O3-δ) (LSCF) films deposited onto yttria stabilized zirconia (YSZ) substrates, applicable to solid oxide fuel cells. We investigated composite LSCFYSZ and pure LSCF films deposited onto commercial YSZ substrate. Photoacoustics was used to obtain the effective thermal diffusivity and thermal expansion coefficient of the two-layers samples. Based on a thermal-electrical analogy model, it was possible to get the thermo-elastic properties of the films and to confirm the desired reduction on the thermo-elastic mismatch between film and substrate when comparing composite LSCFYSZ and pure LSCF films. © 2013 American Institute of Physics.10213Zivkovic, L., Lair, V., Lupan, O., Ringuedé, A., (2011) Thin Solid Films, 519, pp. 3538-3543. , 10.1016/j.tsf.2011.01.245Ramesh, S., Raju, K.C.J., (2012) Int. J. 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