Major Logistics Lessons of World War II

The subject of this paper is Major Logistics Lessons of World War II, or- Enough was Too Much. I think it would be better if we calied it Some Major Logistics Lessons of World War II, because we can\u27t go into all of them here, and therefore I have selected a few that I feel are among the most important

Impact of the anti-diabetic drug metformin on tumor growth «in vivo»

The prevalence of obesity is rapidly increasing in affluent countries and in many urban areas of the developing world. Epidemiologic studies have associated obesity with increased burden of many cancer types but the mechanisms by which obesity induces transformation or promotes neoplastic growth remain to be fully elucidated. Possible mediators include insulin, free fatty acids, increased bio-availability of steroid hormones and inflammation. It is important to gain better understanding of the relationship between these diseases as new insights may provide new opportunities for cancer prevention and treatment. Metformin, a biguanide, is a drug often prescribed for treatment of type II diabetes. Recent retrospective epidemiologic data comparing diabetics taking metformin to diabetics taking other therapies suggests that metformin may reduce the risk of developing cancer or the risk of dying from cancer. These data contribute to the rationale for research to study the physiologic links between cancer and diabetes. Preliminary laboratory work has shown that metformin is an indirect activator of AMPK via its inhibitory action on oxidative phosphorylation in the mitochondria. AMPK is a sensor of cellular energy supply and activation of this serine/threonine kinase leads to inhibition of gluconeogenesis in the liver and reduced cell proliferation in transformed cells. We wished to expand these studies by using an in vivo model of cancer and diet-induced hyperinsulinemia in order to determine if metformin has anti-neoplastic action and if so, if the indirect (insulin lowering) systemic action of metformin or the direct AMPK mediated effect on neoplastic cells is responsible. We used mouse models of diet induced hyperinsulinemia by providing a high energy/high fat diet and a control diet ad lib in order to induce the desired metabolic phenotypes. As described in Chapter II, our results reveal that metformin attenuated the stimulatory effect of the high energy diet on growth of LLC1 carcinoma in vivo while having no effect on tumor growth in mice consuming a control diet. This suggested that the indirect, insulin lowering, effects of metformin played an important role in the attenuation of tumor burden, and these effects might be independent of AMPK activation in neoplastic cells. In Chapter III we show that the effects of diet and metformin on tumor growth described in Chapter II are reproducible in another cell line, MC38 colon carcinoma. In addition to the observed effects of metformin on tumor growth, we report that metformin reduced the cleavage of SREBP-1 and the expression of fatty acid synthase in MC38 colon carcinoma. The results presented in Chapters II and III did not separate the 'direct' from the 'indirect' effects of metformin on the attenuation of tumor growth. We address this problem in Chapter IV where we present data from an experiment that allowed us to study these effects independently by using cancer cell lines engineered to be insensitive to the 'direct' AMPK-mediated effects of metformin, grown in mice that were sensitive to metformin. We used shRNA to the decrease expression of LKB1 in two cancer cell lines and observed that these cells were resistant to metformin in vitro but were sensitive to metformin in vivo when grown in animals on either a high fat or control diet. Further analysis revealed that the loss of LKB1, a known tumor suppressor and activator of AMPK, may sensitize transformed cells to metformin under conditions of energy stress.La fréquence d'apparition du nombre de personnes atteintes d'obésité augmente rapidement dans les pays riches ainsi que dans plusieurs zones urbaines des pays en voie de développement. L'augmentation du nombre de certains cancers est associée à l'obésité dans plusieurs études épidémiologiques mais le mécanisme par lequel l'obésité induit ou favorise l'apparition des tumeurs demeure encore à élucider. L'insuline, les acides gras, l'augmentation de la biodisponibilité des hormones stéroïdes ainsi que l'inflammation sont considérés comme des déclencheurs potentiels. De meilleures connaissances sur les interrelations entre ces maladies pouvant conduire a de nouvelles découvertes sur la prévention et le traitement du cancer, il est important de poursuivre les études sur ce sujet. La metformine, un biguanide, est un médicament généralement prescrit pour le traitement du diabète de type II. Une rétrospective de données épidémiologiques suggère que les patients traités avec la metformine présentent une diminution du risque de développer un cancer et du risque de décès lies à un cancer comparativement a des patients diabétiques recevant un autre traitement. Ces résultats sont à la base de plusieurs études sur les liens physiologiques existant entre le cancer et le diabète. Nos études préliminaires ont démontré que la metformine est un activateur indirect de l'AMPK par le biais de son action inhibitrice sur le mécanisme de phosphorylation oxydative dans les mitochondries. L'AMPK est un senseur du niveau d'énergie disponible pour la cellule et l'activation de cette sérine/thréonine kinase conduit à l'inhibition de la gluconéogenèse dans le foie ainsi qu'à la diminution de la prolifération des cellules transformées. Nous avons par la suite poursuivit ce travail grâce à l'étude d'un modèle animal composé de souris soumises a un régime contrôle ou hypercalorique dans le but d'induire un phénotype métabolique d'hyperinsulinisme. Ce modèle in vivo avait pour but de déterminer si les différences du taux d'apparition de cancer observées sont dues au mécanisme systémique (diminution du taux d'insuline) de ce médicament ou aux conséquences de son action au niveau l'AMPK dans les cellules néoplasique. Tels que décrits dans le chapitre II, nos résultats démontrent que contrairement aux souris du groupe contrôle, la metformine atténue la croissance tumorale stimulée par le régime hypercalorique. Ceci suggère que l'effet indirect de la metformine sur la diminution du taux d'insuline joue un rôle important dans la régression de la taille des tumeurs, indépendamment de l'activation de l'AMPK dans les cellules néoplasiques. Dans le chapitre III, nous avons démontrés que les effets sur la croissance tumorale, décrits dans le chapitre II, d'un régime hypercalorique et de la metformine sont reproductibles dans un autre modèle de lignée cellulaire, les cellules MC38 issues de carcinome de cancer du colon. En plus de son rôle au niveau de la voie de signalisation de l'insuline, nous avons observé que la metformine diminue le clivage de la protéine SREBP-1 et l'expression de l'enzyme acide gras synthase par les cellules MC38. Les résultats présentés dans les chapitres II et III ne nous permettent cependant pas de faire la distinction entre les effets directs et indirects de la metformine. Dans le chapitre IV, nous avons utilisé des shRNA dirigés contre la protéine LKB1, un suppresseur de tumeur et activateur de l'AMPK, dans deux lignées cellulaires et observé que ces cellules sont résistantes à la metformine in vitro. En revanche, ces cellules sont sensibles à ce médicament in vivo lorsqu'elles sont injectées dans les animaux, qu'ils soient ou non soumis à un régime hypercalorique. D'autres analyses ont révélé que la perte de la protéine LKB1 peut, dans des conditions de stress énergétique, sensibiliser à la metformine les cellules transformées

Interview on The Grange and Community Life

The Crafts, and Larry Algire discuss the Grange, which is a fraternal order of farmers founded in secret in 1868. Specifically, they discuss Wayne Grange, which was founded in 1873. The Grange system has masters, overseers and stewards as its leadership structure. They also discuss what the Grange does for the community, including square dances, and helping out the farm community.https://digital.kenyon.edu/ffp_interviews/1039/thumbnail.jp

Cell encapsulation systems toward modular tissue regeneration: from immunoisolation to multifunctional devices

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Conserved functional domains and a novel tertiary interaction near the pseudoknot drive translational activity of hepatitis C virus and hepatitis C virus-like internal ribosome entry sites

The translational activity of the hepatitis C virus (HCV) internal ribosome entry site (IRES) and other HCV-like IRES RNAs depends on structured RNA elements in domains II and III, which serve to recruit the ribosomal 40S subunit, eukaryotic initiation factor (eIF) 3 and the ternary eIF2/Met-tRNAiMet/GTP complex and subsequently domain II assists subunit joining. Porcine teschovirus-1 talfan (PTV-1) is a member of the Picornaviridae family, with a predicted HCV-like secondary structure, but only stem-loops IIId and IIIe in the 40S-binding domain display significant sequence conservation with the HCV IRES. Here, we use chemical probing to show that interaction sites with the 40S subunit and eIF3 are conserved between HCV and HCV-like IRESs. In addition, we reveal the functional role of a strictly conserved co-variation between a purine–purine mismatch near the pseudoknot (A–A/G) and the loop sequence of domain IIIe (GAU/CA). These nucleotides are involved in a tertiary interaction, which serves to stabilize the pseudoknot structure and correlates with translational efficiency in both the PTV-1 and HCV IRES. Our data demonstrate conservation of functional domains in HCV and HCV-like IRESs including a more complex structure surrounding the pseudoknot than previously assumed

Phosphate release contributes to the rate-limiting step for unwinding by an RNA helicase

RNA helicases function in numerous aspects of RNA biology. These enzymes are RNA-stimulated ATPases that translocate on RNA and unwind or remodel structured RNA in an ATP-dependent fashion. How ATP and the ATPase cycle fuel the work performed by helicases is not completely clear. The hepatitis C virus RNA helicase, NS3, is an important model system for this class of enzymes. NS3 binding to a single-/double-strand RNA or DNA junction leads to ATP-independent melting of the duplex and formation of a complex capable of ATP-dependent unwinding by using a spring-loaded mechanism. We have established an RNA substrate for NS3 that can be unwound in a single sub-step. Our studies are consistent with a model in which a single ATP binding and/or hydrolysis event sets the unwinding spring and phosphate dissociation contributes to release of the spring, thereby driving the power stroke used for unwinding

Position of eukaryotic translation initiation factor eIF1A on the 40S ribosomal subunit mapped by directed hydroxyl radical probing

The universally conserved eukaryotic initiation factor (eIF), eIF1A, plays multiple roles throughout initiation: it stimulates eIF2/GTP/Met-tRNAiMet attachment to 40S ribosomal subunits, scanning, start codon selection and subunit joining. Its bacterial ortholog IF1 consists of an oligonucleotide/oligosaccharide-binding (OB) domain, whereas eIF1A additionally contains a helical subdomain, N-terminal tail (NTT) and C-terminal tail (CTT). The NTT and CTT both enhance ribosomal recruitment of eIF2/GTP/Met-tRNAiMet, but have opposite effects on the stringency of start codon selection: the CTT increases, whereas the NTT decreases it. Here, we determined the position of eIF1A on the 40S subunit by directed hydroxyl radical cleavage. eIF1A's OB domain binds in the A site, similar to IF1, whereas the helical subdomain contacts the head, forming a bridge over the mRNA channel. The NTT and CTT both thread under Met-tRNAiMet reaching into the P-site. The NTT threads closer to the mRNA channel. In the proposed model, the NTT does not clash with either mRNA or Met-tRNAiMet, consistent with its suggested role in promoting the ‘closed’ conformation of ribosomal complexes upon start codon recognition. In contrast, eIF1A-CTT appears to interfere with the P-site tRNA-head interaction in the ‘closed’ complex and is likely ejected from the P-site upon start codon recognition

Position of eukaryotic translation initiation factor eIF1A on the 40S ribosomal subunit mapped by directed hydroxyl radical probing

The universally conserved eukaryotic initiation factor (eIF), eIF1A, plays multiple roles throughout initiation: it stimulates eIF2/GTP/Met-tRNAiMet attachment to 40S ribosomal subunits, scanning, start codon selection and subunit joining. Its bacterial ortholog IF1 consists of an oligonucleotide/oligosaccharide-binding (OB) domain, whereas eIF1A additionally contains a helical subdomain, N-terminal tail (NTT) and C-terminal tail (CTT). The NTT and CTT both enhance ribosomal recruitment of eIF2/GTP/Met-tRNAiMet, but have opposite effects on the stringency of start codon selection: the CTT increases, whereas the NTT decreases it. Here, we determined the position of eIF1A on the 40S subunit by directed hydroxyl radical cleavage. eIF1A's OB domain binds in the A site, similar to IF1, whereas the helical subdomain contacts the head, forming a bridge over the mRNA channel. The NTT and CTT both thread under Met-tRNAiMet reaching into the P-site. The NTT threads closer to the mRNA channel. In the proposed model, the NTT does not clash with either mRNA or Met-tRNAiMet, consistent with its suggested role in promoting the ‘closed’ conformation of ribosomal complexes upon start codon recognition. In contrast, eIF1A-CTT appears to interfere with the P-site tRNA-head interaction in the ‘closed’ complex and is likely ejected from the P-site upon start codon recognition

Understanding the benefit of metformin use in cancer treatment

Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR) signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed