The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We ...characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs.
Antibiotic-induced dysbiosis is a key predisposing factor for Clostridium difficile infections (CDIs), which cause intestinal disease ranging from mild diarrhea to pseudomembranous colitis. Here, we ...examined the impact of a microbiota-derived metabolite, short-chain fatty acid acetate, on an acute mouse model of CDI. We found that administration of acetate is remarkably beneficial in ameliorating disease. Mechanistically, we show that acetate enhances innate immune responses by acting on both neutrophils and ILC3s through its cognate receptor free fatty acid receptor 2 (FFAR2). In neutrophils, acetate-FFAR2 signaling accelerates their recruitment to the inflammatory sites, facilitates inflammasome activation, and promotes the release of IL-1β; in ILC3s, acetate-FFAR2 augments expression of the IL-1 receptor, which boosts IL-22 secretion in response to IL-1β. We conclude that microbiota-derived acetate promotes host innate responses to C. difficile through coordinate action on neutrophils and ILC3s.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and cerebral cortex. Biomarkers for ALS ...are essential for disease detection and to provide information on potential therapeutic targets. Aminopeptidases catalyze the cleavage of amino acids from the amino terminus of protein or substrates such as neuropeptides. Since certain aminopeptidases are known to increase the risk of neurodegeneration, such mechanisms may reveal new targets to determine their association with ALS risk and their interest as a diagnostic biomarker. The authors performed a systematic review and meta-analyses of genome-wide association studies (GWASs) to identify reported aminopeptidases genetic loci associated with the risk of ALS. PubMed, Scopus, CINAHL, ISI Web of Science, ProQuest, LILACS, and Cochrane databases were searched to retrieve eligible studies in English or Spanish, published up to 27 January 2023. A total of 16 studies were included in this systematic review, where a series of aminopeptidases could be related to ALS and could be promising biomarkers (DPP1, DPP2, DPP4, LeuAP, pGluAP, and PSA/NPEPPS). The literature reported the association of single-nucleotide polymorphisms (SNPs: rs10260404 and rs17174381) with the risk of ALS. The genetic variation rs10260404 in the DPP6 gene was identified to be highly associated with ALS susceptibility, but meta-analyses of genotypes in five studies in a matched cohort of different ancestry (1873 cases and 1861 control subjects) showed no ALS risk association. Meta-analyses of eight studies for minor allele frequency (MAF) also found no ALS association for the "C" allele. The systematic review identified aminopeptidases as possible biomarkers. However, the meta-analyses for rs1060404 of DPP6 do not show a risk associated with ALS.
Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and ...pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection.
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•Butyrate mitigates the pathogenicity of colitis induced by Clostridium difficile•Butyrate increases expression of tight junctions in epithelial cells•Butyrate reduces intestinal inflammation and bacterial translocation•HIF-1 stabilization is necessary to the protection induced by butyrate
Fachi et al. demonstrate that butyrate is able to protect the intestinal epithelium from the damage caused by Clostridium difficile toxins by stabilizing HIF-1 and increasing tight junctions, which reduces intestinal epithelial permeability, thus inhibiting intestinal inflammation and bacterial translocation.
Immune-mediated inflammatory diseases (IMIDs) are prevalent diseases. There is, however, a lack of understanding of the link between diet and IMIDs, how much dietary patterns vary between them and if ...there are food groups associated with a worsening of the disease.
To answer these questions we analyzed a nation-wide cohort of n = 11,308 patients from six prevalent IMIDs and 2050 healthy controls. We compared their weekly intake of the major food categories, and used a Mendelian randomization approach to determine which dietary changes are caused by disease. Within each IMID, we analyzed the association between food frequency and disease severity.
After quality control, n = 11,230 recruited individuals were used in this study. We found that diet is profoundly altered in all IMIDs: at least three food categories are significantly altered in each disease (P < 0.05). Inflammatory bowel diseases showed the largest differences compared to controls (n ≥ 8 categories, P < 0.05). Mendelian randomization analysis supported that some of these dietary changes, like vegetable reduction in Crohn's Disease (P = 2.5 × 10
, OR(95% CI) = 0.73(0.65, 0.80)), are caused by the disease. Except for Psoriatic Arthritis and Systemic Lupus Erythematosus, we have found ≥2 food groups significantly associated with disease severity in the other IMIDs (P < 0.05).
This cross-disease study demonstrates that prevalent IMIDs are associated to a significant change in the normal dietary patterns. This variation is highly disease-specific and, in some cases, it is caused by the disease itself. Severity in IMIDs is also associated with specific food groups. The results of this study underscore the importance of studying diet in IMIDs.
Fabaceae (legumes) is one of the largest families of flowering plants, and some members are important crops. In contrast to what we know about their great diversity or economic importance, our ...knowledge at the genomic level of chloroplast genomes (cpDNAs or plastomes) for these crops is limited.
