Carvedilol targets beta-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy

Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to β-adrenergic blockade but is dependent on β-arrestins and is reversed by β-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment

Forensic Odontology and its applicability in processing crime scenes and other catastrophic events

En los últimos años la odontología forense alcanza a nivel mundial fundamental importancia, consiguiendo, mediante determinados procedimientos, estimar hora y fecha de muerte de una persona, facilitando la resolución de múltiples y complicados casos de muerte. Los procedimientos empleados también permiten el levantamiento de huellas aplicando técnicas para queiloscopía, mordidas, registro de rugas palatinas, brindando de esta forma un gran aporte en la investigación criminal en su primera fase indagatoria, dentro de la cual el procesamiento de la escena busca colectar indicios y evidencias vinculantes al hecho, que posteriormente a través de una cadena de custodia se trasladarán al laboratorio donde los indicios y evidencias serán estudiados, pasando a ser medios de prueba pericial para poder identificar el hecho y la autoria de un acto presuntamente criminal. Se presenta así una recopilacion de literatura concerniente al tema que busca informar al odontólogo de practica general sobre terminología, procedimientos y demás relacionados a las ciencias forenses, con el propósito de informar y actualizar sus conocimientos al respecto.In recent years, forensic dentistry reaches critical importance worldwide, getting through certain procedures to estimate, time and date of death of a person, facilitating the resolution of multiple and complicated cases of death. The procedures employed also allow the lifting of fingerprints by applying techniques; Queiloscopía, Biting, Registration Rugas Palatine, providing thus a great contribution in the Criminal Investigation in its first phase Inquest, within which the processing of the scene seeks to collect evidence and binding evidence the fact that subsequently through a chain of custody is transferred to the laboratory where the evidence and evidence will be studied, becoming media expert evidence to identify the fact and authorship of an allegedly criminal act, thus presents a collection of literature concerning the subject that seeks to inform the general practice dentist on terminology, procedures and other related forensic sciences in order to inform and update their knowledge about it

Latent ion tracks in amorphous silicon

We present experimental evidence for the formation of ion tracks in amorphous Si induced by swift heavy-ion irradiation. An underlying core-shell structure consistent with remnants of a high-density liquid structure was revealed by small-angle x-ray scattering and molecular dynamics simulations. Ion track dimensions differ for as-implanted and relaxed Si as attributed to differentmicrostructures andmelting temperatures. The identification and characterization of ion tracks in amorphous Si yields new insight into mechanisms of damage formation due to swift heavy-ion irradiation in amorphous semiconductors

Competing biosecurity and risk rationalities in the Chittagong poultry commodity chain, Bangladesh

This paper anthropologically explores how key actors in the Chittagong live bird trading network perceive biosecurity and risk in relation to avian influenza between production sites, market maker scenes and outlets. They pay attention to the past and the present, rather than the future, downplaying the need for strict risk management, as outbreaks have not been reported frequently for a number of years. This is analysed as ‘temporalities of risk perception regarding biosecurity’, through Black Swan theory, the idea that unexpected events with major effects are often inappropriately rationalized (Taleb in The Black Swan. The impact of the highly improbable, Random House, New York, 2007). This incorporates a sociocultural perspective on risk, emphasizing the contexts in which risk is understood, lived, embodied and experienced. Their risk calculation is explained in terms of social consent, practical intelligibility and convergence of constraints and motivation. The pragmatic and practical orientation towards risk stands in contrast to how risk is calculated in the avian influenza preparedness paradigm. It is argued that disease risk on the ground has become a normalized part of everyday business, as implied in Black Swan theory. Risk which is calculated retrospectively is unlikely to encourage investment in biosecurity and, thereby, points to the danger of unpredictable outlier events

Resultados de la implantación de catgut en el tratamiento de la coroidopatia serosa central

Central serous choroidopathy is the sporadic disease of young adult men characterized by a serous detachment to macular level; it manifests acutely with blurred vision and metamorphopsia (or both), darkening of the central visual field and xanthopsia. The objective of this research is to evaluate the degree of effectiveness of the implantation of catgut as a treatment in this disease. A quasi-experimental study was conducted in patients with this condition at “Arnaldo Milián Castro” Hospital from April 2010 to September 2015. In group 1 (study) was applied the technique of implantation of catgut and it was applied a therapy of anxiolytic, in group 2 (control) was not applied the acupuncture technique. In both groups prevailed patients between 30 and 50 years old and the stress was the most frequent risk factor, decreased vision and central scotoma were the most reported symptoms; in group 1 there was a better recovery of vision with respect to group 2; it is obtained high effectiveness and satisfaction in group 1, in group 2 it was possible to improve the quality of health and life with a less expensive treatment and the drug consumption decreased and the time of incapacity for work. It was applied a modality of Traditional and Natural Medicine to an eye infection not reported in previous research.La coroidopatía serosa central es una enfermedad esporádica de hombres adultos jóvenes que se caracteriza por un desprendimiento seroso a nivel macular; se manifiesta de forma aguda con visión borrosa y metamorfopsia (o ambas), oscurecimiento del campo visual central y xantopsia. El objetivo de esta investigación es evaluar el grado de efectividad de la implantación de catgut en su tratamiento. Se realizó un estudio cuasi experimental en pacientes con este padecimiento en el Hospital “Arnaldo Milián Castro” desde abril de 2010 hasta septiembre de 2015. Al grupo 1 (estudio) se le aplicó la técnica de implantación de catgut y se le indicó tratamiento con ansiolíticos, al grupo 2 (control) no se le aplicó la técnica acupuntural. En ambos grupos predominaron los pacientes entre 30 y 50 años de edad y el stress fue el factor de riesgo más frecuente, la disminución de la visión y el escotoma central fueron los síntomas más referidos; en el grupo 1 hubo una mejor recuperación de la visión con respecto al grupo 2; se obtuvieron alta efectividad y satisfacción en el grupo 1, en el grupo 2 se logró mejorar la calidad de la salud y de vida con un tratamiento menos costoso y se disminuyeron el consumo de medicamentos y el tiempo de incapacidad laboral. Se aplicó una modalidad de Medicina Tradicional y Natural en una afección ocular no informada en investigaciones anteriores

The Functions of Myosin II and Myosin V Homologs in Tip Growth and Septation in Aspergillus nidulans

Because of the industrial and medical importance of members of the fungal genus Aspergillus, there is considerable interest in the functions of cytoskeletal components in growth and secretion in these organisms. We have analyzed the genome of Aspergillus nidulans and found that there are two previously unstudied myosin genes, a myosin II homolog, myoB (product = MyoB) and a myosin V homolog, myoE (product = MyoE). Deletions of either cause significant growth defects. MyoB localizes in strings that coalesce into contractile rings at forming septa. It is critical for septation and normal deposition of chitin but not for hyphal extension. MyoE localizes to the Spitzenkörper and to moving puncta in the cytoplasm. Time-lapse imaging of SynA, a v-SNARE, reveals that in myoE deletion strains vesicles no longer localize to the Spitzenkörper. Tip morphology is slightly abnormal and branching occurs more frequently than in controls. Tip extension is slower than in controls, but because hyphal diameter is greater, growth (increase in volume/time) is only slightly reduced. Concentration of vesicles into the Spitzenkörper before incorporation into the plasma membrane is, thus, not required for hyphal growth but facilitates faster tip extension and a more normal hyphal shape

Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis

The small GTPase Cdc42 is a key regulator of polarity, but little is known in mammals about its spatial regulation and the relevance of spatial Cdc42 pools for polarity. Here we report the identification of a GM130-RasGRF complex as a regulator of Cdc42 at the Golgi. Silencing GM130 results in RasGRF-dependent inhibition of the Golgi pool of Cdc42, but does not affect Cdc42 at the cell surface. Furthermore, active Cdc42 at the Golgi is important to sustain asymmetric front-rear Cdc42-GTP distribution in directionally migrating cells. Concurrent to Cdc42 inhibition, silencing GM130 also results in RasGRF-dependent Ras-ERK pathway activation. Moreover, depletion of GM130 is sufficient to induce E-cadherin downregulation, indicative of a loss in cell polarity and epithelial identity. Accordingly, GM130 expression is frequently lost in colorectal and breast cancer patients. These findings establish a previously unrecognized role for a GM130-RasGRF-Cdc42 connection in regulating polarity and tumorigenesis

The Assembly of the Plasmodial PLP Synthase Complex Follows a Defined Course

Background: Plants, fungi, bacteria and the apicomplexan parasite Plasmodium falciparum are able to synthesize vitamin B6 de novo, whereas mammals depend upon the uptake of this essential nutrient from their diet. The active form of vitamin B6 is pyridoxal 5-phosphate (PLP). For its synthesis two enzymes, Pdx1 and Pdx2, act together, forming a multimeric complex consisting of 12 Pdx1 and 12 Pdx2 protomers. Methodology/Principal Findings: Here we report amino acid residues responsible for stabilization of the structural and enzymatic integrity of the plasmodial PLP synthase, identified by using distinct mutational analysis and biochemical approaches. Residues R85, H88 and E91 (RHE) are located at the Pdx1:Pdx1 interface and play an important role in Pdx1 complex assembly. Mutation of these residues to alanine impedes both Pdx1 activity and Pdx2 binding. Furthermore, changing D26, K83 and K151 (DKK), amino acids from the active site of Pdx1, to alanine obstructs not only enzyme activity but also formation of the complex. In contrast to the monomeric appearance of the RHE mutant, alteration of the DKK residues results in a hexameric assembly, and does not affect Pdx2 binding or its activity. While the modelled position of K151 is distal to the Pdx1:Pdx1 interface, it affects the assembly of hexameric Pdx1 into a functional dodecamer, which is crucial for PLP synthesis. Conclusions/Significance: Taken together, our data suggest that the assembly of a functional Pdx1:Pdx2 complex follows