Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca(2+) handling is a key feature of HF pathophysiology. Restoring the Ca(2+) regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp(−/−)), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF

Mapping Peptidergic Cells in Drosophila: Where DIMM Fits In

The bHLH transcription factor DIMMED has been associated with the differentiation of peptidergic cells in Drosophila. However, whether all Drosophila peptidergic cells express DIMM, and the extent to which all DIMM cells are peptidergic, have not been determined. To address these issues, we have mapped DIMM expression in the central nervous system (CNS) and periphery in the late larval stage Drosophila. At 100 hr after egg-laying, DIMM immunosignals are largely congruent with a dimm-promoter reporter (c929-GAL4) and they present a stereotyped pattern of 306 CNS cells and 52 peripheral cells. We assigned positional values for all DIMM CNS cells with respect to reference gene expression patterns, or to patterns of secondary neuroblast lineages. We could assign provisional peptide identities to 68% of DIMM-expressing CNS cells (207/306) and to 73% of DIMM-expressing peripheral cells (38/52) using a panel of 24 markers for Drosophila neuropeptide genes. Furthermore, we found that DIMM co-expression was a prevalent feature within single neuropeptide marker expression patterns. Of the 24 CNS neuropeptide gene patterns we studied, six patterns are >90% DIMM-positive, while 16 of 22 patterns are >40% DIMM-positive. Thus most or all DIMM cells in Drosophila appear to be peptidergic, and many but not all peptidergic cells express DIMM. The co-incidence of DIMM-expression among peptidergic cells is best explained by a hypothesis that DIMM promotes a specific neurosecretory phenotype we term LEAP. LEAP denotes Large cells that display Episodic release of Amidated Peptides

The Study of Composting TIME Period by Using Tofu Cesspool Activator\u27s and Fish Cesspool Activator\u27s

      Tofu and fish cesspool has contained an organic substance for microorganism growth in decomposing process of organic substances. The purpose of this research was to know the ability of tofu cesspool activators and fish cesspool activators in composting process.      The research type was pre-experiment research and used posttest only design. The independent variables are tofu cesspool activator and fish cesspool activator. Dependent variables are composting period time, temperature, pH, humidity, and C/N ratio. Data collected were measured result of parameter area, and laboratory test. The data was analyzed descriptively.      Research result indicated that in tofu cesspool activator treatment got pH, 6,9, temperature was 34,7ᴼC, humidity was 64,9% RH and C/N ratio was 13,83% and needed 12 days composting. For group of fish cesspool activator treatment got pH 7, temperature was 35,4ᴼC, humidity was 66,8%RH and C/N ratio was 17,5% and needed 14 days composting. Based on some literatures descripted best temperature was 25ᴼC-60ᴼC, and best Ph about 6.5-7.5, optimum humidity 40-60% RH, period time of composting was 2-3 weeks, and C/N best ratio was 10-20%.      Activator of tofu cesspool\u27s and fish cesspool\u27s can be used in composting process. It was suggested to community to use both activators in composting