Decreased myocardial injury and improved contractility after administration of a peptide derived against the alpha-interacting domain of the L-type calcium channel.

BackgroundMyocardial infarction remains the leading cause of morbidity and mortality associated with coronary artery disease. The L-type calcium channel (IC a-L) is critical to excitation and contraction. Activation of the channel also alters mitochondrial function. Here, we investigated whether application of a alpha-interacting domain/transactivator of transcription (AID-TAT) peptide, which immobilizes the auxiliary β2 subunit of the channel and decreases metabolic demand, could alter mitochondrial function and myocardial injury.Methods and resultsTreatment with AID-TAT peptide decreased ischemia-reperfusion injury in guinea-pig hearts ex vivo (n=11) and in rats in vivo (n=9) assessed with uptake of nitroblue tetrazolium, release of creatine kinase, and lactate dehydrogenase. Contractility (assessed with catheterization of the left ventricle) was improved after application of AID-TAT peptide in hearts ex vivo (n=6) and in vivo (n=8) up to 12 weeks before sacrifice. In search of the mechanism for the effect, we found that intracellular calcium ([Ca(2+)]i, Fura-2), superoxide production (dihydroethidium fluorescence), mitochondrial membrane potential (Ψm, JC-1 fluorescence), reduced nicotinamide adenine dinucleotide production, and flavoprotein oxidation (autofluorescence) are decreased after application of AID-TAT peptide.ConclusionsApplication of AID-TAT peptide significantly decreased infarct size and supported contractility up to 12 weeks postcoronary artery occlusion as a result of a decrease in metabolic demand during reperfusion

Evaluasi Peningkatan Kinerja Produksi Melalui Penerapan Total Productive Maintenance Di PT Xacti Indonesia

Peningkatan kinerja produksi di industri manufaktur sangat penting dalam upaya peningkatkan produktivitas. Salah satu cara untuk meningkatkan kinerja produksi yaitu melalui penerapan Total Productive Maintenance (TPM). Tujuan penelitian ini, yaitu mengidentifikasi penerapan Total Productive Maintenance di PT Xacti Indonesia, menghitung kinerja produksi dengan menggunakan Overall Equipment Effectiveness (OEE), dan mengevaluasi faktor-faktor penyebab rendahnya kinerja produksi dan memberikan solusi perbaikan. Metode analisis data yang digunakan adalah Overall Equipment Effectiveness (OEE). Hasil dari penelitian ini, yaitu Perusahaan telah menerapkan TPM, namun masih ada operator yang lalai dalam melakukan 5S dan pada implementasi pilar-pilar autonomous maintenance masih perlu dilakukan perbaikan. Rata-rata nilai OEE selama bulan Januari 2014 hingga Januari 2015 sebesar 70,4%. Rendahnya nilai OEE disebabkan oleh mesin sering mengalami idle, waktu siklus aktual mesin tinggi karena kurangnya kegiatan preventive maintenance, dan tingginya downtime. Solusi perbaikan yang diberikan yaitu memberikan training kembali kepada operator tentang 5S, meningkatkan kegiatan preventive maintenance secara benar, dan dibuatnya cleaning room untuk sedapat mungkin menghindari terjadinya breakdown mesin

Optimization of carbon and energy utilization through differential translational efficiency.

Control of translation is vital to all species. Here we employ a multi-omics approach to decipher condition-dependent translational regulation in the model acetogen Clostridium ljungdahlii. Integration of data from cells grown autotrophically or heterotrophically revealed that pathways critical to carbon and energy metabolism are under strong translational regulation. Major pathways involved in carbon and energy metabolism are not only differentially transcribed and translated, but their translational efficiencies are differentially elevated in response to resource availability under different growth conditions. We show that translational efficiency is not static and that it changes dynamically in response to mRNA expression levels. mRNAs harboring optimized 5'-untranslated region and coding region features, have higher translational efficiencies and are significantly enriched in genes encoding carbon and energy metabolism. In contrast, mRNAs enriched in housekeeping functions harbor sub-optimal features and have lower translational efficiencies. We propose that regulation of translational efficiency is crucial for effectively controlling resource allocation in energy-deprived microorganisms

