Tailoring therapy for heart failure: the pharmacogenomics of adrenergic receptor signaling.

Heart failure is one of the leading causes of mortality in Western countries, and β-blockers are a cornerstone of its treatment. However, the response to these drugs is variable among individuals, which might be explained, at least in part, by genetic differences. Pharmacogenomics is the study of genetic contributions to drug response variability in order to provide evidence for a tailored therapy in an individual patient. Several studies have investigated the pharmacogenomics of the adrenergic receptor system and its role in the context of the use of β-blockers in treating heart failure. In this review, we will focus on the most significant polymorphisms described in the literature involving adrenergic receptors and adrenergic receptor-related proteins, as well as genetic variations influencing β-blocker metabolism

Kv7 Channel Activation Underpins EPAC-Dependent Relaxations of Rat Arteries.

OBJECTIVE: To establish the role of Kv7 channels in EPAC (exchange protein directly activated by cAMP)-dependent relaxations of the rat vasculature and to investigate whether this contributes to β-adrenoceptor-mediated vasorelaxations. APPROACH AND RESULTS: Isolated rat renal and mesenteric arteries (RA and MA, respectively) were used for isometric tension recording to study the relaxant effects of a specific EPAC activator and the β-adrenoceptor agonist isoproterenol in the presence of potassium channel inhibitors and cell signaling modulators. Isolated myocytes were used in proximity ligation assay studies to detect localization of signaling intermediaries with Kv7.4 before and after cell stimulation. Our studies showed that the EPAC activator (8-pCPT-2Me-cAMP-AM) produced relaxations and enhanced currents of MA and RA that were sensitive to linopirdine (Kv7 inhibitor). Linopirdine also inhibited isoproterenol-mediated relaxations in both RA and MA. In the MA, isoproterenol relaxations were sensitive to EPAC inhibition, but not protein kinase A inhibition. In contrast, isoproterenol relaxations in RA were attenuated by protein kinase A but not by EPAC inhibition. Proximity ligation assay showed a localization of Kv7.4 with A-kinase anchoring protein in both vessels in the basal state, which increased only in the RA with isoproterenol stimulation. In the MA, but not the RA, a localization of Kv7.4 with both Rap1a and Rap2 (downstream of EPAC) increased with isoproterenol stimulation. CONCLUSIONS: EPAC-dependent vasorelaxations occur in part via activation of Kv7 channels. This contributes to the isoproterenol-mediated relaxation in mesenteric, but not renal, arteries

Estimation of Elasticities of Substitution for CES and VES Production Functions using Firm-level Data for Food-processing Industries in Pakistan

This study, based on the time-series data covering the period from 1956 to 1986, estimates production function in the agricultural sector of Pakistan. The strategy for agricultural development in the country has been based on greater utilization of "high pay-off' low-cost technology. The government advanced loans through financial institutions to make it possible for the farmers to acquire this technology. Despite the infusion of seed-fertilizer technology, per acre yield of major crops like wheat, rice, cereal and sugar-cane in Pakistan is lower than in most LDCs in the region. Therefore, it is concluded that the use of present technology has reached a plateau and it is time to look for additional inputs for improvement in productivity

Protective role of Kv7 channels in oxygen and glucose deprivation-induced damage in rat caudate brain slices

Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since Kv7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The Kv7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Retigabine also reduced OGD-induced necrotic cell death evaluated by lactate dehydrogenase activity assay. The Kv7 blocker linopirdine increased OGD-evoked dopamine efflux and OGD-induced damage, and attenuated the effects of retigabine. Quantitative-PCR experiments showed that OGD caused an ~ 6-fold decrease in Kv7.2 transcript, while levels of mRNAs encoding for other Kv7 subunits were unaffected; western blot experiments showed a parallel reduction in Kv7.2 protein levels. Retigabine also decreased the peak level of dopamine efflux induced by L-glutamate, and attenuated the loss of TTC staining induced by the excitotoxin. These results suggest a role for Kv7.2 in modulating ischemia-evoked caudate damage

Identifying the oncogenic potential of gene fusions exploiting miRNAs

It is estimated that oncogenic gene fusions cause about 20% of human cancer morbidity. Identifying potentially oncogenic gene fusions may improve affected patients’ diagnosis and treatment. Previous approaches to this issue included exploiting specific gene-related information, such as gene function and regulation. Here we propose a model that profits from the previous findings and includes the microRNAs in the oncogenic assessment. We present ChimerDriver, a tool to classify gene fusions as oncogenic or not oncogenic. ChimerDriver is based on a specifically designed neural network and trained on genetic and post-transcriptional information to obtain a reliable classification. The designed neural network integrates information related to transcription factors, gene ontologies, microRNAs and other detailed information related to the functions of the genes involved in the fusion and the gene fusion structure. As a result, the performances on the test set reached 0.83 f1-score and 96% recall. The comparison with state-of-the-art tools returned comparable or higher results. Moreover, ChimerDriver performed well in a real-world case where 21 out of 24 validated gene fusion samples were detected by the gene fusion detection tool Starfusion. ChimerDriver integrates transcriptional and post-transcriptional information in an ad-hoc designed neural network to effectively discriminate oncogenic gene fusions from passenger ones. ChimerDriver source code is freely available at https://github.com/martalovino/ChimerDriver

Identifying the oncogenic potential of gene fusions exploiting miRNAs

It is estimated that oncogenic gene fusions cause about 20% of human cancer morbidity. Identifying potentially oncogenic gene fusions may improve affected patients’ diagnosis and treatment. Previous approaches to this issue included exploiting specific gene-related information, such as gene function and regulation. Here we propose a model that profits from the previous findings and includes the microRNAs in the oncogenic assessment. We present ChimerDriver, a tool to classify gene fusions as oncogenic or not oncogenic. ChimerDriver is based on a specifically designed neural network and trained on genetic and post-transcriptional information to obtain a reliable classification. The designed neural network integrates information related to transcription factors, gene ontologies, micro RNAs and other detailed information related to the functions of the genes involved in the fusion and the gene fusion structure. As a result, the performances on the test set reached 0.83 f1-score and 96% recall. The com parison with state-of-the-art tools returned comparable or higher results. Moreover, ChimerDriver performed well in a real-world case where 21 out of 24 validated gene fusion samples were detected by the gene fusion detection tool Starfusion. ChimerDriver integrates transcriptional and post-transcriptional information in an ad-hoc designed neural network to effectively discriminate oncogenic gene fusions from passenger ones. ChimerDriver source code is freely available at https://github.com/martalovino/ChimerDriver

Decoding Methods for Linear Codes

It is necessary to encode data when transmitting over a noisy channel in order for errors to be detected and corrected. List decoding algorithms provide all code words within a specified distance of a received word in order to be sufficiently robust for cases when two or more code words are equidistant from a received word. This paper details a probabilistic method to obtain multiple close code words, motivated by list decoding methods, for linear codes over fields of two or three elements. It employs a variation on the LLL-Algorithm for lattice reduction that allows the LLL-Algorithm to determine small elements in a vector space. Although it fails to return all code words within a specified distance of a received word, the method is sufficiently robust to provide some information if a received word is equidistant to multiple code words

Specification of skeletal muscle differentiation by repressor element-1 silencing transcription factor (REST)-regulated Kv7.4 potassium channels

Changes in the expression of potassium (K(+)) channels is a pivotal event during skeletal muscle differentiation. In mouse C(2)C(12) cells, similarly to human skeletal muscle cells, myotube formation increased the expression of K(v)7.1, K(v)7.3, and K(v)7.4, the last showing the highest degree of regulation. In C(2)C(12) cells, K(v)7.4 silencing by RNA interference reduced the expression levels of differentiation markers (myogenin, myosin heavy chain, troponinT-1, and Pax3) and impaired myotube formation and multinucleation. In K(v)7.4-silenced cells, the differentiation-promoting effect of the K(v)7 activator N-(2-amino-4-(4-fluorobenzylamino)-phenyl)-carbamic acid ethyl ester (retigabine) was abrogated. Expression levels for the repressor element-1 silencing transcription factor (REST) declined during myotube formation. Transcript levels for K(v)7.4, as well as for myogenin, troponinT-1, and Pax3, were reduced by REST overexpression and enhanced upon REST suppression by RNA interference. Four regions containing potential REST-binding sites in the 5′ untranslated region and in the first intron of the K(v)7.4 gene were identified by bioinformatic analysis. Chromatin immunoprecipitation assays showed that REST binds to these regions, exhibiting a higher efficiency in myoblasts than in myotubes. These data suggest that K(v)7.4 plays a permissive role in skeletal muscle differentiation and highlight REST as a crucial transcriptional regulator for this K(+) channel subunit