Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study

Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin

Job Shop Planning and Scheduling for Manufacturers with Manual Operations

Job shop scheduling systems are widely employed to optimise the efficiency of machine utilisation in the manufacturing industry, by searching the most cost-effective permutation of job operations based on the cost of each operation on each compatible machine and the relations between job operations. Such systems are paralysed when the cost of operations are not predictable led by the involvement of complex manual operations. This paper proposes a new genetic algorithm-based job shop scheduling system by integrating a fuzzy learning and inference sub-system in an effort to address this limitation. In particular, the fuzzy sub-system adaptively estimates the completion time and thus cost of each manual task under different conditions based on a knowledge base which is initialised by domain experts and then constantly updated based on its built-in learning ability and adaptability. The manufacturer of Point of Sale and Point of Purchase products is taken in this paper as an example case for both theoretical discussion and experimental study. The experimental results demonstrate the promising of the proposed system in improving the efficiency of manual manufacturing operations

EXAME DE PAPANICOLAOU: FATORES QUE INFLUENCIAM AS MULHERES A NÃO RECEBEREM O RESULTADO

The increase in providing services, prevention and treatment of cancer in the uterine neck will be limited in their application, if women do not return to receive the result of the Papanicoulau exam. Not receiving the citopathological reports means discontinued treatment, which impedes efficient therapy for detected lesions. The objective of this study is to identify the reasons that cause women not to receive the results of the preventative exams. The study was carried out with women that had their prevented exam from the year 2005 through June 2006, and did not return to receive the result. A total of 29 women collaborated in the investigation. Factors that made it difficult to receive the results of the Papanicolau exam, according to the interviewed women range from questions related to the organization of the institution to questions related to the individual woman. However, the questions related to the institution represent a percentage much higher (27.3%) in comparison with other questions. From factors that affect women not receiving the results, professionals can intervene in the hospital visit and emphasize the importance of obtaining the result and having regular follow-ups.El aumento en la prestación de servicios, prevención y tratamiento de casos de cáncer de cuello de útero tendrá limitado su ámbito de aplicación, si las mujeres no vuelven para recibir el resultado del examen de Papanicolaou. La no recepción de los informes citopatológicos acarrea discontinuidad del tratamiento, lo que impide terapias eficaces para las lesiones detectadas. Este estudio tiene como objetivo identificar las razones que llevan a las mujeres a no recibir los resultados de los exámenes de prevención. La encuesta se realizó con mujeres que han realizado su examen de prevención en el año 2005 hasta junio de 2006 y no volvieron para recibir el resultado. Un total de 29 mujeres colaboraron en la investigación. Los factores dificultadores para recibir el resultado del examen de Papanicoloau, según las mujeres entrevistadas, van desde cuestiones relacionadas con la organización de la institución a cuestiones relacionadas con la propia mujer. Sin embargo, las cuestiones relacionadas con la institución representan un porcentaje mucho mayor (27,3%) en comparación con las demás. A partir de los factores que influyen en las mujeres a no recibir los informes, los profesionales podrán intervenir en la consulta haciendo hincapié en la importancia de recibir el resultado y tener un seguimiento regular.O incremento na oferta de serviços, na prevenção e tratamento dos casos de câncer de colo uterino terá seu alcance limitado, se as mulheres não retornarem para receber o resultado do exame de Papanicolaou. O não recebimento dos laudos citopatológicos acarreta descontinuidade do tratamento, impedindo ações terapêuticas eficazes para as lesões detectadas. Este estudo teve como objetivo identificar os motivos que levam as mulheres a não receberem os resultados dos exames de prevenção. A pesquisa foi realizada com mulheres que fizeram seu exame de prevenção no ano de 2005 até junho de 2006 e não retornaram para receber o resultado. Um total de 29 mulheres colaboraram com a pesquisa. Os fatores dificultadores para o recebimento do resultado do exame de Papanicoloau, segundo as mulheres entrevistadas, perpassam desde questões ligadas à organização da instituição até questões ligadas à própria mulher. Todavia, as questões ligadas à instituição representaram uma parcela bem maior (27,3%) quando comparada às demais. A partir dos fatores que influenciam as mulheres a não receberem os laudos, os profissionais poderão intervir durante a consulta enfatizando a importância de receber o resultado e ter um seguimento regula

