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ABSTRACT The fission yeast PHO regulon genes pho1, pho84, and tgp1—encoding a cell surface-associated acid phosphatase (Pho1), a plasma membrane inorganic phosphate transporter (Pho84), and a plasma membrane glycerophosphocholine transporter (Tgp1)—are strongly upregulated in response to acute phosphate starvation, as are the SPBPB2B2.06c and SPAC1039.02 genes that encode putative 5'-nucleotidase paralogs of the binuclear metallophosphoesterase enzyme superfamily. Via proteomic analysis of the medium harvested from phosphate-replete and phosphate-starved fission yeast, we define a starvation secretome that includes SPBPB2B2.06c (renamed Efn1, for extracellular five-prime nucleotidase), SPAC1039.02 (henceforth Efn2), and Pho1 among the most abundant exported proteins elaborated by phosphate-starved cells. We demonstrate and characterize a 5'-nucleotidase activity secreted into the medium of phosphate-starved efn1+efn2+ cells, which is eliminated by simultaneous deletion of efn1 and efn2. By singly deleting efn1 and efn2, we find that Efn1 contributes the greater share of secreted 5'-nucleotidase activity. Efn1 and Efn2 catalyze the release of inorganic phosphate from all four standard ribonucleoside monophosphates, in order of preference: CMP > UMP > AMP > GMP. Whereas efn1+efn2+ cells can use extracellular CMP as a source of phosphate during phosphate starvation, efn1∆ efn2∆ cells cannot. The secretion of 5'-nucleotidase enzymes during phosphate limitation is a newly appreciated facet of fission yeast phosphate homeostasis.IMPORTANCESchizosaccharomyces pombe adapts to phosphate starvation by upregulating the expression of a cell surface acid phosphatase that mobilizes inorganic phosphate from the extracellular milieu, as well as transmembrane transporters that take up inorganic phosphate and glycerophosphocholine. This study identifies two paralogous extracellular 5'-nucleotidase enzymes, Efn1 and Efn2, encoded by genes that are highly transcriptionally induced during acute phosphate starvation, as major proteins secreted into the medium by phosphate-starved fission yeast cells. Secreted Efn1 and Efn2 catalyze the release of inorganic phosphate from all ribonucleoside monophosphates, with a preference for CMP. Secretion of Efn1 and Efn2 enables phosphate-starved fission yeast to thrive by using extracellular CMP as a source of inorganic phosphate. The starvation-induced production of extracellular 5'-nucleotidases adds a new layer of pro-adaptive function during phosphate limitation.

ObjectiveWe investigated whether there are differences in cancer incidence by geographical area of origin in North-eastern Italy.MethodsWe selected all incident cases recorded in the Veneto Tumour Registry in the period 2015-2019. Subjects were classified, based on the country of birth, in six geographical areas of origin (Italy, Highly Developed Countries-HDC, Eastern Europe, Asia, Africa, South-central America). Age-standardized incidence rates and incidence rate ratio (IRR) were calculated, for all cancer sites and for colorectal, liver, breast and cervical cancer separately.ResultsWe recorded 159,486 all-site cancer cases; 5.2% cases occurred in subjects born outside Italy, the majority from High Migratory Pressure Countries (HMPC) (74.3%). Incidence rates were significantly lower in subjects born in HMPC in both sexes. Immigrants, in particular born in Asia and Africa, showed lower rates of all site cancer incidence. The lowest IRR for colorectal cancer was observed in males from South-Central America (IRR 0.19, 95%CI 0.09-0.44) and in females from Asia (IRR 0.32, 95%CI 0.18-0.70). The IRR of breast cancer appeared significantly lower than Italian natives in all female populations, except for those coming from HDC. Females from Eastern Europe showed a higher IRR for cervical cancer (IRR 2.02, 95%CI 1.57-2.61).ConclusionCancer incidence was found lower in subjects born outside Italy, with differences in incidence patterns depending on geographical area of origin and the cancer type in question. Further studies, focused on the country of birth of the immigrant population, would help to identify specific risk factors influencing cancer incidence.

Abstract Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice. Structure-activity relationship studies led to identification of a thiazole series of BDK inhibitors; however, these inhibitors did not improve metabolism in mice upon chronic administration. While the thiophenes demonstrated sustained branched chain ketoacid (BCKA) lowering and reduced BDK protein levels, the thiazoles increased BCKAs and BDK protein levels. Thiazoles increased BDK proximity to BCKDH-E2, whereas thiophenes reduced BDK proximity to BCKDH-E2, which may promote BDK degradation. Thus, we describe two BDK inhibitor series that possess differing attributes regarding BDK degradation or stabilization and provide a mechanistic understanding of the desirable features of an effective BDK inhibitor.

Abstract Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male mice and skeletal muscle. Inversely, chronic elevation of UCN2 by injection with adenovirus encoding UCN2 resolves metabolic complications, improving glucose tolerance. CRHR2 recruits Gs in response to low concentrations of UCN2, as well as Gi and β-Arrestin at high concentrations of UCN2. Pre-treating cells and skeletal muscle ex vivo with UCN2 leads to internalization of CRHR2, dampened ligand-dependent increases in cAMP, and blunted reductions in insulin signaling. These results provide mechanistic insights into how UCN2 regulates insulin sensitivity and glucose metabolism in skeletal muscle and in vivo. Importantly, a working model was derived from these results that unifies the contradictory metabolic effects of UCN2.

El comportamiento sexual íntimo de las parejas (normales o no-patológicas) deben ser descritos por los psicólogos, para ello usan dos perspectivas; una es la primera a) psicopatológica del DSM 5 y CIE-10 o, la segunda b) la perspectiva de la psicología positiva, que utilizan los modelos de Kinsey (1953), Masters y Johnson (1966), Kaplan (1979), Schnarch (1991), Whipple y Brash-Mc.Greer (1997), y Basson (2000). Un panel de expertos buscó validar una nueva taxonomía de conductas eróticas. La música sexual se refiere a la conducta individual y diádica que una pareja hace para llegar al coito sexual; las cualidades de la conducta monódica de un amante son: a) Intensidad, b) Duración, c) Timbre y d) Tono sexual; y la coordinación musical diádica de dos amantes son: x) Ritmo, y) Melodía y z) Armonía sexual. Un panel de siete expertos usando el método Delphi validó el contenido de la teoría siete dimensiones de la música sexual proporcionando la definición conceptual y la operacionalización de las variables sexuales usadas; además, los expertos proporcionaron la casuística clínica de sus casos particulares.

The SPES (Selective Production of Exotic Species) facility, currently under development at Legnaro National Laboratories of INFN, aims at the production of intense RIB (Radioactive Ion Beams) employing the Isotope Separation On-Line (ISOL) technique for interdisciplinary research. The radioactive isotopes of interest are produced by the interaction of a multi-foil uranium carbide target with a 40 MeV 200 μA proton beam generated by a cyclotron proton driver. The Target Ion Source (TIS) is the core of the SPES project, here the radioactive nuclei, mainly neutron-rich isotopes, are stopped, extracted, ionized, separated, accelerated and delivered to specific experimental areas. Due to efficiency reasons, the TIS unit needs to be replaced periodically during operation. In this highly radioactive environment, the employment of autonomous systems allows the manipulation, transport, and storage of the TIS unit without the need for human intervention. A dedicated remote handling infrastructure is therefore under development to fulfill the functional and safety requirement of the project. This contribution describes the layout of the SPES target area, where all the remote handling systems operate to grant the smooth operation of the facility avoiding personnel exposure to a high dose rate or contamination issues.

Between 1964 and 1985, a military dictatorship in Brazil combined an arsenal of political instruments—surveillance, violent repression, and propaganda, among others—to justify its illegal rule. How did the Brazilian military regime attempt to justify its claim to power for more than two decades? What discursive strategies did it use to win popular support, despite the violence it perpetrated? This paper investigates how discourse is used to legitimize power and create meaning in authoritarian regimes. Using ethnographic content analysis of archival materials, I pinpoint and analyze three key discursive frames employed in regime propaganda: "defenders of democracy," "Great Brazil" and "model citizenship." I argue that the Brazilian military regime used these frames to justify its authority, forge national values and social norms, and redefine the boundaries of the national community. These findings not only contribute to our understanding of authoritarian power that is wielded and legitimized through discourse, but also speak to the enduring consequences of authoritarianism in sociopolitical subjects. [ABSTRACT FROM AUTHOR]