Modeling spectral changes in singing voice for pitch modification

We present an advanced method to achieve natural modifications when applying a pitch shifting process to singing voice by modifying the spectral envelope of the audio ex- cerpt. To this end, an all-pole spectral envelope model has been selected to describe the global variations of the spectral envelope with the changes of the pitch. We performed a pitch shifting process of some sustained vowels with the envelope processing and without it, and compared both by means of a survey open to volunteers in our website.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This work has been funded by the Ministerio de Economía y Competitividad of the Spanish Government under Project No. TIN2013-47276-C6-2-R and by the Junta de Andalucía under Project No. P11-TIC-7154

Effect of ultrasound transducer design on the acoustically-assisted supercritical fluid extraction of antioxidants from oregano

[EN] Power ultrasound is applied in food technology to intensify extraction processes, due to the phenomena ultrasonic energy induces in the medium, enhancing mass transfer. The purpose of this work was the acoustic characterization of four transducers of different geometries and the evaluation of their performance in the ultrasonically assisted supercritical fluid extraction of antioxidants from oregano. The transducers differed in the amount of energy transmitted into the medium. Designs varied from the base model (T1), a larger cylindrical headmass (T2), a stepped circular section sonotrode (T3) and a multiplate configuration (T4). The highest nominal power density provided according to the calorimetric method was for T4 (151.6 +/- 7.1 W/L). The T2 produced a more uniform acoustic field and a higher acoustic pressure (150.6 +/- 20.5 kPa). Both parameters had an impact on total phenolics and antioxidants extraction with CO2 under supercritical conditions (35 MPa, 35 degrees C, 2.3% ethanol as co-solvent). T4 and T2 were equally efficient (4.0 +/- 0.2 and 4.2 +/- 0.2 mg GA/g) for phenolic extraction, and with respect to antioxidant capacity, the best performance was that of T4 (26.4 +/- 1.1 mu mol TE/g). Of the antioxidant compounds extracted, flavones and flavanones were identified. Therefore, transducer geometry influenced the amount and distribution of energy transmitted into the medium, thus determining the efficiency of the extraction process.This work was supported by the PROMETEOII\2014\005 project financed by the Generalitat Valenciana (Conselleria d'Educacio, Cultura i Esport, Valencia, Spain).Santos-Zea, L.; Antunes-Ricardo, M.; Gutierrez-Uribe, J.; Garcia-Perez, J.; Benedito Fort, JJ. (2018). Effect of ultrasound transducer design on the acoustically-assisted supercritical fluid extraction of antioxidants from oregano. Ultrasonics Sonochemistry. 47:47-56. https://doi.org/10.1016/j.ultsonch.2018.04.019S47564

Semaglutide in type 2 diabetes with chronic kidney disease at high risk progression—real-world clinical practice

Albuminuria; Obesity; SemaglutideAlbuminúria; Obesitat; SemaglutidaAlbuminuria; Obesidad; SemaglutidaBackground Semaglutide [glucagon-like peptide-1 receptor-agonist (GLP-1RA)] has shown nephroprotective effects in previous cardiovascular studies. However, its efficacy and safety in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) have been rarely studied. Methods This is a multicenter, retrospective, observational study in patients with T2D and CKD with glycosylated hemoglobin A1c (HbA1c) of 7.5–9.5% treated with subcutaneous semaglutide for 12 months in real-world clinical practice. The main objectives were glycemic control as HbA1c 5%. Results We studied a total of 122 patients, ages 65.50 ± 11 years, 62% men, duration of T2D 12 years, baseline HbA1c 7.57% ± 1.36% and an estimated glomerular filtration rate (eGFR) 50.32 ± 19.21 mL/min/1.73 m2; 54% had a urinary albumin:creatinine ratio (UACR) of 30–300 mg/g and 20% had a UACR >300 mg/g. After 12 months of follow-up, HbA1c declined −0.73% ± 1.09% (P 5% of their body weight. Systolic and diastolic blood pressure decreased −9.85 mmHg and −5.92 mmHg, respectively (P 300 mg/g). The mean eGFR (by the Chronic Kidney Disease Epidemiology Collaboration) remained stable. The need for basal insulin decreased 20% (P < .005). Only 7% of patients on insulin had mild hypoglycemic episodes. Semaglutide was stopped in 5.7% of patients for digestive intolerance. Conclusions In this real-world study, patients with T2D and CKD treated with subcutaneous semaglutide for 12 months significantly improved glycemic control and decreased weight. Albuminuria decreased by >50% in patients with macroalbuminuria. The administration of GLP-1RA in patients with T2D and CKD was safe and well tolerated

