Taxa de crescimento e fragmentação Miofibrilar diferenciadas em ratos submetidos a restrição alimentar e realimentação

Feed regimens alter muscle growth rate, hence they might impact the proteolytic system involved in tenderization during meat conditioning. The aim of this project was to verify the effects of feed restriction regimens on muscular and animal growth and their impact on postmortem myofibrillar fragmentation. The regimens were: 1) Feeding ad libitum for 11 d (Al/2); 2) Feed restriction (60% of Net Energy for maintenance - NEm) for 11 d (Rt/2); 3) Ad libitum for 22 d (Al); 4) Ad libitum for 4 d and feed restriction (60% NEm) for 18 d (Rt); 5) Ad libitum for 19 d and 3 d of fast (Ft); 6) Feed restriction (60% NEm) for 11 d and ad libitum until 22 d (Ral). The regimens Al/2 and Rt/2 had different intestine weights (19.3 &plusmn; 1.1 and 15.8 &plusmn; 1.9 g, respectively; P < 0.07). At 22 d, Al animals had higher (P < 0.07) intestine weight (21.8 &plusmn; 3.8). Moreover, Ral animals had heavier intestine (19.9 &plusmn; 1.5) as compared to Rt (16.6 &plusmn; 1.6) or Ft (12.8 &plusmn; 1.9). The intestine/live weight percentage ratio was lower (P < 0.05) for Ft (6.3%) as compared to Al (8.4%) and to Ral (9.2%), but it was similar to Rt (7.6%). Liver weight (g) in the Ral (9.5 &plusmn; 1.1) did not differ from Al (10.7 &plusmn; 2.5) or Rt (8.5 &plusmn; 1.1), although the two latter were different (P < 0.05). There was an effect of feed restriction over muscle protein degradation verified by Myofibrillar Fragmentation Index (MFI). The animals at Rt, Ft or Ral showed the lowest MFI 0d (42 &plusmn; 1.9; 40 &plusmn; 2.7; 40 &plusmn; 3.6; respectively) and MFI 5d (77 &plusmn; 2.7; 74 &plusmn; 3.0; 74 &plusmn; 2.9; respectively) as compared to Al, whose indexes were 54 &plusmn; 3.0 and 82 &plusmn; 3.3. Even though the MFI 5d were lower for the restricted animals, the rates of fragmentation postmortem were higher. Feed restriction altered myofibrillar protein degradation, reflected in lower extended fragmentation of the myofibrils.Regimes alimentares alteram a taxa de crescimento muscular, e podem impactar o sistema proteolítico envolvido no amaciamento da carne durante maturação. O objetivo do trabalho foi verificar a existência de reflexo do regime alimentar sobre crescimento animal e muscular, e o impacto na fragmentação miofibrilar pós-morte. Os regimes foram: 1) Consumo ad libitum por 11 d (Al/2); 2) Restrição alimentar (60% energia de mantença - NEm) por 11 d (Rt/2); 3) Ad libitum por 22 d (Al); 4) Ad libitum por 4 d e restrição alimentar (60% NEm) por 18 d (Rt); 5) Ad libitum por 19 d e 3 d de jejum (Ft); 6) Restrição alimentar (60% NEm) por 11 d e ad libitum até 22 d (Ral). Os regimes Al/2 e Rt/2 apresentaram diferenças no peso de intestino (19,3 &plusmn; 1,1 e 15,8 &plusmn; 1,9 g, respectivamente; P < 0,07). Nos 22 d, o regime Al resultou em intestinos mais pesados (P < 0,07; 21,8 &plusmn; 3,8). Além disso, os animais do regime Ral tiveram maiores pesos de intestino (19,9 &plusmn; 1,5) comparados com Rt (16,6 &plusmn; 1,6) ou Ft (12,8 &plusmn; 1,9). A relação intestino/peso vivo foi menor (P < 0,05) para Ft (6,3%) comparado com Al (8,4%) e com Ral (9,2%), mas foi similar ao Rt (7,6%). O peso do fígado (g) nos animais do regime Ral (9,5 &plusmn; 1,1) não diferiu do regime Al (10,7 &plusmn; 2,5) ou Rt (8,5 &plusmn; 1,1), sendo que os dois últimos foram diferentes (P < 0,05). Houve efeito da restrição alimentar sobre a degradação da proteína muscular verificada pelo Índice de Fragmentação miofibrilar (MFI). Os animais de Rt, Ft ou Ral mostraram os menores valores de MFI 0d (42 &plusmn; 1,9; 40 &plusmn; 2,7; 40 &plusmn; 3,6; respectivamente) e MFI 5d (77 &plusmn; 2,7; 74 &plusmn; 3,0; 74 &plusmn; 2,9; respectivamente) comparados com Al onde os índices foram 54 &plusmn; 3,0 e 82 &plusmn; 3,3, respectivamente. Embora os animais que experimentaram alguma restrição alimentar tenham apresentado menor MFI 5d, as sua taxas de fragmentação pós-morte foram maiores. Restrição alimentar alterou a degradação da proteína miofibrilar, refletida na menor extensão da fragmentação das miofibrilas

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

The expression of calpastatina isoform responsive of ractopamine modifies meat tenderness, with implications on efficiency of swine growth

