Affect Amino Acid Research Articles

Short-Term Changes in Aroma-Related Volatiles in Meat Model: Effect of Fat and D. hansenii Inoculation.

This study assessed the effect of replacing pork lard with coconut oil and Debaryomyces hansenii inoculation on the biotransformation of amino acids into volatile compounds in a meat model system. Yeast counts, solid-phase microextraction, and gas chromatography/mass spectrometry were used to assess yeast growth and volatile production, respectively. Yeast growth was confirmed until 28 d, although the volatile profile changed until 39 d. Forty-three volatiles were quantified, and their odor activity values (OAVs) were calculated. The presence of fat and yeasts contributed to differences in volatiles. In pork lard models, a delayed formation of lipid-derived aldehyde compounds was observed, whereas in coconut oil models, the generation of acid compounds and their respective esters was enhanced. Yeast activity affected amino acid degradation, which produced an increase in branched-chain aldehydes and alcohols. The aroma profile in the coconut models was influenced by hexanal, acid compounds, and their respective esters, whereas in pork lard models, aroma was affected by methional (musty, potato) and 3-methylbutanal (green, cocoa). The yeast inoculation contributed to the generation of 3-methylbutanoic acid (cheesy) and phenylethyl alcohol (floral). The type of fat and yeast inoculation produced a differential effect on the aroma.

Integrative analysis of metabolome and genome-wide transcriptome reveal the flavor changes in apple (Malus pumila Mill) after the novel acaricide cyflumetofen application

Pesticide residues were found to interfere the nutrition and flavor of fruits. Apple flavor changes after pesticides application was investigated based on metabolic dynamics and underlying regulatory networks. In this study, cyflumetofen (CYF) systematically affected the nutrition and flavor formation on apple (Malus pumila Mill). CYF alters nutritional composition, but not total content of soluble sugars and organic acids. Palatability-related amino acid content decreased around 15% in CYF-treated apple. The contents of esters and alcohols responsible for fragrance and flavor decreased by approximately 10% in CYF-treated apples compared with controls. Non-target metabolomic and transcriptomic analysis showed that CYF mainly affected amino acid-, organic acid-, polyphenol-, and lipid-metabolism related pathways, leading to altered nutritional and flavor characteristics. In conclusion, the results suggested that CYF affected the primary metabolism of apple, resulting in unpleasant changes in nutritional and flavor composition. This study provided new insight into the metabolic regulation of flavor after pesticides application.

Selenium-Chitosan Treatment Affects Amino Acid Content and Volatile Components of Red Globe Grape during Storage

Flavor is an essential attribute of grapes, but it quickly deteriorates and loses its quality. This study examined the effects of the selenium-chitosan treatment on the amino acid content and volatile components of freshly harvested grapes stored at 0°C. The amount and composition of precursors such as fatty acids and amino acids have an important influence on the formation of aroma compounds. In this article, the amino acids, volatile components, and some enzyme activities of different treated grapes were analyzed. The results of the analysis of free amino acid composition indicated that the selenium-chitosan treatment significantly reduced the loss of amino acid content by inhibiting the activities of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and pyruvate dehydrogenase (PDH). The analysis also revealed that the significant differences in alcohol and aldehyde compounds primarily accounted for the variation in volatile components between treatments. The selenium-chitosan treatment slowed the decline in the content of aldehyde compounds and inhibited the increase in the range of alcohol compounds. These findings demonstrated that treatment with 25 mg L-1 selenium mixed with 1.0% chitosan solution has a positive effect on maintaining the flavor of Red Globe grapes. This treatment is worthy of future promotion.

Exercise Metabolome: Insights for Health and Performance.

Exercise has many benefits for physical and mental well-being. Metabolomics research has allowed scientists to study the impact of exercise on the body by analyzing metabolites released by tissues such as skeletal muscle, bone, and the liver. Endurance training increases mitochondrial content and oxidative enzymes, while resistance training increases muscle fiber and glycolytic enzymes. Acute endurance exercise affects amino acid metabolism, fat metabolism, cellular energy metabolism, and cofactor and vitamin metabolism. Subacute endurance exercise alters amino acid metabolism, lipid metabolism, and nucleotide metabolism. Chronic endurance exercise improves lipid metabolism and changes amino acid metabolism. Acute resistance exercise changes several metabolic pathways, including anaerobic processes and muscular strength. Chronic resistance exercise affects metabolic pathways, resulting in skeletal muscle adaptations. Combined endurance-resistance exercise alters lipid metabolism, carbohydrate metabolism, and amino acid metabolism, increasing anaerobic metabolic capacity and fatigue resistance. Studying exercise-induced metabolites is a growing field, and further research can uncover the underlying metabolic mechanisms and help tailor exercise programs for optimal health and performance.

