Function of mTOR complex 1 and 2 in skeletal muscle

Growth of an organ during development and during adaptation in the adult can be controlled by alterations either in the number or the size of cells. The two mechanisms are fundamentally different and require distinct regulation. Rapamycin is a cell growth inhibitor used to treat a number of clinical indications including graft rejection and cancer. The molecular target of rapamycin is a Ser/Thr kinase, called TOR in yeast or mTOR in mammals. The evolutionarily conserved TOR pathway controls key aspects of cellular growth and metabolism. Among these are protein synthesis, ribosome biogenesis, nutrient transport and processing, autophagy and mitochondrial function. mTOR assembles into two distinct multiprotein complexes, termed mTORC1 and mTORC2. mTORC1 consists of raptor (regulatory associated protein of mTOR), mLST8 (mammalian lethal with SEC13 protein 8) and mTOR, and is sensitive to rapamycin. mTORC2 consists of rictor (rapamycin insensitive companion of mTOR), mSIN1, mLST8 (mammalian stress activated protein kinase interacting protein 1) and mTOR. As mTORC1 controls cell growth, it has also been implicated in the control of muscle mass. A vast array of genetic and pharmacological studies using rodent models supports this view. In contrast to the role of mTOR in growth, its metabolic readouts in skeletal muscle are poorly characterized. Little is also known of the function of rapamycin-insensitive mTORC2 whose primary readouts are thought to be the organization of the actin cytoskeleton. Recently, mTORC2 has also been proposed to be the essential kinase that phosphorylates PKB/AKT on Ser473. To circumvent the early embryonic lethality of mice deficient for raptor (i.e. mTORC1) or rictor (i.e. mTORC2), we generated mice with floxed raptor or rictor alleles. Here we describe the phenotype of mice that lack functional mTORC1, mTORC2, or both complexes, specifically in skeletal muscle. We find that deletion of rictor does not cause an overt muscle phenotype. In contrast, raptor-deficient muscles manifest signs of atrophy and become progressively dystrophic. These muscles also display fundamental metabolic changes which involve impaired mitochondrial function. Furthermore, muscles display properties of fast-twitch, glycolytic skeletal muscle, but exhibit structural features and contraction properties indicative of slow-twitch, oxidative muscle fibers. These changes are either due to impaired activation of direct downstream substrates of mTORC1 or due to loss of negative feedback regulation of upstream components of the signaling pathway. Interestingly, this increased upstream signaling causes sustained hyperactivation of PKB/AKT, which is independent of mTORC2 kinase activity. Taken together, we provide unprecedented evidence for a crucial role of mTORC1 in the regulation of fundamental aspects of metabolism in a specific tissue. Furthermore we show that in the absence of negative feedback regulation from mTORC1 downstream components, mTORC2 is dispensable for PKB/AKT activation

A note on an integration by parts formula for the generators of uniform translations on configuration space

An integration by parts formula is derived for the first order differential operator corresponding to the action of translations on the space of locally finite simple configurations of infinitely many points on Rd. As reference measures, tempered grand canonical Gibbs measures are considered corresponding to a non-constant non-smooth intensity (one-body potential) and translation invariant potentials fulfilling the usual conditions. It is proven that such Gibbs measures fulfill the intuitive integration by parts formula if and only if the action of the translation is not broken for this particular measure. The latter is automatically fulfilled in the high temperature and low intensity regime

WasmRef-Isabelle: A Verified Monadic Interpreter and Industrial Fuzzing Oracle for WebAssembly

We present WasmRef-Isabelle, a monadic interpreter for WebAssembly written in Isabelle/HOL and proven correct with respect to the WasmCert-Isabelle mechanisation of WebAssembly. WasmRef-Isabelle has been adopted and deployed as a fuzzing oracle in the continuous integration infrastructure of Wasmtime, a widely used WebAssembly implementation. Previous efforts to fuzz Wasmtime against WebAssembly's official OCaml reference interpreter were abandoned by Wasmtime's developers after the reference interpreter exhibited unacceptable performance characteristics, which its maintainers decided not to fix in order to preserve the interpreter's close definitional correspondence with the official specification. With WasmRef-Isabelle, we achieve the best of both worlds - an interpreter fast enough to be useable as a fuzzing oracle that also maintains a close correspondence with the specification through a mechanised proof of correctness.We verify the correctness of WasmRef-Isabelle through a two-step refinement proof in Isabelle/HOL. We demonstrate that WasmRef-Isabelle significantly outperforms the official reference interpreter, has performance comparable to a Rust debug build of the industry WebAssembly interpreter Wasmi, and competes with unverified oracles on fuzzing throughput when deployed in Wasmtime's fuzzing infrastructure. We also present several new extensions to WasmCert-Isabelle which enhance WasmRef-Isabelle's utility as a fuzzing oracle: we add support for a number of upcoming WebAssembly features, and fully mechanise the numeric semantics of WebAssembly's integer operations

A unique MRI-pattern in alcohol-associated Wernicke encephalopathy

There have been concerns about high rates of thus far undiagnosed SARS-CoV-2 infections in the health-care system. The COVID-19 Contact (CoCo) Study follows 217 frontline health-care professionals at a university hospital with weekly SARS-CoV-2-specific serology (IgA/IgG). Study participants estimated their personal likelihood of having had a SARS-CoV-2 infection with a mean of 21% [median 15%, interquartile range (IQR) 5-30%]. In contrast, anti-SARS-CoV-2 IgG prevalence was about 1-2% at baseline. Regular anti-SARS-CoV-2 IgG testing of health-care professionals may aid in directing resources for protective measures and care of COVID-19 patients in the long run

Phenolic compounds as marker compounds for botanical origin determination of German propolis samples based on TLC and TLC-MS

Propolis, a complex mixture of different plant exudates collected and processed by honeybees, contains a wide range of bioactive substances. German propolis has so far only rarely been studied with respect to its constituents and botanical origin. To investigate the composition of specific phenolic constituents in bud extracts and German propolis, TLC and TLC-MS methods were developed. Ethanolic extracts from representative propolis samples and tree buds were analyzed by TLC. Compound assignment was achieved through mass spectrometric detection, and TLC using the DPPH assay was used to assess the antioxidant capacity.According to their TLC fingerprints, propolis samples were classified into three types (O/B/G) based on the results of former investigations. Identification of flavonoid aglycones and their methyl esters as well as acetates or butyrates was possible in both bud exudates of black poplar hybrids (Populus × canadensis Moench ‘Robusta’) and O-type propolis with TLC-MS. In aspen (Populus tremula L.) and B-type propolis, phenolic acid glycerols were detected as common constituents. Based on the marker compounds identified in the present study, black poplar hybrids and aspens were identified as major sources of the investigated propolis samples whereas horse chestnut (Aesculus hippocastanum L.) and birch (Betula pendula Roth) were of minor importance. The O-type pro-polis displayed superior antioxidant activity, but also contained higher amounts of potential allergens like caffeic acid derivatives than B-type propolis

Guest Editors' Introduction

‘I shall have to speak of things, of which I cannot speak’, writes Samuel Beckett in The Unnameable, ‘but also, which is even more interesting, but also that I, which is if possible even more interesting, that I shall have to, I forget, no matter’. Listening to the voice of folly can be like this: an endless flow of inconsistencies, of contradictions, sayings and unsayings; a tantalising, mischievous mockery of speech –unable to go on, unable to end. And yet – as this volume shows – we are irresistibly drawn to folly, its promises, its whispers of ‘even more interesting’ things: of how we are split between conscious and unconscious, familiar and unfamiliar, same and other. For psychoanalysis, folly is not only a site of hidden truths; it is also, perhaps more importantly, a source of unconscious freedom, a momentary escape from our obsession with rules and order. According to Christopher Bollas, the unconscious self is like a fool, who ‘raises potentially endless questions about diverse and disparate issues’ and thereby provides us with a ‘separate sense’, which opens us to others and to our own creative potential. As Rachel Bowlby elegantly puts it, folly is a ‘soul-mole’, forever shovelling our secrets out into the light: ‘there’s no possible moment of release or resignation when the mole might stop vainly, interminably working away’. Folly’s subversive, creative soliloquies reveal to us a psychic ‘underground repertoire of secrets’; they challenge our established knowledge and invite us, as Bolwby shows, to endless, titillating games of ‘suppression and confession’. For Anne Duprat, this deep-seated playfulness explains folly’s close relation to fiction: what makes them so atone is their ‘capacity of creating alternative representations of the world — and thus of re-figuring the world depicted by reason or history – […] but also their paradoxical structure, and hence the instability of their speech acts, which deny, suspend, or do not seriously guarantee the truth of their statements’. (First paragraph

Проектирование цеха для производства транспортировочных крышек

Объектом исследования является технология печати и установка для 3Dпечати. Предметом проектирования – транспортировочные крышки. Целью работы является исследование и расчёт физических характеристик напечатанных деталей. В процессе работы проведен аналитический обзор. Также изучены основные виды технологий печати, принципы их работы и создания 3D моделей с помощью 3D принтера.The object of research is printing technology and installation for 3D printing. The subject of design is transportation covers. The aim of the work is to study and calculate the physical characteristics of printed parts. In the process, an analytical review was carried out. The main types of printing technologies, the principles of their work and the creation of 3D models with using a 3D printer

Early divergence, broad distribution, and high diversity of animal chitin synthases

Even though chitin is one of themost abundant biopolymers in nature, current knowledge on chitin formation is largely based only on data from fungi and insects. This study reveals unanticipated broad taxonomic distribution and extensive diversification of chitin synthases (CSs) in Metazoa, shedding newlight on the relevance of chitin in animals and suggesting unforeseen complexity of chitin synthesis in many groups. We uncovered robust orthologs to insect type CSs in several representatives of deuterostomes, which generally are not thought to possess chitin. This suggests a broader distribution and function of chitin in this branch of the animal kingdom. We characterize a new CS type present not only in basal metazoans such as sponges and cnidarians but also in several bilaterian representatives. Themost extensive diversification of CSs took place during emergence of lophotrochozoans, the third large group of protostomes next to arthropods and nematodes, resulting in coexistence of up to ten CS paralogs inmolluscs. Independent fusion to different kinds of myosinmotor domains in fungi and lophotrochozoans points toward high relevance of CS interaction with the cytoskeleton for fine-tuned chitin secretion. Given the fundamental role that chitin plays in themorphology of many animals, the here presented CS diversification revealsmany evolutionary complexities. Our findings strongly suggest a very broad andmultifarious occurrence of chitin and question an ancestral role as cuticular component. The molecular mechanisms underlying regulation of animal chitin synthesis are most likely far more complex and diverse than existing data from insects suggest