O mercado consumidor está cada vez mais exigente com relação à qualidade dos produtos cárneos. A ractopamina exerce influência pronunciada sobre as variáveis de desempenho, aumentando, principalmente, o percentual de carne magra, por meio da redução da espessura de toucinho e aumento da área de olho de lombo. Porém estas modificações são acompanhadas de redução na qualidade da carne, alterando cor e principalmente maciez, pois a ractopamina atua na expressão de isoformas da calpastatina, inibidor do processo de amaciamento da carne. Sessenta animais (30 machos castrados e 30 fêmeas), sendo 30 Large White (LW) e 30 Duroc (DU) foram divididos aleatoriamente em grupos que receberam diferentes doses de ractopamina (RAC): 0 (controle), 10 ppm e 20 ppm na dieta. O fornecimento de RAC iniciou-se quando os animais atingiram 85,0 kg±6.5 de peso vivo e terminou quatro semanas depois com os animais pesando 115,0 kg±11,0. Após o abate, as carcaças foram resfriadas por 24 horas e as medições de pH e temperatura foram feitas 0, 3, 6, 9 e 24 horas. O músculo L. dorsi da meia carcaça direita foi separado para medição da área de olho do lombo (AOL), espessura de gordura subcutânea (EG) e cor 24 horas. Amostras do mesmo músculo foram separadas para quantificação da expressão gênica relativa das três isoformas (Calp1 - 1xa; Calp2 - 1xb; Calp 3 - 1u) do gene da calpastatina e relacionadas com índice de fragmentação miofibrilar, medido 0, 3 e 5 dias pós-abate, e força de cisalhamento 1 e 5 dias pós-abate. Houve melhora na conversão alimentar para os animais tratados com RAC. Os animais LW apresentaram maior AOL do que os animais DU. Fêmeas e machos apresentaram diferença na AOL. A EG apresentou interação entre raça e sexo e ainda apresentou diferenças entre as doses de RAC e também quando comparadas com o controle. A carne dos animais DU apresentou valores superiores para a* e b*, e menor valor de pH final comparada as amostras de LW, gerando carne com coloração vermelha mais clara. Os resultados confirmam a produção de carne mais magra quando adicionado ractopamina na dieta, entretanto nestas raças puras a adição de RAC não influenciou na AOL. Em relação às isoformas, a Calp 1 e 3 foram expressas em quantidades muito acima da isoforma Calp 2, esta ultima apresentando esperada baixa expressão. Os animais DU apresentaram, tanto no dia 1 como no dia 5, uma menor força de cisalhamento em relação aos animais Large White e isto pode ser explicado pelo aumento da expressão da isoforma Calp1 nesses últimos, o mesmo ocorrendo quando houve o fornecimento da ractopamina. Os animais tratados com 10 e 20 ppm apresentaram uma maior força de cisalhamento, que coincidiu com aumento da expressão da isoforma Calp 1. O índice de fragmentação miofibrilar foi inferior para todos os tempos pós-abate para 20 ppm de ractopamina e para ou 0 e 5 dias pós-abate em animais DU. Houve alta correlação positiva entre nível de expressão da Calp1 e força de cisalhamento. Portanto a raça e a dose influenciaram na expressão relativa das isoformas de calpastatina, o que alterou a maciez da carne suína.The consumer market is each more demanding time with relation to the meat quality products. Ractopamine exerts sharp influence on performance variable, increasing, meanly, percentage of lean meat, by reduction of fat thickness and increase of rib eye area. However these modifications are associate with reduction in meat quality, as color and meanly tenderness, therefore the ractopamine acts in the isoforms expression of calpastatina, inhibitor of muscular proteolysis process. Sixty animals (30 barrows and 30 gilts) being 30 Large White (LW) and 30 Duroc (DU) were randomly assigned to different doses of ractopamine (RAC): 0 (control), 10 ppm and 20 ppm in the diet. The animals were fed with RAC after 10 weeks of their arrival and 85.0 kg±6.5 of live weight and ended up 4 weeks later with animals at 115.0 kg±11.0. After slaughter, carcasses were cooled for 24h and pH and temperature measurements were 0, 3, 6, 9 and 24h after slaughter. The L. dorsi muscle was collected 24h PM from the right carcass side for rib eye area (REA), fat thickness (FT) and color measurements Samples of the same muscle had been separate for quantification of relative gene expression of three isoformas (Calp1 - 1xa; Calp2 - 1xb; Calp 3 - 1u) of calpastatin gene and related with myofibrillar fragmentation index, measured 0, 3 and 5 days after slaughter, and shear force 1 and 5 days after slaughter. Reaching an improvement of feed conversion on animals with RAC. LW animals had greater REA than DU breed. Sex condition influenced REA. FT presented interaction between breeds and sex condition and were different between RAC doses and also compared to the control diet. The DU meat presented superior values for a* and b*, and also lower ultimate pH value compared to LW, generating meat with reddish pink color. The results confirmed the production on leaner carcasses when RAC is added to diet. However, in those pure breeds doses of RAC did not modify REA. In relation isoforms, Calp 1 and 3 were express in amounts very high of Calp2 isoform, this last presenting waited low expression. Animals DU presented, on day 1 and day 5, a low shear in relation to animals Large White and this can be explained by the increase of the Calp1 isoform expression in these last ones, the same occur when ractopamina was supplied. Treated animals with 10 and 20 ppm presented a higher shear force, that coincided with increase of Calp1 isoform expression. The myofibrillar fragmentation index was low for all times after slaughter for 20 ppm of ractopamina and for 0 and 5 days after slaughter on animals DU. High positive correlation between level of Calp1 expression and shear force was founded. Therefore breed and dose influenced on relative expression of calpastatina isoforms, that modified swine meat tenderness

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)

COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p