mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue

Activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) has been proposed as an anti-obesity treatment. Moreover, cold-induced glucose uptake could normalize blood glucose levels in insulin-resistant patients. It is therefore important to identify novel regulators of NST and cold-induced glucose uptake. Mammalian target of rapamycin complex 2 (mTORC2) mediates insulin-stimulated glucose uptake in metabolic tissues, but its role in NST is unknown. We show that mTORC2 is activated in brown adipocytes upon β-adrenergic stimulation. Furthermore, mice lacking mTORC2 specifically in adipose tissue (AdRiKO mice) are hypothermic, display increased sensitivity to cold, and show impaired cold-induced glucose uptake and glycolysis. Restoration of glucose uptake in BAT by overexpression of hexokinase II or activated Akt2 was sufficient to increase body temperature and improve cold tolerance in AdRiKO mice. Thus, mTORC2 in BAT mediates temperature homeostasis via regulation of cold-induced glucose uptake. Our findings demonstrate the importance of glucose metabolism in temperature regulation

Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

Ketone bodies (KBs) are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of KB homeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic KB homeostasis, but the regulation of KB metabolism is still enigmatic. In our study in mice with either knockout or overexpression of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α in skeletal muscle, PGC-1α regulated ketolytic gene transcription in muscle. Furthermore, KB homeostasis of these mice was investigated during withholding of food, exercise, and ketogenic diet feeding, and after streptozotocin injection. In response to these ketogenic stimuli, modulation of PGC-1α levels in muscle affected systemic KB homeostasis. Moreover, the data demonstrate that skeletal muscle PGC-1α is necessary for the enhanced ketolytic capacity in response to exercise training and overexpression of PGC-1α in muscle enhances systemic ketolytic capacity and is sufficient to ameliorate diabetic hyperketonemia in mice. In cultured myotubes, the transcription factor estrogen-related receptor-α was a partner of PGC-1α in the regulation of ketolytic gene transcription. These results demonstrate a central role of skeletal muscle PGC-1α in the transcriptional regulation of systemic ketolytic capacity.-Svensson, K., Albert, V., Cardel, B., Salatino, S., Handschin, C. Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

Effective microRNAs for cell line engineering and cellular mechanisms of action

MicroRNAs (miRNAs) constitute an important class of small non-coding RNAs and are imperative for the regulation of gene expression in mammalian cells. By post-transcriptionally modulating the expression of hundreds of different genes concomitantly, miRNAs are capable of regulating entire cellular pathways to control cellular phenotypes. Thus, miRNAs represent promising tools for cell engineering of biopharmaceutical production cells. By taking advantage of a functional high-content miRNA screening procedure we were able to identify \u3e750 miRNAs significantly affecting protein expression, cell growth, apoptosis and necrosis in CHO cells. Functionality of impactful miRNAs could be successfully validated in secondary screening approaches as well as by stable miRNA overexpression. Furthermore, we demonstrate that identified pro-productive miRNAs were able to substantially increase monoclonal antibody yields of two industrial high-producing CHO cell lines expressing different monoclonal antibodies. To better understand the molecular mechanisms behind this improved phenotype, we analyzed selected pro-productive miRNAs and were able to reveal downstream mRNA targets and underlying cellular mechanisms of action. In this conjunction, we identified the ubiquitin pathway to be involved in enhanced protein production induced by the miR-30 family, miR-2861 was discovered as a potential HDAC5 inhibitor enhancing productivity in CHO cells while maintaining product quality and miR-483 was shown to act as species independent universal enhancer of cellular antibody and viral productivity while mimicking mild hypothermia. These significant findings reveal not only the existence of effective miRNAs for the use in cell line engineering but also shed light on underlying mechanisms of action within the cellular environment supporting the hypothesis that miRNAs regulate diverse and essential cellular pathways important for industrial protein production. Engineering production cell lines using miRNAs therefore constitutes a highly attractive and easy-to-use methodology to substantially enhance cellular productivity

Herausforderungen und Chancen eines innovativen Konzeptes zur Bewertung von Tierschutzleistungen

Die Verbesserung der Tiergesundheit ist auch für ökologische Milchviehbetriebe ein bedeutendes Ziel, um sowohl den ökologischen Prinzipien als auch den Erwartungen der Verbraucher gerecht zu werden. Die Verknüpfung von Leistungsdaten mit ökonomischen Daten auf der Ebene von Kuh-Jahren ermöglicht die Identifikation und Priorisierung von Handlungsfeldern für das Tiergesundheitsmanagement. Herausforderungen liegen in der Datenverfügbarkeit

Gender differences in noise concerns about civil drones

Rapid technological developments provide people with an increasing number of opportunities for applying civil drones (e.g., rescue operations). However, one crucial aspect for the future use of drones will be their public acceptance. Importantly, drone acceptance is considered to substantially rely on noise concerns. Recent research demonstrated differences between certain groups of individuals (e.g., females vs. males) in their attitudes towards civil drones. By means of a representative telephone survey in Germany (n = 832), we aimed at further investigating the influence of gender on drone acceptance. Chi-square Automatic Interaction Detection (CHAID) revealed noise concerns to be the most important of all assessed concerns for explaining female respondents’ attitudes towards civil drones, while concerns about damages/injuries best explained male participants’ attitudes. Moreover, our survey corroborates prior studies by showing males to be less concerned about civil drones than females (e.g., regarding noise). Additionally, we explored whether these effects could have been driven by confounding variables (e.g., drone experience). Thus, the present study highlights aspects of gender differences in concerns about drones which need to be examined further in future research

Integrated microfluidic biosensing platform for simultaneous confocal microscopy and electrophysiological measurements on bilayer lipid membranes and ion channels

Combining high-resolution imaging and electrophysiological recordings is key for various types of experimentation on lipid bilayers and ion channels. Here, we propose an integrated biosensing platform consisting of a microfluidic cartridge and a dedicated chip-holder to conduct such dual measurements on suspended lipid bilayers, in a user-friendly manner. To illustrate the potential of the integrated platform, we characterize lipid bilayers in terms of thickness and fluidity while simultaneously monitoring single ion channel currents. For that purpose, POPC lipid bilayers are supplemented with a fluorescently-tagged phospholipid (NBD-PE, 1% mol) for Fluorescence Recovery After Photobleaching (FRAP) measurements and a model ion channel (gramicidin, 1 nM). These combined measurements reveal that NBD-PE has no effect on the lipid bilayer thickness while gramicidin induces thinning of the membrane. Furthermore, the presence of gramicidin does not alter the lipid bilayer fluidity. Surprisingly, in lipid bilayers supplemented with both probes, a reduction in gramicidin open probability and lifetime is observed compared to lipid bilayers with gramicidin only, suggesting an influence of NBD-PE on the gramicidin ion function. Altogether, our proposed microfluidic biosensing platform in combination with the herein presented multi-parametric measurement scheme paves the way to explore the interdependent relationship between lipid bilayer properties and ion channel function

High-coverage genome of the Tyrolean Iceman reveals unusually high Anatolian farmer ancestry

The Tyrolean Iceman is known as one of the oldest human glacier mummies, directly dated to 3350-3120 calibrated BCE. A previously published low-coverage genome provided novel insights into European prehistory, despite high present-day DNA contamination. Here, we generate a high-coverage genome with low contamination (15.3×) to gain further insights into the genetic history and phenotype of this individual. Contrary to previous studies, we found no detectable Steppe-related ancestry in the Iceman. Instead, he retained the highest Anatolian-farmer-related ancestry among contemporaneous European populations, indicating a rather isolated Alpine population with limited gene flow from hunter-gatherer-ancestry-related populations. Phenotypic analysis revealed that the Iceman likely had darker skin than present-day Europeans and carried risk alleles associated with male-pattern baldness, type 2 diabetes, and obesity-related metabolic syndrome. These results corroborate phenotypic observations of the preserved mummified body, such as high pigmentation of his skin and the absence of hair on his head