Band gap control via tuning of inversion degree in CdIn2_2S4_4 spinel

Based on theoretical arguments we propose a possible route for controlling the band-gap in the promising photovoltaic material CdIn$_2$S$_4$. Our \textit{ab initio} calculations show that the experimental degree of inversion in this spinel (fraction of tetrahedral sites occupied by In) corresponds approximately to the equilibrium value given by the minimum of the theoretical inversion free energy at a typical synthesis temperature. Modification of this temperature, or of the cooling rate after synthesis, is then expected to change the inversion degree, which in turn sensitively tunes the electronic band-gap of the solid, as shown here by accurate screened hybrid functional calculations.Comment: In press in Applied Physics Letters (2012); 4 pages, 2 figures, 1 tabl

Is Chronic Systemic Inflammation a Determinant Factor in Developing Parkinson’s Disease?

The etiology of Parkinson’s disease (PD) is complex and involves numerous risk factors as environmental and hereditary. Nevertheless, recent studies have established that systemic inflammation and neuroinflammation are both present in the prodromal phase and sustained during the progression of the disease. Evidence suggests that the activation of the peripheral immune system exacerbates the brain inflammatory response, which may initiate or enhance neurodegenerative processes. Understanding the impact of chronic systemic inflammation in the neuroinflammation and the progression of the disease will provide a broader view of the etiology and pathology of PD. In this chapter, we review the role of the chronic systemic inflammation in neuroinflammation and its effect on PD, considering cell types, molecular, and inflammatory mediators that predispose to the development of the disease

3D electrical resistivity of Gran Canaria island using magnetotelluric data

Gran Canaria, one of the two main islands of the Canary Archipelago off NW Africa, has been volcanically active for at least 15 million years. The island went through several volcanic cycles that varied greatly in composition and extrusive and intrusive activity. The complex orography of the island has excluded extensive land geophysical surveys on the island. A review of the available geophysical information on the island shows that it has been obtained mainly through marine and airborne geophysical surveys. A new dataset comprising 100 magnetotelluric soundings acquired on land has been used to obtain the first 3D electrical resistivity model of the island at crustal scale. The model shows high resistivity values close to the surface in the exposed Tejeda Caldera that extends at depth to the SE cutting the islands in half. Outside the inferred limits of the Tejeda Caldera the 3D model shows low resistivity values that could be explained by hydrothermal alteration at deeper levels and the presence of marine saltwater intrusion at shallower levels near the coast. The presence of unconnected vertical-like structures, with very low resistivity (<10 ohm m) could be associated to small convective cells is confirmed by the sensitivity analysis carried out in the present study. Those structures are the most likely candidates for a detailed analysis in order to determine their geothermal economic potential. A comprehensive review of existing geophysical data and models of Gran Canaria island and their comparison with the new 3D electrical resistivity model is presented.</p

The pharmacokinetics of ceftazidime in lactating and non-lactating cows

The pharmacokinetics of ceftazidime (CAZ) were studied in lactating (LTG) and non-lactating (NLTG) cows. Two groups (LTG and NLTG) of 5 healthy dairy cows were given ceftazidime (10 mg/ kg body weight) intravenously (i.v.) and intramuscularly (i.m.). Serum and milk (LTG) and serum samples (NLTG) were collected over a 24-h period post-administration. CAZ concentrations in serum and milk were determined by high-performance liquid chromatography, and an interactive and weighted-non-linear least-squares regression analysis was used to perform the pharmacokinetic analysis. The pharmacokinetic profiles in LTG and NLTG cows which had received CAZ i.v. fitted a three-compartment model and a two-compartment model, respectively. The CAZ concentration-time curves in serum and the area under the curve were greater and more sustained (p<0.05) in the LTG cows by both routes, while the serum clearance (Cls=72.5±18.1 ml/h per kg) was lower (p<0.05) than that in the NLTG cows (Cls=185.9±44.2 ml/h per kg). CAZ given i.v. exhibited a relatively long half-life of elimination (t; 1/2 β (LTG)=1.1±0.2 h; t; 1/2 β (NLTG)=1.4±0.3 h). Compared with other cephalosporins, CAZ had good penetration into the mammary gland (47.7±38.2% for CAZ i.v.; 51.1±39.0% for CAZ i.m.). Finally, the bioavailability of CAZ (F(LTG)=98.9±36.8%; F(NLTG)=77.1±25.3%) was suitable for its use by the i.m. route in lactating and non-lactating cows.Facultad de Ciencias MédicasComisión de Investigaciones Científicas de la provincia de Buenos Aire

Role of Myotonic Dystrophy Protein Kinase (DMPK) in Glucose Homeostasis and Muscle Insulin Action

Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease

Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis. Here we show that hepatic disruption of Ldlr with AAV-CRISPR results in severe hypercholesterolemia and atherosclerosis. We further demonstrate that co-disruption of Apob, whose germline loss is embryonically lethal, completely prevented disease through compensatory inhibition of hepatic LDL production. This new concept of metabolic disease modeling by somatic genome editing could be applied to many other systemic as well as liver-restricted disorders which are difficult to study by germline manipulation

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

Altres ajuts: This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias cofinanced by the European Regional Development Fund (ERDF); Fundación Asociación Española Contra el Cáncer (M.C. and P.A.) and Gilead Fellowships (GLD16/00144, GLD18/00047, F.B). M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades. S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero.Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential. The online version of this article (10.1007/s11060-020-03580-y) contains supplementary material, which is available to authorized users

LncRNA HORAS5 promotes taxane resistance in castration-resistant prostate cancer via a BCL2A1-dependent mechanism.

Background: Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. Materials & methods: LncRNA HORAS5 role in cabazitaxel resistance (i.e., cell-count, IC50 and caspase activity) was studied via lentiviral-mediated overexpression and siRNA-based knockdown. Genes expression was analyzed with RNA-sequencing, reverse transcription quantitative PCR (RT-qPCR) and western blot. HORAS5 expression was queried in clinical database. Results: Cabazitaxel increased HORAS5 expression that upregulated BCL2A1, thereby protecting CRPC cells from cabazitaxel-induced apoptosis. BCL2A1 knockdown decreased cell-count and increased apoptosis in CRPC cells. HORAS5-targeting antisense oligonucleotide decreased cabazitaxel IC50. In CRPC clinical samples, HORAS5 expression increased upon taxane treatment. Conclusion:HORAS5 stimulates the expression of BCL2A1 thereby decreasing apoptosis and enhancing cabazitaxel resistance in CRPC cells

Transcriptional changes in prostate of men on active surveillance after a 12-mo glucoraphanin-rich broccoli intervention—results from the Effect of Sulforaphane on prostate CAncer PrEvention (ESCAPE) randomized controlled trial

Background Epidemiological evidence suggests that consumption of cruciferous vegetables is associated with reduced risk of prostate cancer progression, largely attributed to the biological activity of glucosinolate degradation products, such as sulforaphane derived from glucoraphanin. Because there are few therapeutic interventions for men on active surveillance for prostate cancer to reduce the risk of cancer progression, dietary approaches are an appealing option for patients. Objective We evaluated whether consumption of a glucoraphanin-rich broccoli soup for 1 y leads to changes in gene expression in prostate tissue of men with localized prostate cancer. Methods Forty-nine men on active surveillance completed a 3-arm parallel randomized double-blinded intervention study for 12 mo and underwent transperineal template biopsy procedures and dietary assessment at the start and end of the study. Patients received a weekly 300 mL portion of soup made from a standard broccoli (control) or from 1 of 2 experimental broccoli genotypes with enhanced concentrations of glucoraphanin, delivering 3 and 7 times that of the control, respectively. Gene expression in tissues from each patient obtained before and after the dietary intervention was quantified by RNA sequencing followed by gene set enrichment analyses. Results In the control arm, there were several hundred changes in gene expression in nonneoplastic tissue during the 12 mo. These were associated with an increase in expression of potentially oncogenic pathways including inflammation processes and epithelial–mesenchymal transition. Changes in gene expression and associated oncogenic pathways were attenuated in men on the glucoraphanin-rich broccoli soup in a dose-dependent manner. Although the study was not powered to assess clinical progression, an inverse association between consumption of cruciferous vegetables and cancer progression was observed. Conclusion Consuming glucoraphanin-rich broccoli soup affected gene expression in the prostate of men on active surveillance, consistent with a reduction in the risk of cancer progression. This trial was registered at clinicaltrials.gov as NCT01950143