All roads lead to Rome: inter-origin variation in metabolomics reprogramming of the northern shrimp exposed to global changes leads to a comparable physiological status

Impacts of global ocean changes on species have historically been investigated at the whole-organism level. However, acquiring an in-depth understanding of the organisms’ cellular metabolic responses is paramount to better define their sensitivity to environmental challenges. This is particularly relevant for species that experience highly different environmental conditions across their distribution range as local acclimatization or adaptation can influence their responses to rapid global ocean changes. We aimed at shedding light on the cellular mechanisms underpinning the sensitivity to combined ocean warming (OW) and acidification (OA) in the northern shrimp Pandalus borealis, from four different geographic origins defined by distinctive environmental regimes in the northwest Atlantic: i.e. St. Lawrence Estuary (SLE), Eastern Scotian Shelf (ESS), Esquiman Channel (EC) and Northeast Newfoundland Coast (NNC). We characterized targeted metabolomics profiles of the muscle of shrimp exposed to three temperatures (2, 6 or 10°C) and two pH levels (7.75 or 7.40). Overall, shrimp metabolomics profiles were modulated by a significant interaction between temperature, pH and origin. Temperature drove most of the metabolomics reprogramming, confirming that P. borealis is more sensitive to OW than OA. Inter-origin differences in metabolomics profiles were also observed, with temperature*pH interactions impacting only shrimp from SLE and ESS, pH affecting only shrimp from SLE and temperature impacting shrimp from all origins. Temperature influenced metabolomics pathways related to the tricarboxylic acid cycle (TCA) and amino acid metabolism, resulting mainly in an accumulation of TCA intermediates and tyrosine. Temperature*pH and pH in isolation only affected amino acid metabolism, leading to amino acids accumulation under low pH. However, the ratio of ATP : ADP remained constant across conditions in shrimp from all origins suggesting that their energetic status is not affected by OW and OA. Still, the accumulation of TCA intermediates and tyrosine suggests the possible enhancement of immune responses under future OW and OA conditions. Our findings suggest that shrimp from SLE are more sensitive at the molecular level, compared to others, to future complex environmental conditions. This underlines the importance of investigating intraspecific variation in mechanisms of responses to combined drivers when trying to define species’ sensitivity to global ocean changes.

Perturbations of gut microbiome and metabolome of pigs infected with Mycoplasma hyorhinis.

Mycoplasma hyorhinis is a prevalent respiratory pathogen in swine, causing significant economic loss to pig producers. There is growing evidence that respiratory pathogen infections have a great impact on intestinal microecology. To study the effect of M. hyorhinis infection on gut microbial composition and metabolome profile, we infected pigs with M. hyorhinis and performed metagenomic sequencing analysis of fecal sample and liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of gut digesta. RESULTS: It is discovered that pigs infected with M. hyorhinis can enrich Sutterella and Mailhella, and deplete Dechloromonas, Succinatimonas, Campylobacter, Blastocystis, Treponema and Megasphaera. Moreover, the M. hyorhinis infected pigs had higher abundances of bacterium_0_1xD8_71, Ruminococcus_sp__CAG_353, Firmicutes_bacterium_CAG_194, Firmicutes_bacterium_CAG_534, bacterium_1xD42_87, etc., and lower abundances of Chlamydia_suis, Megasphaera_elsdenii, Treponema_porcinum, Bacteroides_sp__CAG_1060, Faecalibacterium_prausnitzii, etc. Metabolomics analysis revealed that some lipids and lipid-like molecules were increased in small intestine, while most of lipids and lipid-like molecules metabolites were decreased in large intestine. These altered metabolites induce changes in intestinal sphingolipid metabolism, amino acid metabolism and thiamine metabolism. These findings demonstrate that the pigs infection with M. hyorhinis can alter the gut microbial composition and metabolites structure, which may further affect amino acid metabolism and lipid metabolism in intestine. This article is protected by copyright. All rights reserved.

Metabolic profiles reflect weight loss maintenance and the composition of diet after very-low-energy diet

Diet and weight loss affect circulating metabolome. However, metabolite profiles induced by different weight loss maintenance diets and underlying longer term weight loss maintenance remain unknown. Herein, we investigated after-weight-loss metabolic signatures of two isocaloric 24-wk weight maintenance diets differing in satiety value due to dietary fibre, protein and fat contents and identified metabolite features that associated with successful weight loss maintenance. Non-targeted LC-MS metabolomics approach was used to analyse plasma metabolites of 79 women and men (mean age±SD 49.7±9.0 years; BMI 34.2±2.5kg/m2) participating in a weight management study. Participants underwent a 7-week very-low-energy diet (VLED) and were thereafter randomised into two groups for a 24-week weight maintenance phase. Higher satiety food (HSF) group consumed high-fibre, high-protein, and low-fat products, while lower satiety food (LSF) group consumed isocaloric low-fibre products with average protein and fat content as a part of their weight maintenance diets. Plasma metabolites were analysed before the VLED and before and after the weight maintenance phase. Metabolite features discriminating HSF and LSF groups were annotated. We also analysed metabolite features that discriminated participants who maintained ≥10% weight loss (HWM) and participants who maintained <10% weight loss (LWM) at the end of the study, irrespective of the diet. Finally, we assessed robust linear regression between metabolite features and anthropometric and food group variables. We annotated 126 metabolites that discriminated the HSF and LSF groups and HWM and LWM groups (p<0.05). Compared to LSF, the HSF group had lower levels of several amino acids, e.g. glutamine, arginine, and glycine, short-, medium- and long-chain acylcarnitines (CARs), odd- and even-chain lysoglycerophospholipids, and higher levels of fatty amides. Compared to LWM, the HWM group in general showed higher levels of glycerophospholipids with a saturated long-chain and a C20:4 fatty acid tail, and unsaturated free fatty acids (FFAs). Changes in several saturated odd- and even-chain LPCs and LPEs and fatty amides were associated with the intake of many food groups, particularly grain and dairy products. Increase in several (lyso)glycerophospholipids was associated with decrease in body weight and adiposity. Increased short- and medium-chain CARs were related to decreased body fat-free mass. Our results show that isocaloric weight maintenance diets differing in dietary fibre, protein, and fat content affected amino acid and lipid metabolism. Increased abundances of several phospholipid species and FFAs were related with greater weight loss maintenance. Our findings indicate common and distinct metabolites for weight and dietary related variables in the context of weight reduction and weight management. The study was registered in isrctn.org with identifier 67529475.

Identification and Characterization of an Antifungal Gene Mt1 from Bacillus subtilis by Affecting Amino Acid Metabolism in Fusarium graminearum.

Fusarium head blight is a devastating disease that causes significant economic losses worldwide. Fusarium graminearum is a crucial pathogen that requires close attention when controlling wheat diseases. Here, we aimed to identify genes and proteins that could confer resistance to F. graminearum. By extensively screening recombinants, we identified an antifungal gene, Mt1 (240 bp), from Bacillus subtilis 330-2. We recombinantly expressed Mt1 in F. graminearum and observed a substantial reduction in the production of aerial mycelium, mycelial growth rate, biomass, and pathogenicity. However, recombinant mycelium and spore morphology remained unchanged. Transcriptome analysis of the recombinants revealed significant down-regulation of genes related to amino acid metabolism and degradation pathways. This finding indicated that Mt1 inhibited amino acid metabolism, leading to limited mycelial growth and, thus, reduced pathogenicity. Based on the results of recombinant phenotypes and transcriptome analysis, we hypothesize that the effect of Mt1 on F. graminearum could be related to the metabolism of branched-chain amino acids (BCAAs), the most affected metabolic pathway with significant down-regulation of several genes. Our findings provide new insights into antifungal gene research and offer promising targets for developing novel strategies to control Fusarium head blight in wheat.

A very mild phenotype in six individuals of a three-generation family with the novel HRAS variant c.176C > G p.(Ala59Gly): Emergence of a new HRAS-related RASopathy distinct from Costello syndrome.

Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60.