Decadal changes of the Western Arabian sea ecosystem

Historical data from oceanographic expeditions and remotely sensed data on outgoing longwave radiation, temperature, wind speed and ocean color in the western Arabian Sea (1950–2010) were used to investigate decadal trends in the physical and biochemical properties of the upper 300 m. 72 % of the 29,043 vertical profiles retrieved originated from USA and UK expeditions. Increasing outgoing longwave radiation, surface air temperatures and sea surface temperature were identified on decadal timescales. These were well correlated with decreasing wind speeds associated with a reduced Siberian High atmospheric anomaly. Shoaling of the oxycline and nitracline was observed as well as acidification of the upper 300 m. These physical and chemical changes were accompanied by declining chlorophyll-a concentrations, vertical macrofaunal habitat compression, declining sardine landings and an increase of fish kill incidents along the Omani coast

Transcription of toll-like receptors 2, 3, 4 and 9, FoxP3 and Th17 cytokines in a susceptible experimental model of canine Leishmania infantum infection

Canine leishmaniosis (CanL) due to Leishmania infantum is a chronic zoonotic systemic disease resulting from complex interactions between protozoa and the canine immune system. Toll-like receptors (TLRs) are essential components of the innate immune system and facilitate the early detection of many infections. However, the role of TLRs in CanL remains unknown and information describing TLR transcription during infection is extremely scarce. The aim of this research project was to investigate the impact of L. infantum infection on canine TLR transcription using a susceptible model. The objectives of this study were to evaluate transcription of TLRs 2, 3, 4 and 9 by means of quantitative reverse transcription polymerase chain reaction (qRT-PCR) in skin, spleen, lymph node and liver in the presence or absence of experimental L. infantum infection in Beagle dogs. These findings were compared with clinical and serological data, parasite densities in infected tissues and transcription of IL-17, IL-22 and FoxP3 in different tissues in non-infected dogs (n = 10), and at six months (n = 24) and 15 months (n = 7) post infection. Results revealed significant down regulation of transcription with disease progression in lymph node samples for TLR3, TLR4, TLR9, IL-17, IL-22 and FoxP3. In spleen samples, significant down regulation of transcription was seen in TLR4 and IL-22 when both infected groups were compared with controls. In liver samples, down regulation of transcription was evident with disease progression for IL-22. In the skin, upregulation was seen only for TLR9 and FoxP3 in the early stages of infection. Subtle changes or down regulation in TLR transcription, Th17 cytokines and FoxP3 are indicative of the silent establishment of infection that Leishmania is renowned for. These observations provide new insights about TLR transcription, Th17 cytokines and Foxp3 in the liver, spleen, lymph node and skin in CanL and highlight possible markers of disease susceptibility in this model

Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy

Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential (ΔΨm). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy-associated proteins, including p62/SQSTM1. Here we show that PMI promotes mitochondrial respiration, leading to a superoxide-dependent activation of mitophagy. Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimethyl fumarate (DMF), are unable to induce a similar response. Additionally, we demonstrate that SFN reverses the effects of PMI in co-treated cells by reducing the accumulation of p62 in mitochondria and subsequently limiting their autophagic degradation. This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and their potential as pharmacological agents for the treatment of pathological conditions characterized by impaired mitochondrial quality control

Step-by-step design of proteins for small molecule interaction: a review on recent milestones

Protein design is the field of synthetic biology that aims at developing de-novo custom made proteins and peptides for specific applications. Despite exploring an ambitious goal, recent computational advances in both hardware and software technologies have paved the way to high-throughput screening and detailed design of novel folds and improved functionalities. Modern advances in the field of protein design for small molecule targeting are described in this review, organized in a step-by-step fashion: from the conception of a new or upgraded active binding site, to scaffold design, sequence optimization and experimental expression of the custom protein. In each step, contemporary examples are described, and state-of-the art software is briefly explored.publishe

A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders

\ua9 2024 The AuthorsMitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre

Portfolio Approaches for Constraint Optimization Problems

International audienceWithin the Constraints Satisfiability Problems (CSP) context, a methodology that has proved to be particularly performant consists in using a portfolio of different constraint solvers. Nevertheless, comparatively few studies and investigations has been done in the world of Constraint Optimization Problems (COP). In this work, we provide a generalization to COP as well as an empirical evaluation of different state of the art existing CSP portfolio approaches properly adapted to deal with COP. Experimental results confirm the effectiveness of portfolios even in the optimization field, and could give rise to some interesting future research