Numerical mode matching in dissipative silencers with temperature gradients and mean flow

This work presents a mathematical approach based on the mode matching method to compute the transmission loss of perforated dissipative silencers with temperature gradients and mean flow. Three-dimensional wave propagation is considered in silencer geometries with arbitrary, but axially uniform, cross section. To reduce the computational requirements of a full multidimensional finite element calculation, a method is developed combining axial and transversal solutions of the wave equation. First, the finite element method is employed in a twodimensional problem to extract the eigenvalues and associated eigenvectors for the silencer cross section. Mean flow as well as radial temperature gradients and the corresponding thermal-induced material heterogeneities are included in the model. Assuming a low acoustic influence of axial gradients (compared to radial variations), an axially uniform temperature field is taken into account, its value being the inlet/outlet average. A weighted residual approach is then used to match the acoustic fields (pressure and axial acoustic velocity) at the geometric discontinuities between the silencer chamber and the inlet and outlet pipes. Transmission loss predictions are compared favourably with a general three-dimensional finite element approach, offering a reduction in the computational effort

Mitochondrial Fission Factor (MFF) inhibits mitochondrial metabolism and reduces breast cancer stem cell (CSC) activity

Elevated mitochondrial biogenesis and metabolism represent key features of breast cancer stem cells (CSCs), whose propagation is conducive to disease onset and progression. Therefore, interfering with mitochondria biology and function may be regarded as a useful approach to eradicate CSCs. Here, we used the breast cancer cell line MCF7 as a model system to interrogate how mitochondrial fission contributes to the development of mitochondrial dysfunction toward the inhibition of metabolic flux and stemness. We generated an isogenic MCF7 cell line transduced with Mitochondrial Fission Factor (MCF7-MFF), which is primarily involved in mitochondrial fission. We evaluated the biochemical, molecular and functional properties of MCF7-MFF cells, as compared to control MCF7 cells transduced with the empty vector (MCF7-Control). We observed that MFF over-expression reduces both mitochondrial mass and activity, as evaluated using the mitochondrial probes MitroTracker Red and MitoTracker Orange, respectively. The analysis of metabolic flux using the Seahorse XFe96 revealed the inhibition of OXPHOS and glycolysis in MCF7-MFF cells, suggesting that increased mitochondrial fission may impair the biochemical properties of these organelles. Notably, CSCs activity, assessed by 3D-tumorsphere assays, was reduced in MCF7-MFF cells. A similar trend was observed for the activity of ALDH, a well-established marker of stemness. We conclude that enhanced mitochondrial fission may compromise CSCs propagation, through the impairment of mitochondrial function, possibly leading to a quiescent cell phenotype. Unbiased proteomic analysis revealed that proteins involved in mitochondrial dysfunction, oxidative stress-response, fatty acid metabolism and hypoxia signaling are among the most highly up-regulated in MCF7-MFF cells. Of note, integrated analysis of top regulatory networks obtained from unbiased proteomics in MCF7-MFF cells predicts that this cell phenotype activates signaling systems and effectors involved in the inhibition of cell survival and adhesion, together with the activation of specific breast cancer cell death programs. Overall, our study shows that unbalanced and abnormal activation of mitochondrial fission may drive the impairment of mitochondrial metabolic function, leading to inhibition of CSC propagation, and the activation of quiescence programs. Exploiting the potential of mitochondria to control pivotal events in tumor biology may, therefore, represent a useful tool to prevent disease progression

Construct and face validity of SINERGIA laparoscopic virtual reality simulator

Purpose Laparoscopic techniques have nowadays become a gold standard in many surgical procedures, but they imply a more difficult learning skills process. Simulators have a fundamental role in the formative stage of new surgeons. This paper presents the construct and face validity of SINERGIA laparoscopic virtual reality simulator in order to decide whether it can be considered as an assessment tool. Methods Twenty people participated in this study, 14 were novices and 6 were experts. Five tasks of SINERGIA were included in the study: coordination, navigation, navigation and touch, precise grasping and coordinate traction. For each one of these tasks, a certain number of metrics are automatically recorded. All subjects accomplished each task only once and filled in two questionnaires. A statistical analysis was made and results from both groups were compared with the Mann–Whitney U-test, considering significant differences when P ≤ 0.05. Internal consistency of the system has been analyzed with the Cronbach’s alpha test. Results Novices and experts positively rated SINERGIA characteristics. At least one of the evaluated metrics of each exercise presented significant differences between both groups. Nevertheless, all metrics under study gave a better punctuation to the executions accomplished by experts (lower time, higher efficiency, fewer errors. . .) than to those made by novices. Conclusion SINERGIA laparoscopic virtual reality simulator is able to discriminate subjects according to their level of experience in laparoscopic surgery; therefore, it can be used within a training program as an assessment too

Differential impact of classical and non-canonical NF-κB pathway-related gene expression on the survival of breast cancer patients

Inflammation is a well-known driver of carcinogenesis and cancer progression, often attributed to the tumor microenvironment. However, tumor cells themselves are capable of secreting a variety of inflammatory molecules, leading to the activation of specific signaling pathways that promote tumor progression. The NF-κB signaling pathway is one of the most important connections between inflammation and tumorigenesis. NF-κB is a superfamily of transcription factors that plays an important role in several types of hematological and solid tumors, including breast cancer. However, the role of the NF-κB pathway in the survival of breast cancer patients is poorly studied. In this study, we analyzed and related the expression of both canonical and alternative NF-κB pathways and selected target genes with the relapse-free and overall survival of breast cancer patients. We used the public database Kaplan-Meier plotter (KMplot) which includes gene expression data and survival information of 3951 breast cancer patients. We found that the expression of IKKα was associated with poor relapse-free survival in patients with ER-positive tumors. Moreover, the expression of IL-8 and MMP-1 was associated with poor relapse-free and overall survival. In contrast, expression of IKKβ, p50, and p65 from the canonical pathway, and NIK and RELB from the alternative pathway correlated with better relapse-free survival also when the patients were classified by their hormonal and nodal status. Our study suggests that the expression of genes of the canonical and alternative NF-κB pathways is ultimately critical for tumor persistence. Understanding the communication between both pathways would help to find better therapeutic and prophylactic targets to prevent breast cancer progression and relapse

APOE-ε4 Shapes the Cerebral Organization in Cognitively Intact Individuals as Reflected by Structural Gray Matter Networks

Gray matter networks (GMn) provide essential information on the intrinsic organization of the brain and appear to be disrupted in Alzheimer’s disease (AD). Apolipoprotein E (APOE)-ε4 represents the major genetic risk factor for AD, yet the association between APOE-ε4 and GMn has remained unexplored. Here, we determine the impact of APOE-ε4 on GMn in a large sample of cognitively unimpaired individuals, which was enriched for the genetic risk of AD. We used independent component analysis to retrieve sources of structural covariance and analyzed APOE group differences within and between networks. Analyses were repeated in a subsample of amyloid-negative subjects. Compared with noncarriers and heterozygotes, APOE-ε4 homozygotes showed increased covariance in one network including primarily right-lateralized, parietal, inferior frontal, as well as inferior and middle temporal regions, which mirrored the formerly described AD-signature. This result was confirmed in a subsample of amyloid-negative individuals. APOE-ε4 carriers showed reduced covariance between two networks encompassing frontal and temporal regions, which constitute preferential target of amyloid deposition. Our data indicate that, in asymptomatic individuals, APOE-ε4 shapes the cerebral organization in a way that recapitulates focal morphometric alterations observed in AD patients, even in absence of amyloid pathology. This suggests that structural vulnerability in neuronal networks associated with APOE-ε4 may be an early event in AD pathogenesis, possibly upstream of amyloid deposition

Análisis de daño cromosomico espontáneo e inducido por mutágenos químicos en linfocitos de sangre periférica de personal aeronáutico de flota internacional

Se analizó el daño citogenético en linfocitos de sangre periférica de personal aeronáutico de flota internacional de la Argentina con el fin de evaluar los efectos de la radiación cósmica sobre el material genético de dicho grupo de individuos y determinar su sensibilidad a mutágenos químicos, como una primera aproxima­ción a determinar riesgo de cáncer en dicha población. Mediante técnicas citogenéticas convencionales, se determinó la frecuencia de aberraciones cromosómicas (AC) “espontáneas” e inducidas in vitro por bleomicina (BLM) en las etapas G0 y G2 del ciclo celular y de intercambios de cromátidas hermanas (ICH) espon­táneos e inducidos por estreptonigrina (EN) en linfocitos de sangre periférica de 21 tripulantes de flota inter­nacional (pilotos y azafatas) y 18 individuos controles. El personal aeronáutico presentó una frecuencia 3,5 veces mayor de AC “espontáneas” y 2 veces mayor de AC inducidas por BLM en la etapa G0 del ciclo celu­lar que los individuos de la población control. Estos resultados permiten sugerir que el personal aeronáutico de flota internacional de nuestro país debería ser considerado “grupo laboralmente expuesto a la radiación” y que el ensayo de BLM G0 sería el más apropiado para determinar sensibilidad a mutágenos en personal aeronáutico de flota internacional.Universidad Nacional de La Plat