Effect of Cd(II) shock loading on performance, microbial enzymatic activity and microbial community in a sequencing batch reactor

The performance, microbial enzymatic activity and microbial community of a sequencing batch reactor (SBR) were explored under instantaneous Cd(II) shock loading. After a 24-h Cd(II) shock loading of 100 mg/L, the chemical oxygen demand and NH4+-N removal efficiencies decreased significantly from 92.73% and 99.56% on day 22 to 32.73% and 43% on day 24, respectively, and then recovered to the normal values gradually. The specific oxygen utilization rate (SOUR), specific ammonia oxidation rate (SAOR), specific nitrite oxidation rate (SNOR), specific nitrite reduction rate (SNIRR) and specific nitrate reduction rate (SNRR) decreased by 64.81%, 73.28%, 77.77%, 56.84% and 52.46% on day 23 in comparison with the absence of Cd(II) shock loading, respectively, and they gradually returned to the normal levels. The changing trends of their associated microbial enzymatic activities including dehydrogenase, ammonia monooxygenase, nitrite oxidoreductase, nitrite reductase and nitrate reductase were in accordance with SOUR, SAOR, SNOR, SNIRR and SNRR, respectively. Cd(II) shock loading promoted the microbial reactive oxygen species production and lactate dehydrogenase release, indicating that instantaneous shock caused oxidative stress and damaged to cell membranes of the activated sludge. The microbial richness and diversity, and the relative abundance of Nitrosomonas and Thauera obviously decreased under the stress of Cd(II) shock loading. PICRUSt prediction showed that Cd (II) shock loading significantly affected Amino acid biosynthesis, Nucleoside and nucleotide biosynthesis. The present results are conducive to take adequate precautions to reduce the adverse effect on bioreactor performance in wastewater treatment systems.

Rumen-protected choline and methionine during the periparturient period affect choline metabolites, amino acids, and hepatic expression of genes associated with one-carbon and lipid metabolism

Feeding supplemental choline and Met during the periparturient period can have positive effects on cow performance; however, the mechanisms by which these nutrients affect performance and metabolism are unclear. The objective of this experiment was to determine if providing rumen-protected choline, rumen-protected Met, or both during the periparturient period modifies the choline metabolitic profile of plasma and milk, plasma AA, and hepatic mRNA expression of genes associated with choline, Met, and lipid metabolism. Cows (25 primiparous, 29 multiparous) were blocked by expected calving date and parity and randomly assigned to 1 of 4 treatments: control (no rumen-protected choline or rumen-protected Met); CHO (13 g/d choline ion); MET (9 g/d DL-methionine prepartum; 13.5 g/d DL-methionine, postpartum); or CHO + MET. Treatments were applied daily as a top dress from ~21 d prepartum through 35 d in milk (DIM). On the day of treatment enrollment (d -19 ± 2 relative to calving), blood samples were collected for covariate measurements. At 7 and 14 DIM, samples of blood and milk were collected for analysis of choline metabolites, including 16 species of phosphatidylcholine (PC) and 4 species of lysophosphatidylcholine (LPC). Blood was also analyzed for AA concentrations. Liver samples collected from multiparous cows on the day of treatment enrollment and at 7 DIM were used for gene expression analysis. There was no consistent effect of CHO or MET on milk or plasma free choline, betaine, sphingomyelin, or glycerophosphocholine. However, CHO increased milk secretion of total LPC irrespective of MET for multiparous cows and in absence of MET for primiparous cows. Furthermore, CHO increased or tended to increase milk secretion of LPC 16:0, LPC 18:1, and LPC 18:0 for primi- and multiparous cows, although the response varied with MET supplementation. Feeding CHO also increased plasma concentrations of LPC 16:0 and LPC 18:1 in absence of MET for multiparous cows. Although milk secretion of total PC was unaffected, CHO and MET increased secretion of 6 and 5 individual PC species for multiparous cows, respectively. Plasma concentrations of total PC and individual PC species were unaffected by CHO or MET for multiparous cows, but MET reduced total PC and 11 PC species during wk 2 postpartum for primiparous cows. Feeding MET consistently increased plasma Met concentrations for both primi- and multiparous cows. Additionally, MET decreased plasma serine concentrations during wk 2 postpartum and increased plasma phenylalanine in absence of CHO for multiparous cows. In absence of MET, CHO tended to increase hepatic mRNA levels of betaine-homocysteine methyltransferase and phosphate cytidylyltransferase 1 choline, α, but tended to decrease expression of 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and peroxisome proliferator activated receptor α irrespective of MET. Although shifts in the milk and plasma PC profile were subtle and inconsistent between primi- and multiparous cows, gene expression results suggest that supplemental choline plays a probable role in promoting the cytidine diphosphate-choline and betaine-homocysteine S-methyltransferase pathways. However, interactive effects suggest that this response depends on Met availability, which may explain the inconsistent results observed among studies when supplemental choline is fed.

Evaluation of antimicrobial activity and mechanism of Mentha longifolia L. essential oil

AbstractAs the interest in “natural” and “safe” products grows, the use of natural products instead of synthetic preservatives to combat food spoilage and poisoning caused by microorganisms during processing and storage has become a prioritized option. The present research evaluated the antibacterial activity of the Mentha longifolia L. essential oil (MLEO) against several pathogenic bacteria, and the mechanism of action against methicillin‐resistant Staphylococcus aureus (MRSA). Gas Chromatography Quadrupole Time‐of‐Flight Mass Spectrometry (GC‐Q‐TOF MS) analysis suggested that main components of MLEO were carvone (47.39%) and limonene (12.48%). The oil showed considerable antibacterial activity with MIC values of 0.394–1.576 mg/mL, and could be a promising bactericide. Non‐targeted metabolomics analysis based on GC‐Q‐TOF MS identified 66 different metabolites, and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of these metabolites revealed that MLEO achieves the effects by affecting amino acid metabolism in MRSA.

Impact of Processing Methods on the In Vitro Protein Digestibility and DIAAS of Various Foods Produced by Millet, Highland Barley and Buckwheat.

Cereals are rich sources of dietary protein, whose nutritional assessments are often performed on raw grains or protein isolates. However, processing and gastrointestinal digestion may affect amino acid (AA) compositions, then change the protein quality. In this study, we determined the digestibility and AA compositions of various foods produced by whole grains (PG) or flour (PF) from three cereals (millet, highland barley and buckwheat) and analyzed the impact of processing methods on the digestible indispensable amino acid score (DIAAS) using the INFOGEST protocol. The in vitro protein digestibility of cereal-based foods was lower than raw grains, and PF showed a better digestion property than PG. The intestinal digestibility of individual AA within a food varied widely, and the digestibility of Cys and Ile was the lowest among all AAs. The DIAAS values of PG were lower than those of PF in each kind of cereal, and PF of buckwheat had the highest DIAAS value, followed by highland barley. The first limiting AA was still Lys for millet and highland barley compared to the raw grains; however, for buckwheat it was Leu. This study provided nutritional information on cereal products and helped to guide the collocation of different foods in diets.

Influence of phosphorylation on intermediate filaments.

The cytoskeleton of eukaryotes consists of actin filaments, microtubules and intermediate filaments (IF). IFs, in particular, are prone to pronounced phosphorylation, leading to additional charges on the affected amino acids. In recent years, a variety of experiments employing either reconstituted protein systems or living cells have revealed that these altered charge patterns form the basis for a number of very diverse cellular functions and processes, including reversible filament assembly, filament softening, network remodeling, cell migration, interactions with other protein structures, and biochemical signaling.

Genotype and Phenotype Characterization of Patients with Mucopolysaccharidosis IV-A in Chile

Introduction: Morquio syndrome or mucopolysaccharidosis type IV-A (MPS IV-A) is an autosomal recessive disease caused by biallelic variants in the GALNS gene, encoding the lysosomal enzyme GalN6S, responsible for glycosaminoglycan keratan sulfate and chondroitin-6-sulfate degradation. Studies have shown that the degree of evolutionary and chemical divergence of missense variants in GalN6S when compared to ancestral amino acids is associated with the severity of the syndrome, suggesting a genotype-phenotype correlation. There is little information on Latin American patients with MPS IV-A that replicate these findings. This study aimed to characterize the phenotype and genotype from patients with MPS IV-A, who are under Enzyme Replacement Therapy at the Children’s Neuropsychiatry Service of the Hospital Clínico San Borja Arriarán, Santiago, Chile, and to determine if there is any association between genotype and phenotype with those findings. Methods: Information was collected from medical charts, all patients went through a GalN6S enzymatic activity measurement in leukocytes from peripheral blood, and the GALNS gene was sequenced for all cases. Results: 12 patients with MPS IV-A were recruited, all patients presented multisystem involvement, mostly skeletal, and 75% of cases underwent surgical interventions, and cervical arthrodesis was the most frequent procedure. In regards of the genotype, the two most frequent variants were c.319+2T>C (n = 10, 41.66%) and p.(Arg386Cys) (n = 8, 33.33%), the first one was previously described in 2018 in a patient from Chile [Bochernitsan et al., 2018]. Conclusion: This is the first time that a genotype-phenotype correlation has been studied by analyzing the variants effect on the molecular structure of human GalN6S and the evolutionary conservation degree of affected residues in a cohort of patients in Chile. Albeit our work could not find statistically significant associations, we may infer that the evolutionary conservations of affected amino acids and the effect of variants on enzyme structure may play a main role. Further analyzes should consider a meta-analysis of published cases with genotype data and larger samples and include other variables that could provide more information. Finally, our data strongly suggest that variant c.319+2T>C could have a founder effect in Chilean patients with MPS IV-A.

Nutritional and reproductive status affect amino acid appetite in house crickets (Acheta domesticus).

We examined amino acid appetite in the omnivorous house cricket (Acheta domesticus), a common model organism for both research and teaching. Our first experiment addressed the hypothesis that house crickets can discriminate between sucrose and essential amino acids (EAA), and that preference for the latter would be affected by prior feeding experience. To test this hypothesis, we compared feeding responses of juvenile and adult crickets following pre-feeding with sucrose or an essential amino acid mixture, predicting that sucrose-only pre-feeding would enhance subsequent intake of amino acids in a two-choice preference test. Based on previous studies, we also predicted that amino acid consumption would be enhanced in females compared to males, and in mated compared to virgin females. Hence we compared responses in male and female last instar nymphs, adult males, virgin females, mated females, and mated females allowed to lay eggs. The second experiment examined how extended periods of essential amino acid deprivation (48 h to 6 days) affected appetite for these nutrients in adult male and female insects. Finally, we examined growth and survival of juvenile and adult crickets fed a holidic diet lacking all amino acids and protein. Our results demonstrated that house crickets can distinguish EAA from sucrose and that consumption of the former is enhanced following sucrose-only pre-feeding. We also found sex and developmental differences, with juvenile and virgin females showing a greater preference for EAA than juvenile or adult males. Contrary to expectation, mated females preferred sucrose over EAA both prior to and after egg laying. We also found that the crickets of both sexes increased their intake of EAA when exposed to longer periods of deprivation, indicating that they engage in compensatory feeding on these nutrients. Finally, as expected we found that growth was severely limited in juveniles fed a diet lacking all amino acids, but adults and many juveniles survived for 30 days on this diet.

Serum Metabolomics Combined With 16S rRNA Gene Sequencing to Analyze the Changes of Intestinal Flora in Rats With MI and the Intervention Effect of Fuling-Guizhi

Objective: This research aimed to assess the relationship between intestinal flora and metabolites in rats with myocardial ischemia (MI) and to offer a new perspective to elucidate the pathological mechanisms of MI and Fuling-Guizhi (FLGZ). Methods: Sprague-Dawley rats were divided into control check (CK), model (MX), propranolol (XDAZ), and FLGZ groups. Metabolomic analysis was performed by gas chromatography-mass spectrometry to obtain differential metabolites and 16S rRNA gene sequencing analysis to obtain differential intestinal flora and perform functional prediction. In addition, Pearson correlation analysis was conducted to reveal the correlation between different metabolites and altered intestinal flora. Results: By serum metabolomics, 14 different metabolites were identified, mainly involving amino acid, lipid, carbohydrate, and energy metabolic pathways. Linear discriminant analysis effect size analysis indicated that at the genus level, MI was associated with Phascolarctobacterium, Oscillospira, Allobaculum, and Ruminococcus, involving amino acids, carbohydrates, energy, lipids, cofactors and vitamins, other amino acids, terpenoids, and polyketides metabolism. Correlation analysis showed that ethanolamine, phosphate, L-glutamine, L-threonine, oxalic acid, and linoleic acid were closely associated with Phascolarctobacterium, Oscillospira, Allobaculum, and Ruminococcus. Conclusion: In conclusion, the results tentatively confirm that MI is closely tied to the dysregulation of metabolites and intestinal flora. FLGZ may affect amino acid, carbohydrate, lipid, and energy metabolism through Phascolarctobacterium, Oscillospira, Allobaculum, and Ruminococcus to attenuate inflammatory response, oxidative stress, and apoptosis.

