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

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

Interplay between moment-dependent and field-driven unidirectional magnetoresistance in CoFeB/InSb/CdTe heterostructures

Magnetoresistance effects are crucial for understanding the charge/spin transport as well as propelling the advancement of spintronic applications. Here we report the coexistence of magnetic moment-dependent (MD) and magnetic field-driven (FD) unidirectional magnetoresistance (UMR) effects in CoFeB/InSb/CdTe heterostructures. The strong spin-orbital coupling of InSb and the matched impedance at the CoFeB/InSb interface warrant a distinct MD-UMR effect at room temperature, while the interaction between the in-plane magnetic field and the Rashba effect at the InSb/CdTe interface induces the marked FD-UMR signal that dominates the high-field region. Moreover, owning to the different spin transport mechanisms, these two types of nonreciprocal charge transport show opposite polarities with respect to the magnetic field direction, which further enable an effective phase modulation of the angular-dependent magnetoresistance. Besides, the demonstrations of both the tunable UMR response and two-terminal spin-orbit torque-driven magnetization switching validate our CoFeB/InSb/CdTe system as a suitable integrated building block for multifunctional spintronic device design

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

ICDP workshop on scientific drilling of Nam Co on the Tibetan Plateau: 1 million years of paleoenvironmental history, geomicrobiology, tectonics and paleomagnetism derived from sediments of a high-altitude lake

The Tibetan Plateau is of peculiar societal relevance as it provides freshwater from the so-called “Water Tower of Asia” to a large portion of the Asian population. However, future climate change will affect the hydrological cycle in this area. To define parameters for future climate change scenarios it is necessary to improve the knowledge about thresholds, timing, pace and intensity of past climatic changes and associated environmental impacts. Sedimentary archives reaching far back in time and spanning several glacial–interglacial cycles such as Nam Co provide the unique possibility to extract such information. In order to explore the scientific opportunities that an ICDP drilling effort at Nam Co would provide, 40 scientists from 13 countries representing various scientific disciplines met in Beijing from 22 to 24 May 2018. Besides paleoclimatic investigations, opportunities for paleomagnetic, deep biosphere, tectonic and paleobiological studies were discussed. After having explored the technical and logistical challenges and the scientific opportunities all participants agreed on the great value and need to drill this extraordinary archive, which has a sediment thickness of more than 1 km, likely covering more than 1 Ma

Carbon Accumulation Associated with Its Influencing Factors in Sediments from the Poyang Basin

Carbon burial in lake sediments has a profound impact on the global carbon cycle. In this study, the burial characteristics of organic carbon (OC) in typical sediments from the Poyang basin over the past hundred years were investigated and the influencing factors and driving mechanism were determined. The results showed that carbon burial in the Poyang basin sediments was mainly driven by human activities, whereas the change in the OC accumulation rate was related to precipitation, forest land area, water area, construction land area, urbanization rate, application of agricultural fertilizers, per capita GDP and population

Experimental and Numerical Investigation on the Interaction between Hydraulic Fractures and Vugs in Fracture-Cavity Carbonate Reservoirs

In karstic-fractured carbonate reservoirs, most of the oil resources are hosted in vugs. Connecting as many vugs as possible by hydraulic fracturing is the key to achieving effective development. However, the interaction mechanism between vugs and hydraulic fractures is complicated and has not been fully revealed. In this study, both experimental and numerical simulations were implemented to investigate the interaction between vugs and hydraulic fractures. Key factors, such as vug size, horizontal stress difference, and the internal pressure of the vug, were considered. The results showed that the vug played an important role in the propagation of hydraulic fractures. Three interaction modes of vugs and hydraulic fractures were observed: crossing, arresting, and bypassing. Owing to the variation of the stress concentration existing around the vug, the hydraulic fracture could be arrested by a small vug but would bypass a vug with a larger size. Whether the hydraulic fracture could communicate with the vug was mainly controlled by the horizontal stress difference. Under large horizontal stress differences (≥20 MPa), the hydraulic fracture could cross and connect multiple vugs. The difference between the horizontal minimum stress and the internal pressure of the vug was also particularly significant for fracture propagation. The smaller the difference, the easier the fracture communicated with the vug. The above findings would be valuable and constructive for the optimal design of field hydraulic fracturing in karstic-fractured carbonate reservoirs