BCR-ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein

Patients with chronic myeloid leukemia in whom tyrosine kinase inhibitors (TKIs) fail often present mutations in the BCR-ABL catalytic domain. We noticed a lack of substitutions involving 4 amino acids (E286, M318, I360, and D381) that form hydrogen bonds with ponatinib. We therefore introduced mutations in each of these residues, either preserving or altering their physicochemical properties. We found that E286, M318, I360, and D381 are dispensable for ABL and BCR-ABL protein stability but are critical for preserving catalytic activity. Indeed, only a "conservative" I360T substitution retained kinase proficiency and transforming potential. Molecular dynamics simulations of BCR-ABLI360T revealed differences in both helix αC dynamics and protein-correlated motions, consistent with a modified ATP-binding pocket. Nevertheless, this mutant remained sensitive to ponatinib, imatinib, and dasatinib. These results suggest that changes in the 4 BCR-ABL residues described here would be selected against by a lack of kinase activity or by maintained responsiveness to TKIs. Notably, amino acids equivalent to those identified in BCR-ABL are conserved in 51% of human tyrosine kinases. Hence, these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.This work was supported by an investigator grant to P.V. from Associazione Italiana per la Ricerca sul Cancro (AIRC) and by funding from the Biotechnology and Biological Sciences Research Council (BB/I023291/1 and BB/H018409/1 to AP and FF). P.B. is the recipient of an AIRC - Marie Curie fellowship

Metabolic Factors and Their Influence on the Clinical Course and Response to HCV Treatment

Nowadays, direct-acting antivirals (DAA) have been used for hepatitis C virus (HCV) treatment leading to cure in 90–95% of non-cirrhotic patients depending on genotype, treatment experience, and regimen used. It was observed rates of antiviral response above 90% in compensated cirrhotic patients that should be treated for long time and/or ribavirin may be required. Metabolic syndrome, obesity, and insulin resistance are increasing worldwide and further contribute to hepatic steatosis and have long been recognized as a cause of lipid deposition in the liver. These factors affect the rate of antiviral response to interferon-based therapy, but it seems not impact DAA treatment. The effect of HCV eradication on hepatic steatosis and progression to fibrosis, cirrhosis, and hepatocellular carcinoma warrants further study in the era of direct-acting antivirals. Other factors that could be related to increase liver damage are vitamin D and associated polymorphisms. Patients with low concentration of total vitamin D [25(OH)D] presented high degree of fibrosis and high values of total cholesterol and triglycerides. In this chapter, we review the challenges and metabolic pathology associated with HCV infection and, discuss the influence of some metabolic factors which can cause liver damage

Amplituhedron meets Jeffrey-Kirwan Residue

The tree amplituhedra A^(m)_n,k are mathematical objects generalising the notion of polytopes into the Grassmannian. Proposed for m=4 as a geometric construction encoding tree-level scattering amplitudes in planar N=4 super Yang-Mills theory, they are mathematically interesting for any m. In this paper we strengthen the relation between scattering amplitudes and geometry by linking the amplituhedron to the Jeffrey-Kirwan residue, a powerful concept in symplectic and algebraic geometry. We focus on a particular class of amplituhedra in any dimension, namely cyclic polytopes, and their even-dimensional conjugates. We show how the Jeffrey-Kirwan residue prescription allows to extract the correct amplituhedron volume functions in all these cases. Notably, this also naturally exposes the rich combinatorial and geometric structures of amplituhedra, such as their regular triangulations.Peer reviewedFinal Accepted Versio

Exhaustive Screening of the Acid β-Glucosidase Gene, by Fluorescence-Assisted Mismatch Analysis Using Universal Primers: Mutation Profile and Genotype/Phenotype Correlations in Gaucher Disease

SummaryGaucher disease (GD) is one of the most prevalent lysosomal storage disorders and one of the rare genetic diseases now accessible to therapy. Outside the Ashkenazi Jewish community, a high molecular diversity is observed, leaving ∼30% of alleles undetected. Nevertheless, very few exhaustive methods have been developed for extensive gene screening of a large series of patients. Our approach for a complete search of mutations was the association of fluorescent chemical cleavage of mismatches with a universal strand-specific labeling system. The glucocerebrosidase (GBA) gene was scanned by use of a set of six amplicons, comprising 11 exons, all exon/intron boundaries, and the promoter region. By use of this screening strategy, the difficulties due to the existence of a highly homologous pseudogene were easily overcome, and both GD mutant alleles were identified in all 25 patients studied, thus attesting to a sensitivity that approaches 100%. A total of 18 different mutations and a new glucocerebrosidase haplotype were detected. The mutational spectrum included eight novel acid β-glucosidase mutations: IVS2 G(+1)→T, I119T, R170P, N188K, S237P, K303I, L324P, and A446P. These data further indicate the genetic heterogeneity of the lesions causing GD. Established genotype/phenotype correlations generally were confirmed, but notable disparities were disclosed in several cases, thus underlining the limitation in the prognostic value of genotyping. The observed influence of multifactorial control on this monogenic disease is discussed