De novo variants in MAST4 related to neurodevelopmental disorders with developmental delay and infantile spasms: Genotype-phenotype association.

This study aims to prove that the de novo variants in MAST4 gene are associated with neurodevelopmental disorders (NDD) with developmental delay (DD) and infantile spasm (IS) and to determine the genotype-phenotype correlations. Trio-based exome sequencing (ES) was performed on the four families enrolled in this study. We collected and systematically reviewed the four probands' clinical data, magnetic resonance images (MRI), and electroencephalography (EEG). We also carried out bioinformatics analysis by integrating published exome/genome sequencing data and human brain transcriptomic data. We described four patients whose median age of seizure onset was 5 months. The primary manifestation was infantile spasms with typical hypsarrhythmia on EEG. Developmental delays or intellectual disabilities varied among the four individuals. Three de novo missense variants in MAST4 gene were identified from four families, including chr5:66438324 (c.2693T > C: p.Ile898Thr) z, chr5:66459419 (c.4412C > T: p.Thr1471Ile), and chr5:66462662 (c.7655C > G:p.Ser2552Trp). The missense variant p.Ile898Thr is mapped to the AGC-kinase C-terminal with phosphatase activity. The other variant p.Ser2552Trp is located in a phosphoserine-modified residue which may affect cell membrane stability and signal transduction. Besides, the variant p.Thr1471Ile is a recurrent site screened out in two unrelated patients. Compared to private mutations (found only in a single family or a small population) of MAST4 in the gnomAD non-neuro subset, all de novo variants were predicted to be damaging or probably damaging through different bioinformatic analyses. Significantly higher CADD scores of the variant p.Thr1471Ile indicate more deleteriousness of the recurrent site. And the affected amino acids are highly conserved across multiple species. According to the Brainspan Atlas database, MAST4 is expressed primarily in the mediodorsal nucleus of the thalamus and medial prefrontal cortex during the prenatal period, potentially contributing to embryonic brain development. Our results revealed that the variants of MAST4 gene might lead to neurodevelopmental disorders with developmental delay and infantile spasm. Thus, MAST4 variants should be considered the potential candidate gene in patients with neurodevelopmental disorders clinically marked by infantile spasms.

The essential roles of FXR in diet and age influenced metabolic changes and liver disease development: a multi-omics study

BackgroundAging and diet are risks for metabolic diseases. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases that progress into cancer as they age, which is accelerated by Western diet (WD) intake. The current study uncovers the molecular signatures for diet and age-linked metabolic liver disease development in an FXR-dependent manner.MethodsWild-type (WT) and FXR KO male mice, either on a healthy control diet (CD) or a WD, were euthanized at the ages of 5, 10, or 15 months. Hepatic transcriptomics, liver, serum, and urine metabolomics as well as microbiota were profiled.ResultsWD intake facilitated hepatic aging in WT mice. In an FXR-dependent manner, increased inflammation and reduced oxidative phosphorylation were the primary pathways affected by WD and aging. FXR has a role in modulating inflammation and B cell-mediated humoral immunity which was enhanced by aging. Moreover, FXR dictated neuron differentiation, muscle contraction, and cytoskeleton organization in addition to metabolism. There were 654 transcripts commonly altered by diets, ages, and FXR KO, and 76 of them were differentially expressed in human hepatocellular carcinoma (HCC) and healthy livers. Urine metabolites differentiated dietary effects in both genotypes, and serum metabolites clearly separated ages irrespective of diets. Aging and FXR KO commonly affected amino acid metabolism and TCA cycle. Moreover, FXR is essential for colonization of age-related gut microbes. Integrated analyses uncovered metabolites and bacteria linked with hepatic transcripts affected by WD intake, aging, and FXR KO as well as related to HCC patient survival.ConclusionFXR is a target to prevent diet or age-associated metabolic disease. The uncovered metabolites and microbes can be diagnostic markers for metabolic disease.

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature.

AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.