Glucocerebrosidase expression patterns in the non-human primate brain

Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene. Mutations in GBA1 gene lead to Gaucher’s disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alphasynuclein, a common neuropathological finding underlying Parkinson’s disease (PD) and dementia with Lewy bodies. However, it is also worth noting that a direct link between GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date. Bearing in mind that a number of strategies increasing GCase expression for the treatment of PD are currently under development, here we sought to analyze the baseline expression of GCase in the brain of Macaca fascicularis, which has often been considered as the gold-standard animal model of PD. Although as with other lysosomal enzymes, GCase is expected to be ubiquitously expressed, here a number of regional variations have been consistently found, together with several specific neurochemical phenotypes expressing very high levels of GCase. In this regard, the most enriched expression of GCase was constantly found in cholinergic neurons from the nucleus basalis of Meynert, dopaminergic cells in the substantia nigra pars compacta, serotoninergic neurons from the raphe nuclei, as well as in noradrenergic neurons located in the locus ceruleus. Moreover, it is also worth noting that moderate levels of expression were also found in a number of areas within the paleocortex and archicortex, such as the entorhinal cortex and the hippocampal formation, respectively

S-Adenosylmethionine revisited: its essential role in the regulation of liver function

Dietary methionine is mainly metabolized in the liver where it is converted into S-adenosylmethionine (AdoMet), the main biologic methyl donor. This reaction is catalyzed by methionine adenosyltransferase I/III (MAT I/III), the product of MAT1A gene, which is exclusively expressed in this organ. It was first observed that serum methionine levels were elevated in experimental models of liver damage and in liver cirrhosis in human beings. Results of further studies showed that this pathological alteration was due to reduced MAT1A gene expression and MAT I/III enzyme inactivation associated with liver injury. Synthesis of AdoMet is essential to all cells in the organism, but it is in the liver where most of the methylation reactions take place. The central role played by AdoMet in cellular function, together with the observation that AdoMet administration reduces liver damage caused by different agents and improves survival of alcohol-dependent patients with cirrhosis, led us to propose that alterations in methionine metabolism could play a role in the onset of liver disease and not just be a consequence of it. In the present work, we review the recent findings that support this hypothesis and highlight the mechanisms behind the hepatoprotective role of AdoMet

Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction

AIM: Experimental animal studies suggest that the use of skeletal myoblast in patients with myocardial infarction may result in improved cardiac function. The aim of the study was to assess the feasibility and safety of this therapy in patients with myocardial infarction. METHODS AND RESULTS: Twelve patients with old myocardial infarction and ischaemic coronary artery disease underwent treatment with coronary artery bypass surgery and intramyocardial injection of autologous skeletal myoblasts obtained from a muscle biopsy of vastus lateralis and cultured with autologous serum for 3 weeks. Global and regional cardiac function was assessed by 2D and ABD echocardiogram. 18F-FDG and 13N-ammonia PET studies were used to determine perfusion and viability. Left ventricular ejection fraction (LVEF) improved from 35.5+/-2.3% before surgery to 53.5+/-4.98% at 3 months (P=0.002). Echocardiography revealed a marked improvement in regional contractility in those cardiac segments treated with skeletal myoblast (wall motion score index 2.64+/-0.13 at baseline vs 1.64+/-0.16 at 3 months P=0.0001). Quantitative 18F-FDG PET studies showed a significant (P=0.012) increased in cardiac viability in the infarct zone 3 months after surgery. No statistically significant differences were found in 13N-ammonia PET studies. Skeletal myoblast implant was not associated with an increase in adverse events. No cardiac arrhythmias were detected during early follow-up. CONCLUSIONS: In patients with old myocardial infarction, treatment with skeletal myoblast in conjunction with coronary artery bypass is safe and feasible and is associated with an increased global and regional left ventricular function,improvement in the viability of cardiac tissue in the infarct area and no induction of arrhythmias

A humanized mouse model of HPV-associated pathology driven by E7 expression

Human papillomavirus (HPV) is the causative agent of human cervical cancer and has been associated with oropharyngeal squamous cell carcinoma development. Although prophylactic vaccines have been developed, there is a need to develop new targeted therapies for individuals affected with malignant infected lesions in these locations, which must be tested in appropriate models. Cutaneous beta HPV types appear to be involved in skin carcinogenesis. Virus oncogenicity is partly achieved by inactivation of retinoblastoma protein family members by the viral E7 gene. Here we show that the E7 protein of cutaneous beta HPV5 binds pRb and promotes its degradation. In addition, we described an in vivo model of HPV-associated disease in which artificial human skin prepared using primary keratinocytes engineered to express the E7 protein is engrafted onto nude mice. Expression of E7 in the transplants was stably maintained for up to 6 months, inducing the appearance of lesions that, in the case of HPV16 E7, histologically resembled human anogenital lesions caused by oncogenic HPVs. Moreover, it was confirmed through biomarker expression analysis via immunodetection and/or quantitative PCR from mRNA and miRNA that the 16E7-modified engrafted skin shares molecular features with human HPV-associated pretumoral and tumoral lesions. Finally, our findings indicate a decrease of the in vitro capacity of HPV5 E7 to reduce pRb levels in vivo, possibly explaining the phenotypical differences when compared with 16E7-grafts. Our model seems to be a valuable platform for basic research into HPV oncogenesis and preclinical testing of HPV-associated antitumor therapies.This work was supported by Comunidad Autonoma de Madrid (Oncocycle S2006/BIO-0232), by Ministerio de Ciencia e Innovacion (ISCIII-RETIC RD06/0020 and SAF2008-00121), and by Fundación Sandra Ibarra. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Regulation of mammalian liver methionine adenosyltransferase

S-adenosylmethionine (SAM) is an essential metabolite in all cells. SAM is the most important biological methyl group donor and is a precursor in the synthesis of polyamines. Methionine adenosyltransferase (MAT; EC 2.5.1.6) catalyzes the only known SAM biosynthetic reaction from methionine and ATP. In mammalian tissues, three different forms of MAT (MAT I, MAT III and MAT II) have been identified that are the product of two different genes (MAT1A and MAT2A). Although MAT2A is expressed in all mammalian tissues, the expression of MAT1A is primarily restricted to adult liver. In mammals, up to 85% of all methylation reactions and as much as 48% of methionine metabolism occurs in the liver, which indicates the important role of this organ in the regulation of blood methionine. Recent evidence indicates that not only is SAM the main biological methyl group donor and an intermediate metabolite in methionine catabolism, but it is also an intracellular control switch that regulates essential hepatic functions such as liver regeneration and differentiation as well as the sensitivity of this organ to injury. Therefore, knowledge of factors that regulate the activity of MAT I/III, the specific liver enzyme, is essential to understand how cellular SAM levels are controlled

Down-Regulation of hsa-miR-10a in Chronic Myeloid Leukemia CD34+ Cells Increases USF2-Mediated Cell Growth

MicroRNAs (miRNA) are small noncoding, single-stranded RNAs that inhibit gene expression at a posttranscriptional level, whose abnormal expression has been described in different tumors. The aim of our study was to identify miRNAs potentially implicated in chronic myeloid leukemia (CML). We detected an abnormal miRNA expression profile in mononuclear and CD34+ cells from patients with CML compared with healthy controls. Of 157 miRNAs tested, hsa-miR-10a, hsa-miR-150, and hsa-miR-151 were down-regulated, whereas hsa-miR-96 was up-regulated in CML cells. Down-regulation of hsa-miR-10a was not dependent on BCR-ABL1 activity and contributed to the increased cell growth of CML cells. We identified the upstream stimulatory factor 2 (USF2) as a potential target of hsa-miR-10a and showed that overexpression of USF2 also increases cell growth. The clinical relevance of these findings was shown in a group of 85 newly diagnosed patients with CML in which expression of hsa-miR-10a was down-regulated in 71% of the patients, whereas expression of USF2 was up-regulated in 60% of the CML patients, with overexpression of USF2 being significantly associated with decreased expression of hsa-miR-10a (P = 0.004). Our results indicate that down-regulation of hsa-miR-10a may increase USF2 and contribute to the increase in cell proliferation of CML implicating a miRNA in the abnormal behavior of CML

Cell walls of the dimorphic fungal pathogens Sporothrix schenckii and Sporothrix brasiliensis exhibit bilaminate structures and sloughing of extensive and intact layers

This work was supported by the Fundação Carlos Chagas de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), grants E-26/202.974/2015 and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), grants 229755/2013-5, Brazil. LMLB is a senior research fellow of CNPq and Faperj. NG acknowledged support from the Wellcome Trust (Trust (097377, 101873, 200208) and MRC Centre for Medical Mycology (MR/N006364/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD