BDA-410 Treatment Reduces Body Weight and Fat Content by Enhancing Lipolysis in Sedentary Senescent Mice

Loss of muscle mass and force with age leads to fall risk, mobility impairment, and reduced quality of life. This article shows that BDA-410, a calpain inhibitor, induced loss of body weight and fat but not lean mass or skeletal muscle proteins in a cohort of sedentary 23-month-old mice. Food and water intake and locomotor activity were not modified, whereas BDA-410 treatment decreased intramyocellular lipid and perigonadal fat, increased serum nonesterified fatty acids, and upregulated the genes mediating lipolysis and oxidation, lean phenotype, muscle contraction, muscle transcription regulation, and oxidative stress response. This finding is consistent with our recent report that lipid accumulation in skeletal myofibers is significantly correlated with slower fiber-contraction kinetics and diminished power in obese older adult mice. A proteomic analysis and immunoblot showed downregulation of the phosphatase PPP1R12B, which increases phosphorylated myosin half-life and modulates the calcium sensitivity of the contractile apparatus. This study demonstrates that BDA-410 exerts a beneficial effect on skeletal muscle contractility through new, alternative mechanisms, including enhanced lipolysis, upregulation of "lean phenotype-related genes," downregulation of the PP1R12B phosphatase, and enhanced excitation- contraction coupling. This single compound holds promise for treating age-dependent decline in muscle composition and strength.Fil: Pereyra, Andrea Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata ; Argentina. Wake Forest School of Medicine; Estados UnidosFil: Wang, Zhong-Min. Wake Forest School of Medicine; Estados UnidosFil: Messi, Maria Laura. Wake Forest School of Medicine; Estados UnidosFil: Zhang, Tan. Wake Forest School of Medicine; Estados UnidosFil: Wu, Hanzhi. Wake Forest School of Medicine; Estados UnidosFil: Register, Thomas C.. Wake Forest School of Medicine; Estados UnidosFil: Forbes, Elizabeth. Wake Forest School of Medicine; Estados UnidosFil: Devarie Baez, Nelmi O.. Wake Forest School of Medicine; Estados UnidosFil: Files, Daniel Clark. Wake Forest School of Medicine; Estados UnidosFil: Abba, Martín Carlos. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; ArgentinaFil: Furdui, Cristina. Wake Forest School of Medicine; Estados UnidosFil: Delbono, Osvaldo. Wake Forest School of Medicine; Estados Unido

Estudios sobre anuros de Argentina durante la década 2010-2020: tendencias y vacíos de información

Scientific knowledge may present taxonomic, geographic and thematic biases, which could have negative consequences on conservation decisions, especially in highly threatened groups such as amphibians. This work aimed to explore the scientific production of anurans from Argentina during the 2010-2020 decade, to understand the current state of knowledge and identify possible biases and information gaps. Our results showed that the production of scientific knowledge on anurans from Argentina remained constant during the studied period. Nonetheless, we observed taxonomic, geographic and topic biases. The number of studies was higher in areas with higher human population density and on topics related to morphology, as well as for common species with medium body sizes, general habits, with a broad geographic distribution, and occurring in rural-urban areas. Our results represent a baseline to clarify and evidence the different biases of scientific knowledge about anurans from Argentina.La producción del conocimiento científico puede presentar sesgos taxonómicos, geográficos y temáticos, los que a su vez podrían tener consecuencias negativas al momento de tomar decisiones en conservación, sobre todo en grupos altamente amenazados como son los anfibios. El objetivo de este trabajo fue explorar la producción científica sobre anuros de Argentina durante la década 2010-2020, a fin de establecer el estado actual del conocimiento e identificar posibles sesgos y vacíos de información. Nuestros resultados sugieren que la producción del conocimiento científico en anuros de Argentina se mantuvo constante en el período estudiado. Se observaron sesgos en cuanto a la distribución geográfica de las publicaciones, en las especies más estudiadas y en los temas abordados. El número de estudios fue mayor en provincias con una densidad de su población más alta y en temas relacionados con morfología, así como para especies comunes con tamaños corporales medianos, de hábitos generalistas, con una amplia distribución geográfica, y con ocurrencia en zonas rurales-urbanas. Estos resultados constituyen un punto de partida para esclarecer y evidenciar los diferentes sesgos del conocimiento científico sobre anuros de Argentina.Asociación Herpetológica Argentin

BDA-410 Treatment Reduces Body Weight and Fat Content by Enhancing Lipolysis in Sedentary Senescent Mice