Análisis de daño cromosomico espontáneo e inducido por mutágenos químicos en linfocitos de sangre periférica de personal aeronáutico de flota internacional

Se analizó el daño citogenético en linfocitos de sangre periférica de personal aeronáutico de flota internacional de la Argentina con el fin de evaluar los efectos de la radiación cósmica sobre el material genético de dicho grupo de individuos y determinar su sensibilidad a mutágenos químicos, como una primera aproxima­ción a determinar riesgo de cáncer en dicha población. Mediante técnicas citogenéticas convencionales, se determinó la frecuencia de aberraciones cromosómicas (AC) “espontáneas” e inducidas in vitro por bleomicina (BLM) en las etapas G0 y G2 del ciclo celular y de intercambios de cromátidas hermanas (ICH) espon­táneos e inducidos por estreptonigrina (EN) en linfocitos de sangre periférica de 21 tripulantes de flota inter­nacional (pilotos y azafatas) y 18 individuos controles. El personal aeronáutico presentó una frecuencia 3,5 veces mayor de AC “espontáneas” y 2 veces mayor de AC inducidas por BLM en la etapa G0 del ciclo celu­lar que los individuos de la población control. Estos resultados permiten sugerir que el personal aeronáutico de flota internacional de nuestro país debería ser considerado “grupo laboralmente expuesto a la radiación” y que el ensayo de BLM G0 sería el más apropiado para determinar sensibilidad a mutágenos en personal aeronáutico de flota internacional.Universidad Nacional de La Plat

Análisis de daño cromosomico espontáneo e inducido por mutágenos químicos en linfocitos de sangre periférica de personal aeronáutico de flota internacional

Se analizó el daño citogenético en linfocitos de sangre periférica de personal aeronáutico de flota internacional de la Argentina con el fin de evaluar los efectos de la radiación cósmica sobre el material genético de dicho grupo de individuos y determinar su sensibilidad a mutágenos químicos, como una primera aproxima­ción a determinar riesgo de cáncer en dicha población. Mediante técnicas citogenéticas convencionales, se determinó la frecuencia de aberraciones cromosómicas (AC) “espontáneas” e inducidas in vitro por bleomicina (BLM) en las etapas G0 y G2 del ciclo celular y de intercambios de cromátidas hermanas (ICH) espon­táneos e inducidos por estreptonigrina (EN) en linfocitos de sangre periférica de 21 tripulantes de flota inter­nacional (pilotos y azafatas) y 18 individuos controles. El personal aeronáutico presentó una frecuencia 3,5 veces mayor de AC “espontáneas” y 2 veces mayor de AC inducidas por BLM en la etapa G0 del ciclo celu­lar que los individuos de la población control. Estos resultados permiten sugerir que el personal aeronáutico de flota internacional de nuestro país debería ser considerado “grupo laboralmente expuesto a la radiación” y que el ensayo de BLM G0 sería el más apropiado para determinar sensibilidad a mutágenos en personal aeronáutico de flota internacional.Universidad Nacional de La Plat

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog

The porin and the permeating antibiotic: A selective diffusion barrier in gram-negative bacteria

Gram-negative bacteria are responsible for a large proportion of antibiotic resistant bacterial diseases. These bacteria have a complex cell envelope that comprises an outer membrane and an inner membrane that delimit the periplasm. The outer membrane contains various protein channels, called porins, which are involved in the influx of various compounds, including several classes of antibiotics. Bacterial adaptation to reduce influx through porins is an increasing problem worldwide that contributes, together with efflux systems, to the emergence and dissemination of antibiotic resistance. An exciting challenge is to decipher the genetic and molecular basis of membrane impermeability as a bacterial resistance mechanism. This Review outlines the bacterial response towards antibiotic stress on altered membrane permeability and discusses recent advances in molecular approaches that are improving our knowledge of the physico-chemical parameters that govern the translocation of antibiotics through porin channel