We sequenced the complete genome of the common bean (Phaseolus vulgaris cv. Negro Jamapa) chloroplast. The plastome of P. vulgaris is a 150,285 bp circular molecule. It has gene content similar to that of other legume plastomes, but contains two pseudogenes, rpl33 and rps16. A distinct inversion occurred at the junction points of trnH-GUG/rpl14 and rps19/rps8, as in adzuki bean 1. These two pseudogenes and the inversion were confirmed in 10 varieties representing the two domestication centers of the bean. Genomic comparative analysis indicated that inversions generally occur in legume plastomes and the magnitude and localization of insertions/deletions (indels) also vary. The analysis of repeat sequences demonstrated that patterns and sequences of tandem repeats had an important impact on sequence diversification between legume plastomes and tandem repeats did not belong to dispersed repeats. Interestingly, P. vulgaris plastome had higher evolutionary rates of change on both genomic and gene levels than G. max, which could be the consequence of pressure from both mutation and natural selection.
Legume chloroplast genomes are widely diversified in gene content, gene order, indel structure, abundance and localization of repetitive sequences, intracellular sequence exchange and evolutionary rates. The P. vulgaris plastome is a rapidly evolving genome.
Abstract Background Fluid overload refractory to loop diuretic therapy can complicate acute or chronic heart failure (HF) management. The Safety and Efficacy of the Combination of Loop with ...Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) trial ( Clinicaltrials.gov identifier NCT01647932) will test the hypothesis that blocking distal tubule sodium reabsorption with hydrochlorothiazide can antagonize the renal adaptation to chronic loop diuretic therapy and improve diuretic resistance. Methods CLOROTIC is a randomized, placebo-controlled, double-blind, multicenter study. Three hundred and four patients with decompensated HF will be randomly assigned to receive hydrochlorothiazide or placebo in addition to a furosemide regimen. The main inclusion criteria are: age ≥18 years, history of chronic HF (irrespective of etiology and/or ejection fraction), admission for acute decompensation, and previous treatment with an oral loop diuretic for at least 1 month before randomization. The 2 coprimary endpoints are changes in body weight and changes in patient-reported dyspnea during hospital admission. Morbidity, mortality, and safety aspects will also be addressed. Conclusions CLOROTIC is the first large-scale trial to evaluate whether the addition of a thiazide diuretic (hydrochlorothiazide) to a loop diuretic (furosemide) is a safe and effective strategy for improving congestive symptoms resulting from HF. This trial will provide important information and will therefore have a major impact on treatment strategies and future trials in these patients.
The diversity of sorghum grains is related to their intrinsic properties, which include starch type, non-starch components and phenolic compounds. The latter are genotype dependent and affect the ...pericarp characteristics such as color and presence of a pigmented testa. This diversity can be valuable for developing new food products by thermoplastic extrusion intended for human consumption. Flours from sorghum grains from the genotypes of varied pericarp color: white (CMSXS180; 9010032), red (BRS 310; BRS 308) and light brown (BRS 305; 9929034) were processed in a co-rotating twin-screw extruder. Changes promoted by extrusion cooking were evaluated via specific mechanical energy (SME), die pressure, apparent density, sectional expansion index (SEI), water absorption index (WAI) and water solubility index (WSI). Pericarp color affected die pressure, apparent density and WSI values of extrudates. Light brown genotypes, rich in tannin and fiber content, generated the lowest die pressure and SEI values. Red genotypes presented the lowest SME and the highest WAI values. White genotypes presented intermediate SME and the highest die pressure values. These results reflect differences in starch conversion induced by the pericarp type. These results further suggest the potential use of pigmented sorghum extrudates for human consumption.
•Whole sorghum grains of colored genotypes were processed by extrusion.•Specific mechanical energy and die pressure were affected by sorghum genotype.•Fiber and tannin affected the expansion and hydration properties of the extrudates.•Potential inclusion of colored sorghum as ready-to-eat foods.
Las malas condiciones nutricionales en muchas localidades mayas de Yucatán, México, persisten, a pesar de que se han implementado diversos programas. El objetivo fue comparar los efectos de una ...intervención nutricional basada en la comunidad con enfoque intercultural (INBC) y una intervención nutricional convencional (INC), sobre el índice de masa corporal (IMC) y la dieta en mujeres de localidades mayas de Yucatán. Fueron incluidas mujeres adultas con IMC ≥ 25kg/m2 de dos pequeñas localidades rurales mayas vecinas. Ambas intervenciones fueron de tres meses y con 11 sesiones, siguiendo la normatividad vigente; en la INBC fue utilizada la herramienta intercultural, denominada Plato del Bien Comer Maya, además se incluyeron en la INBC estrategias diseñadas con base en información obtenida en una fase previa de estudio cualitativo con entrevistas. El grupo con la INBC (n = 7), en comparación con el grupo con la INC (n = 9), tuvo una mayor disminución de IMC (-0,58 ± 0,70 kg/m2 y +0,27 ± 0,64 kg/m2; p = 0,042), de la circunferencia de cintura (-2,15 ± 2,60 cm y -0,50 ± 0,75 cm; p = 0,042) y del consumo de grasas (-53,23 ± 21,92 gramos y -7,34 ± 25,77 gramos; p = 0,004), así como mayor incremento en las frecuencias semanales de consumo de algunos alimentos locales como nance (p = 0,012), tamarindo (p = 0,001) y chile (p = 0,004), la INBC fue la única que presentó una disminución significativa en el consumo diario de calorías (basal: 2.067 ± 91 kcal/día, a los tres meses: 1.474 ± 31 kcal/día; p = 0,018), hubo en ambos grupos disminuciones en el consumo de alimentos ultraprocesados, pero sin diferencias comparando los grupos; el grupo con la INBC obtuvo mejores resultados que el grupo con la INC.
As más condições nutricionais em muitas localidades maias de Yucatán (México) persistem apesar da implementação de diversos programas. O objetivo era comparar os impactos de uma intervenção nutricional baseada na comunidade com enfoque intercultural (INBC) e uma intervenção nutricional convencional (INC), sobre o índice de massa corporal (IMC) e a dieta de mulheres de localidades maias de Yucatán. Foram incluídas mulheres adultas com IMC ≥ 25kg/m2 de duas pequenas localidades rurais maias vizinhas. Ambas as intervenções duraram três meses e contaram com 11 sessões, conforme as normas vigentes; na INBC, foi utilizada a ferramenta intercultural denominada Prato de Comer Bem Maia Plato del Bien Comer Maya, além de estratégias adicionais idealizadas com base em dados obtidos em uma fase prévia de estudo qualitativo com entrevistas. Em comparação com o grupo com a INC (n = 9), o grupo com a INBC (n = 7) teve maior diminuição de IMC (-0,58 ± 0,70 kg/m2 e +0,27 ± 0,64 kg/m2; p = 0,042), da circunferência abdominal (-2,15 ± 2,60 cm y -0,50 ± 0,75 cm; p = 0,042) e do consumo de gorduras (-53,23 ± 21,92 gramas y -7,34 ± 25,77 gramas; p = 0,004), bem como um aumento maior das frequências semanais de consumo de alguns alimentos locais como o murici (p = 0,012), o tamarindo (p = 0,001) e pimenta (p = 0,004). A INBC foi a única a apresentar uma diminuição significativa do consumo diário de calorias (inicial: 2.067 ± 91 kcal/dia, após três meses: 1.474 ± 31 kcal/dia; p = 0.018). Houve em ambos os grupos redução equivalente do consumo de alimentos ultraprocessados; o grupo com a INBC obteve melhores resultados que o grupo com a INC.
Poor nutritional conditions persist in many Mayan communities in Yucatán, Mexico, even though various programs have been implemented. The study aimed to compare the effects of a community-based nutritional intervention with an intercultural focus versus a conventional nutritional intervention on body mass index (BMI) and diet in women in Mayan communities in Yucatán. The sample included adult women with BMI ≥ 25kg/m2 from neighboring rural Mayan villages. Both interventions lasted three months with 11 sessions and followed the prevailing guidelines. The community-based intervention used an intercultural tool called Good Mayan Food Plato del Bien Comer Maya, besides strategies designed according to information obtained from a prior qualitative study phase using interviews. The group that received the community-based intervention (n = 7), compared to the conventional intervention group (n = 9), showed larger decreases in BMI (-0.58 ± 0.70 kg/m2 and +0.27 ± 0.64kg/m2; p = 0.042), waist circumference (-2.15 ± 2.60 cm and -0.50 ± 0.75 cm; p = 0.042), and consumption of fats (-53.23 ± 21.92 grams and -7.34 ± 25.77 grams; p = 0.004), as well as higher increases in weekly consumption of some local foods such as nance fruit (p = 0.012), tamarind (p = 0.001), and chili peppers (p = 0.004). The community-based intervention was the only one to show a significant decrease in daily calorie intake (baseline: 2,067 ± 91 kcal/day, at three months: 1,474 ± 31 kcal/day; p = 0.018), and both groups showed decreases in the consumption of ultra-processed foods, but without significant differences between the two groups. The community-based intervention group showed better results than the conventional intervention group.
In light of the increasing rate of dengue infections throughout the world despite vector-control measures, several dengue vaccine candidates are in development.
In a phase 3 efficacy trial of a ...tetravalent dengue vaccine in five Latin American countries where dengue is endemic, we randomly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) or placebo at months 0, 6, and 12 under blinded conditions. The children were then followed for 25 months. The primary outcome was vaccine efficacy against symptomatic, virologically confirmed dengue (VCD), regardless of disease severity or serotype, occurring more than 28 days after the third injection.
A total of 20,869 healthy children received either vaccine or placebo. At baseline, 79.4% of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes. In the per-protocol population, there were 176 VCD cases (with 11,793 person-years at risk) in the vaccine group and 221 VCD cases (with 5809 person-years at risk) in the control group, for a vaccine efficacy of 60.8% (95% confidence interval CI, 52.0 to 68.0). In the intention-to-treat population (those who received at least one injection), vaccine efficacy was 64.7% (95% CI, 58.7 to 69.8). Serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3, and 77.7% for serotype 4. Among the severe VCD cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. Vaccine efficacy against hospitalization for dengue was 80.3%. The safety profile for the CYD-TDV vaccine was similar to that for placebo, with no marked difference in rates of adverse events.
The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01374516.).
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