Loss of muscle mass and force with age leads to fall risk, mobility impairment, and reduced quality of life. This article shows that BDA-410, a calpain inhibitor, induced loss of body weight and fat but not lean mass or skeletal muscle proteins in a cohort of sedentary 23-month-old mice. Food and water intake and locomotor activity were not modified, whereas BDA-410 treatment decreased intramyocellular lipid and perigonadal fat, increased serum nonesterified fatty acids, and upregulated the genes mediating lipolysis and oxidation, lean phenotype, muscle contraction, muscle transcription regulation, and oxidative stress response. This finding is consistent with our recent report that lipid accumulation in skeletal myofibers is significantly correlated with slower fiber-contraction kinetics and diminished power in obese older adult mice. A proteomic analysis and immunoblot showed downregulation of the phosphatase PPP1R12B, which increases phosphorylated myosin half-life and modulates the calcium sensitivity of the contractile apparatus. This study demonstrates that BDA-410 exerts a beneficial effect on skeletal muscle contractility through new, alternative mechanisms, including enhanced lipolysis, upregulation of "lean phenotype-related genes," downregulation of the PP1R12B phosphatase, and enhanced excitation- contraction coupling. This single compound holds promise for treating age-dependent decline in muscle composition and strength.Facultad de Ciencias MédicasInstituto de Investigaciones Bioquímicas de La PlataCentro de Investigaciones Inmunológicas Básicas y Aplicada

The sympathetic nervous system regulates skeletal muscle motor innervation and acetylcholine receptor stability

Aim: Symptoms of autonomic failure are frequently the presentation of advanced age and neurodegenerative diseases that impair adaptation to common physiologic stressors. The aim of this work was to examine the interaction between the sympathetic and motor nervous system, the involvement of the sympathetic nervous system (SNS) in neuromuscular junction (NMJ) presynaptic motor function, the stability of postsynaptic molecular organization, and the skeletal muscle composition and function. Methods: Since muscle weakness is a symptom of diseases characterized by autonomic dysfunction, we studied the impact of regional sympathetic ablation on muscle motor innervation by using transcriptome analysis, retrograde tracing of the sympathetic outflow to the skeletal muscle, confocal and electron microscopy, NMJ transmission by electrophysiological methods, protein analysis, and state of the art microsurgical techniques, in C57BL6, MuRF1KO and Thy-1 mice. Results: We found that the SNS regulates motor nerve synaptic vesicle release, skeletal muscle transcriptome, muscle force generated by motor nerve activity, axonal neurofilament phosphorylation, myelin thickness, and myofibre subtype composition and CSA. The SNS also modulates the levels of postsynaptic membrane acetylcholine receptor by regulating the Gα i2 -Hdac4-Myogenin-MuRF1pathway, which is prevented by the overexpression of the guanine nucleotide-binding protein Gα i2 (Q205L), a constitutively active mutant G protein subunit. Conclusion: The SNS regulates NMJ transmission, maintains optimal Gα i2 expression, and prevents any increase in Hdac4, myogenin, MuRF1, and miR-206. SNS ablation leads to upregulation of MuRF1, muscle atrophy, and downregulation of postsynaptic AChR. Our findings are relevant to clinical conditions characterized by progressive decline of sympathetic innervation, such as neurodegenerative diseases and aging.Fil: Rodrigues, Anna C. Zaia. Wake Forest School of Medicine; Estados UnidosFil: Messi, Maria Laura. Wake Forest School of Medicine; Estados UnidosFil: Wang, Zhong Min. Wake Forest School of Medicine; Estados UnidosFil: Abba, Martín Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; ArgentinaFil: Pereyra, Andrea Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Wake Forest School of Medicine; Estados UnidosFil: Birbrair, Alexander. Wake Forest School of Medicine; Estados UnidosFil: Zhang, Tan. Wake Forest School of Medicine; Estados UnidosFil: O´Meara, Meaghan. Wake Forest School of Medicine; Estados UnidosFil: Kwan, Ping. Wake Forest School of Medicine; Estados UnidosFil: Lopez, Elsa I. S.. Wake Forest School of Medicine; Estados UnidosFil: Willis, Monte S.. University of North Carolina; Estados UnidosFil: Mintz, Akiva. Wake Forest School of Medicine; Estados UnidosFil: Files, D. Clark. University of North Carolina; Estados UnidosFil: Furdui, Cristina. Wake Forest School of Medicine; Estados UnidosFil: Oppenheim, Ronald W.. Wake Forest School of Medicine; Estados UnidosFil: Delbono, Osvaldo. Wake Forest School of Medicine; Estados Unido

BDA-410 Treatment Reduces Body Weight and Fat Content by Enhancing Lipolysis in Sedentary Senescent Mice

Loss of muscle mass and force with age leads to fall risk, mobility impairment, and reduced quality of life. This article shows that BDA-410, a calpain inhibitor, induced loss of body weight and fat but not lean mass or skeletal muscle proteins in a cohort of sedentary 23-month-old mice. Food and water intake and locomotor activity were not modified, whereas BDA-410 treatment decreased intramyocellular lipid and perigonadal fat, increased serum nonesterified fatty acids, and upregulated the genes mediating lipolysis and oxidation, lean phenotype, muscle contraction, muscle transcription regulation, and oxidative stress response. This finding is consistent with our recent report that lipid accumulation in skeletal myofibers is significantly correlated with slower fiber-contraction kinetics and diminished power in obese older adult mice. A proteomic analysis and immunoblot showed downregulation of the phosphatase PPP1R12B, which increases phosphorylated myosin half-life and modulates the calcium sensitivity of the contractile apparatus. This study demonstrates that BDA-410 exerts a beneficial effect on skeletal muscle contractility through new, alternative mechanisms, including enhanced lipolysis, upregulation of "lean phenotype-related genes," downregulation of the PP1R12B phosphatase, and enhanced excitation- contraction coupling. This single compound holds promise for treating age-dependent decline in muscle composition and strength.Facultad de Ciencias MédicasInstituto de Investigaciones Bioquímicas de La PlataCentro de Investigaciones Inmunológicas Básicas y Aplicada

Multiwavelength Monitoring of the BL Lacertae Object PKS 2155-304 in May 1994. I. The Ground-Based Campaign

Optical, near-infrared, and radio observations of the BL Lac object PKS2155-304 were obtained simultaneously with a continuous UV/EUV/X-ray monitoring campaign in 1994 May. Further optical observations were gathered throughout most of 1994. The radio, millimeter, and near-infrared data show no strong correlations with the higher energies. The optical light curves exhibit flickering of 0.2-0.3 mag on timescales of 1-2 days, superimposed on longer timescale variations. Rapid variations of ~0.01 mag/min, which, if real, are the fastest seen to date for any BL Lac object. Small (0.2-0.3 mag) increases in the V and R bands occur simultaneously with a flare seen at higher energies. All optical wavebands (UBVRI) track each other well over the period of observation with no detectable delay. For most of the period the average colors remain relatively constant, although there is a tendency for the colors (in particular B-V) to vary more when the source fades. In polarized light, PKS 2155-304 showed strong color dependence and the highest optical polarization (U = 14.3%) ever observed for this source. The polarization variations trace the flares seen in the ultraviolet flux.Comment: 45 pages, latex file with encapsulated postscript, accepted to the Astrophysical Journa

Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection

Deep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained regions of the virus in order to ensure the maintenance of immunodominant CD8 responses and the sustained decline of early viremia

Anandamide Induces Sperm Release from Oviductal Epithelia through Nitric Oxide Pathway in Bovines

Mammalian spermatozoa are not able to fertilize an egg immediately upon ejaculation. They acquire this ability during their transit through the female genital tract in a process known as capacitation. The mammalian oviduct acts as a functional sperm reservoir providing a suitable environment that allows the maintenance of sperm fertilization competence until ovulation occurs. After ovulation, spermatozoa are gradually released from the oviductal reservoir in the caudal isthmus and ascend to the site of fertilization. Capacitating-related changes in sperm plasma membrane seem to be responsible for sperm release from oviductal epithelium. Anandamide is a lipid mediator that participates in the regulation of several female and male reproductive functions. Previously we have demonstrated that anandamide was capable to release spermatozoa from oviductal epithelia by induction of sperm capacitation in bovines. In the present work we studied whether anandamide might exert its effect by activating the nitric oxide (NO) pathway since this molecule has been described as a capacitating agent in spermatozoa from different species. First, we demonstrated that 1 µM NOC-18, a NO donor, and 10 mM L-Arginine, NO synthase substrate, induced the release of spermatozoa from the oviductal epithelia. Then, we observed that the anandamide effect on sperm oviduct interaction was reversed by the addition of 1 µM L-NAME, a NO synthase inhibitor, or 30 µg/ml Hemoglobin, a NO scavenger. We also demonstrated that the induction of bull sperm capacitation by nanomolar concentrations of R(+)-methanandamide or anandamide was inhibited by adding L-NAME or Hemoglobin. To study whether anandamide is able to produce NO, we measured this compound in both sperm and oviductal cells. We observed that anandamide increased the levels of NO in spermatozoa, but not in oviductal cells. These findings suggest that anandamide regulates the sperm release from oviductal epithelia probably by activating the NO pathway during sperm capacitation

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection