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The control of muscle cell size is a physiological process balanced by a fine tuning between protein synthesis and protein degradation. MAFbx/Atrogin-1 is a muscle specific E3 ubiquitin ligase upregulated during disuse, immobilization and fasting or systemic diseases such as diabetes, cancer, AIDS and renal failure. This response is necessary to induce a rapid and functional atrophy. To date, the targets of MAFbx/Atrogin-1 in skeletal muscle remain to be identified. We have recently presented evidence that eIF3-f, a regulatory subunit of the eukaryotic translation factor eIF3 is a key target that accounts for MAFbx/Atrogin-1 function in muscle atrophy. More importantly, we showed that eIF3-f acts as a "translational enhancer" that increases the efficiency of the structural muscle proteins synthesis leading to both in vitro and in vivo muscle hypertrophy. We propose that eIF3-f subunit, a mTOR/S6K1 scaffolding protein in the IGF-1/Akt/mTOR dependent control of protein translation, is a positive actor essential to the translation of specific mRNAs probably implicated in muscle hypertrophy. The central role of eIF3-f in both the atrophic and hypertrophic pathways will be discussed in the light of its promising potential in muscle wasting therapy.

During laparoscopic partial colectomy the specimen can be extracted transrectally. This technique decreases the invasiveness of the surgery, because the abdominal wall incision is avoided. Premises of a new surgical technique are precise technical description as well as a favourable balance of advantages and disadvantages. In this paper the authors review the technique they apply and analyse their first results.45 laparoscopic bowel resections were performed by a multidisciplinary team between 16th April 2014 and 1st November 2015. Indication of surgery was endometriosis, and the specimen was extracted transrectally in 11 patients. Having ligated both bowel ends proximal and distal to the section infiltrated with endometriosis, and the proximal bowel secured with a laparoscopic bulldog. Then the bowel was resected and the specimen was extracted in a camera bag transrectally. A purse-string suture was placed into the proximal bowel end, and the anvil of the circular stapler--which was introduced transrectally--was inserted into the bowel. After closing the rectal stump, the anastomosis was performed with a circular stapler. We used this technique when the upper third of the rectum or sigmoid colon was infiltrated with endometriosis.The difference between the operation time of the two techniques (transabdominal vs. transrectal specimen extraction: 108 min vs. 118 min) was not significant. There was not difference in the WBC count between the first and second postoperative day, and there was not any anastomosis leakage detected either.By using the above technique, postoperative infections could have been reduced to minimum. Transrectal specimen extraction did not increase postoperative complication The authors believe this is a safe way of specimen extraction after partial colectomy.

It is well known that the large caliber vessels, the nutrition of the wall differs in the internal part in comparison to the external one. In the present study we assessed the presence and distribution of vascularisation of aortic media in 3 species: lamb, rabbit and chinchilla. Samples were harvested from a group of 3 animals for each species. After histological processing, we stained the sections and assessed the presence and distribution of vasa vasorum. In lamb, blood vessels were present in the media of the first aortic segments (with a larger caliber), and starting with abdominal descending aorta they were absent. In rabbit and chinchilla, blood vessels were not present in tunica media. The present study shows that vasa vasorum are present only in tunica media of arteries exceeding a certain caliber.

Tunica adventitia of large caliber vessels in lambs presents a highly different thickness from one segment to another, depending on its position in relation to the heart and the irrigated area. In the case of all the studied arteries, adventitia is formed out of collagen and elastic fibers. In some arteries, adventitia contains a small quantity of elastic fibers (ascending aorta, aortic arch, thoracic descending aorta, bicarotid trunk, left subclavian artery). Other arteries contain elastic fibers in a markedly larger quantity, without exceeding a certain limit (abdominal descending aorta, left and right internal iliac arteries, brachiocephalic trunk, right subclavian artery). There are also vessels in which the elastic component from tunica adventitia is formed out of thick and numerous fibers, so that the elastic component in adventitia markedly exceeds the one from tunica media (left and right external iliac arteries, left and right carotid arteries). The large quantity of elastic tissue in tunica adventitia of these vessels seems to be an adaptation to the external solicitations that exert upon them, in direct relation to the irrigated anatomical area.

The stratigraphic dissection of the thorax and ventral cervical region was made on 5 rabbit cadavers. We firstly exposed the heart, and then the aortic arch. The aortic arch has a very curved trajectory and two collaterals (brachiocephalic trunk and left subclavian artery). The brachiocephalic trunk bifurcates in two collaterals (left and right common carotid arteries) and it ends with the right common carotid artery. The bicarotid trunk is absent in leporidae. In subjects taken into study, the diameter of the right subclavian artery (collateral of the brachiocephalic trunk) is larger than the one in the right common carotid artery (terminal of the brachiocephalic trunk).

Some pedological and micromorphological investigations were carried out on representative red clay samples selected from a large number of profiles. On the basis of conclusions drawn from the analytical results, the red clays can be divided into the following groups: - The red clays of the foothills of the Tokaj Mountains were formed on rhyolite or rhyolite tuff, and are covered by loess in some areas. They are relic soils, older than loess, formed under the warm climate of the Tertiary Period. In addition to quartz they contain feldspars, illite, montmorillonite and a small amount of kaolinite. - The red clays of Aggtelek Karst are Tertiary relic soils formed on Mesozoic limestone. The dominant clay mineral is kaolinite, but they contain a siginificant amount of smectite as well. - The red clays of the Northern periphery of the Hungarian Plain are situated on clay, silt and sand layers of different origin or between loess depositions. They were formed in the Pliocene and at the turn of the Pliocene and Pleistocene. These soils have a medium clay content, with a large quantity of montmorillonite and a small amount of kaolinite. - Red clays formed on Permian sandstones . These rocks were formed in the Permian period, and were issued from a mixture of sediments under tropical climate, tropical weathering. They are the signs of the oldest soil formation in Hungary. They can be characterized by their kaolinite, illite, montmorillonite and hematite contents. - The red clays of the Transdanubian hilly region wereformed by the weathering of thePannonian surface between the end of the Miocene Period and the lower Pleistocene. Medium clay content is characteristic of these red clays. They contain kaolinite, montmorillonite, chlorite and a small amount of hematite. Concerning micromorphological features, speckled and granostriated b-fabrics of the groundmass, mainly due to swelling and shrinking, were observed in some samples. Clay coatings are mainly interpreted as micromorphological features of illuviation. The investigated red clays are similar to tropical and sub-tropical ferrallitic soils in respect of their formation and mineral characteristics.

Genomic characterization of hematologic and solid cancers has revealed recurrent somatic mutations affecting genes encoding the RNA splicing factors SF3B1, U2AF1, SRSF2 and ZRSR2. Recent data reveal that these mutations confer an alteration of function inducing aberrant splicing and rendering spliceosome mutant cells preferentially sensitive to splicing modulation compared with wildtype (WT) cells. Here we describe a novel orally bioavailable small molecule SF3B1 modulator identified through a medicinal chemistry effort aimed at optimizing compounds for preferential lethality in spliceosome mutant cells. H3B-8800 potently binds to WT or mutant SF3b complexes and modulates splicing in in vitro biochemical splicing assays and cellular pharmacodynamic assays. The selectivity of H3B-8800 was confirmed by observing lack of activity in cells expressing SF3B1R1074H, the SF3B1 mutation previously shown to confer resistance to other splicing modulators. Although H3B-8800 binds both WT and mutant SF3B1, it results in preferential lethality of cancer cells expressing SF3B1K700E, SRSF2P95H, or U2AF1S34F mutations compared to WT cells. In animals xenografted with SF3B1K700E knock-in leukemia K562 cells or mice transplanted with Srsf2P95H/MLL-AF9 mouse AML cells, oral H3B-8800 treatment demonstrated splicing modulation and inhibited tumor growth, while no therapeutic impact was seen in WT controls. These data were also evident in patient-derived xenografts (PDX) from patients with CMML where H3B-8800 resulted in a substantial reduction of leukemic burden only in SRSF2-mutant but not in WT CMML PDX models. Additionally, due to the high frequency of U2AF1 mutations in non-small cell lung cancer, H3B-8800 was tested in U2AF1S34F-mutant H441 lung cancer cells. Similar to the results from leukemia models, H3B-8800 demonstrated preferential lethality of U2AF1-mutant cells in vitro and in in vivo orthotopic xenografts at well tolerated doses. RNA-seq of isogenic K562 cells treated with H3B-8800 revealed dose-dependent inhibition of splicing. Although global inhibition of RNA splicing was not observed; H3B-8800 treatment led to preferential intron retention of transcripts with shorter and more GC-rich regions compared to those unaffected by drug. Interestingly, H3B-8800-retained introns commonly disrupted the expression of spliceosomal genes, suggesting that the preferential effect of H3B-8800 on spliceosome mutant cells is due to the dependency of these cells on expression of WT spliceosomal genes. These data identify a novel therapeutic approach with selective lethality in leukemias and lung cancers bearing a spliceosome mutation. Despite the essential nature of splicing, cancer cells without a spliceosome mutation were less sensitive to H3B-8800 compared with potent eradication of mutant counterparts. H3B-8800 is currently undergoing clinical evaluation in patients with MDS, AML, and CMML. Citation Format: Silvia Buonamici, Akihide Yoshimi, Michael Thomas, Michael Seiler, Betty Chan, Benjamin Caleb, Fred Csibi, Rachel Darman, Peter Fekkes, Craig Karr, Gregg Keaney, Amy Kim, Virginia Klimek, Pavan Kumar, Kaiko Kunii, Stanley Chun-Wei Lee, Xiang Liu, Crystal MacKenzie, Carol Meeske, Yoshiharu Mizui, Eric Padron, Eunice Park, Ermira Pazolli, Sudeep Prajapati, Nathalie Rioux, Justin Taylor, John Wang, Markus Warmuth, Huilan Yao, Lihua Yu, Ping Zhu, Omar Abdel-Wahab, Peter Smith. H3B-8800, a novel orally available SF3b modulator, shows preclinical efficacy across spliceosome mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1185. doi:10.1158/1538-7445.AM2017-1185

Large arteries from 2 rabbits were processed in order to make histological investigations, using two staining techniques: Goldner’s Trichrome and Verhoeff. We noticed that the proportion of the three arterial tunicae modifies as they get farther away from the heart. The changes appear in tunica media, which gradually decreases, and tunica adventitia, which gradually increases. Structurally, we observed that the first arterial segments are typical elastic arteries (pulmonary trunk, ascending aorts, aortic arch and thoracic descending aorta), the next are transitional arteries (abdominal descending aorta, subclavian arteries, carotids), and the iliac arteries are typical muscular arteries.

Polycystic ovary syndrome (PCOS) causes vascular damage to arteries; however, there are no data for its effect on veins. Our aim was to clarify the effects of dihydrotestosterone (DHT)-induced PCOS both on venous biomechanics and on pharmacological reactivity in a rat model and to test the possible modulatory role of vitamin D3(vitD). PCOS was induced in female Wistar rats by DHT treatment (83 μg/day, subcutaneous pellet). After 10 wk, the venous biomechanics, norepinephrine (NE)-induced contractility, and acetylcholine-induced relaxation were tested in saphenous veins from control animals and from animals treated with DHT or DHT with vitD using pressure angiography. Additionally, the expression levels of endothelial nitric oxide synthase (eNOS) and cyclooxygenase (COX-2) were measured using immunohistochemistry. Increased diameter, wall thickness, and distensibility as well as decreased vasoconstriction were detected after the DHT treatment. Concomitant vitD treatment lowered the mechanical load on the veins, reduced distensibility, and resulted in vessels that were more relaxed. Although there was no difference in the endothelial dilation tested using acetylcholine (ACh), the blocking effect of NG-nitro-l-arginine methyl ester (l-NAME) was lower and was accompanied by lower COX-2 expression in the endothelium after the DHT treatment. Supplementation with vitD prevented these alterations. eNOS expression did not differ among the three groups. We conclude that the hyperandrogenic state resulted in thicker vein walls. These veins showed early remodeling and altered vasorelaxant mechanisms similar to those of varicose veins. Alterations caused by the chronic DHT treatment were prevented partially by concomitant vitD administration.

Decoding error probability bounds are derived for slow frequency hopping schemes. For unslotted asynchronous multiple access random protocol sequences with interleaved codes are considered. Nonrandom constructions of protocol sequences with good cyclic correlation properties are given. For slotted access the maximum and average Hamming correlation properties of these protocol sequences imply error bounds.

Growth-promoting signaling molecules, including the mammalian target of rapamycin complex 1 (mTORC1), drive the metabolic reprogramming of cancer cells required to support their biosynthetic needs for rapid growth and proliferation [1]. Glutamine is catabolyzed to α-ketoglutarate (αKG), a tricarboxylic acid (TCA) cycle intermediate, through two deamination reactions, the first requiring glutaminase (GLS) to generate glutamate and the second occurring via glutamate dehydrogenase (GDH) or transaminases [2]. Activation of the mTORC1 pathway has been shown previously to promote the anaplerotic entry of glutamine to the TCA cycle via GDH. Moreover, mTORC1 activation also stimulates the uptake of glutamine, but the mechanism is unknown [3]. It is generally thought that rates of glutamine utilization are limited by mitochondrial uptake via GLS, suggesting that, in addition to GDH, mTORC1 could regulate GLS. Here we demonstrate that mTORC1 positively regulates GLS and glutamine flux through this enzyme. We show that mTORC1 controls GLS levels through the S6K1-dependent regulation of c-Myc (Myc). Molecularly, S6K1 enhances Myc translation efficiency by modulating the phosphorylation of eukaryotic initiation factor eIF4B, which is critical to unwind its structured 5' untranslated region (5'UTR). Finally, our data show that the pharmacological inhibition of GLS is a promising target in pancreatic cancers expressing low levels of PTEN. ispartof: Current biology : CB vol:24 issue:19 pages:2274-80 ispartof: location:England status: published

Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach. ispartof: Cell vol:153 issue:4 pages:840-54 ispartof: location:United States status: published

SummaryDNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here, we find that DNA damage triggers a critical block in glutamine metabolism, which is required for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression.

Metformin inhibits cancer cell proliferation, and epidemiology studies suggest an association with increased survival in patients with cancer taking metformin; however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation, whereas increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer., German Science Foundation (Grant FE1185), National Institutes of Health (U.S.), Glenn Foundation for Medical Research, National Institutes of Health (U.S.) (Grant 5-P50-090381-09), National Institutes of Health (U.S.) (Grant 5-P30-CA14051-39), Burroughs Wellcome Fund, Smith Family Foundation, Damon Runyon Cancer Research Foundation, National Institutes of Health (U.S.) (Grant 1R01DK075850-01), National Institutes of Health (U.S.) (Grant 1R01CA160458-01A1)

The eukaryotic initiation factor 3 subunit f (eIF3f) is one of the 13 subunits of the translation initiation factor complex eIF3 required for several steps in the initiation of mRNA translation. In skeletal muscle, recent studies have demonstrated that eIF3f plays a central role in skeletal muscle size maintenance. Accordingly, eIF3f overexpression results in hypertrophy through modulation of protein synthesis via the mTORC1 pathway. Importantly, eIF3f Was described as a target of the E3 ubiquitin ligase MAFbx/atrogin-1 for proteasome-mediated breakdown under atrophic conditions. The biological importance of the MAFbx/atrogin-1-dependent targeting of eFI3f is highlighted by the finding that expression of ad eIF3f mutant insensitive to MAFbx/atrogin-1 polyubiquitination is associated with enhanced protection against starvation-induced muscle atrophy. A better understanding of the precise role of this subunit should lead to the development of new therapeutic approaches to prevent or limit muscle wasting that prevails in numerous physiological and pathological states such as immobilization, aging, denervated conditions, neuromuscular diseases, AIDS, cancer, diabetes. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. (C) 2013 Elsevier Ltd. All rights reserved.

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Aims In polycystic ovary syndrome (PCOS), metabolic and cardiovascular dysfunction is related to hyperandrogenic status and insulin resistance, however, Vitamin D3 has a beneficial effect partly due to its anti-oxidant capacity. Nitrative stress is a major factor in the development of cardiovascular dysfunction and insulin resistance in various diseases. Our aim was to determine the effects of vitamin D3 in a rat model of PCOS, particularly the pathogenic role of nitrative stress. Main methods Female Wistar rats weighing 100–140 g were administered vehicle (C), dihydrotestosterone (DHT) or dihydrotestosterone plus vitamin D3 (DHT + D) (n = 10 per group). On the 10th week, acetylcholine (Ach) induced relaxation ability of the isolated thoracic aorta rings was determined. In order to examine the possible role of endothelial nitric oxide synthase (eNOS) and cyclooxygenase-2 (COX-2) pathways in the impaired endothelial function, immunohistochemical labeling of aortas with anti-eNOS and anti-COX-2 antibodies was performed. Leukocyte smears, aorta and ovary tissue sections were also immunostained with anti-nitrotyrosine antibody to determine nitrative stress. Key findings Relaxation ability of aorta was reduced in group DHT, and vitamin D3 partly restored Ach induced relaxation. eNOS labeling was significantly lower in DHT rats compared to the other two groups, however COX-2 staining showed an increment. Nitrative stress showed a significant increase in response to dihydrotestosterone, while vitamin D3 treatment, in case of the ovaries, was able to reverse this effect. Significance Nitrative stress may play a role in the pathogenesis of PCOS and in the development of the therapeutic effect of vitamin D3.

Correspondence to: Anthony MJ Sanchez, e-mail: anthony.mj.sanchez@hotmail.fr; International audience; In skeletal muscle, protein levels are determined by relative rates of protein synthesis and breakdown. The balance between synthesis and degradation of intracellular components determines the overall muscle fiber size. AMP-activated protein kinase (AMPK), a sensor of cellular energy status, was recently shown to increase myofibrillar protein degradation through the expression of MAFbx and MuRF1. In the present study, the effect of AMPK activation by AICAR on autophagy was investigated in muscle cells. Our results show that FoxO3a transcription factor activation by AMPK induces the expression of the autophagy-related proteins LC3B-II, Gabarapl1, and Beclin1 in primary mouse skeletal muscle myotubes and in the Tibialis anterior (TA) muscle. Time course studies reveal that AMPK activation by AICAR leads to a transient nuclear relocalization of FoxO3a followed by an increase of its cytosolic level. Moreover, AMPK activation leads to the inhibition of mTORC1 and its subsequent dissociation of Ulk1, Atg13, and FIP200 complex. Interestingly, we identify Ulk1 as a new interacting partner of AMPK in muscle cells and we show that Ulk1 is associated with AMPK under normal conditions and dissociates from AMPK during autophagy process. Moreover, we find that AMPK phosphorylates FoxO3a and Ulk1. In conclusion, our data show that AMPK activation stimulates autophagy in skeletal muscle cells through its effects on the transcriptional function of FoxO3a and takes part in the initiation of autophagosome formation by interacting with Ulk1. Here, we present new evidences that AMPK plays a crucial role in the fine tuning of protein expression programs that control skeletal muscle mass.

The constant-translation workspace, which is the set of all feasible orientations of the mobile platform for a given position, was studied. The design of the robot concerns geometric parameters calculation of the robot so that the moving platform would be found within the given workspace. http://dx.doi.org/10.5755/j01.mech.17.3.506

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Le contrôle de la masse musculaire est sous la dépendance d'un équilibre entre les processus de synthèse et de dégradation. Sur le plan cellulaire, deux voies signalétiques majeures sont impliquées dans cet équilibre : la voie des facteurs de transcription de la famille FoxO qui contrôle l'expression des gènes impliqués dans les processus atrophiques (système ubiquitine-protéasome et autophagie), et la voie IGF-1/AKT/mTOR qui représente la voie majeure de lřhypertrophie du muscle squelettique. Nos travaux mettent en évidence, sur des cellules musculaires différenciées, que l'AMPK, inhibe la voie canonique de synthèse protéique et régule, par le biais du facteur de transcription FoxO3, le système ubiquitine-protéasome ainsi que l'autophagie. Une nouvelle cible de l'AMPK a également été identifiée: la protéine ULK1, protéine clé dans l'activation de l'autophagie.

Vámos, Éva és Vámosné Vigyázó, Lilly, (eds.) Természettudományos, műszaki és orvostudományi fejlődés a hosszú 19. században (a 2010. évi ankét anyaga) = Progress in Sciences, Technology and Medicine throughout the long 19th Century. Tanulmányok a természettudományok, a technika és az orvoslás történetéből = Studies into the History of Science, Technology and Medicine