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Path-like collective variables (CVs) can be very effective for accurately modeling complex biomolecular processes in molecular dynamics simulations. Recently, we have introduced DeepLNE (deep-locally non-linear-embedding), a machine learning-based path-like CV that provides a progression variable s along the path as a non-linear combination of several descriptors. We have demonstrated the effectiveness of DeepLNE by showing that for simple models such as the Müller–Brown potential and alanine dipeptide, the progression along the path variable closely approximates the ideal reaction coordinate. However, DeepLNE is computationally expensive for realistic systems needing many descriptors and limited in its ability to handle multi-state reactions. Here, we present DeepLNE++, which uses a knowledge distillation approach to significantly accelerate the evaluation of DeepLNE, making it feasible to compute free energy landscapes for large and complex biomolecular systems. In addition, DeepLNE++ encodes system-specific knowledge within a supervised multitasking framework, enhancing its versatility and effectiveness. [ABSTRACT FROM AUTHOR]

In the study of stochastic systems, the committor function describes the probability that a system starting from an initial configuration x will reach a set B before a set A. This paper introduces an efficient and interpretable algorithm for approximating the committor, called the "fast committor machine" (FCM). The FCM uses simulated trajectory data to build a kernel-based model of the committor. The kernel function is constructed to emphasize low-dimensional subspaces that optimally describe the A to B transitions. The coefficients in the kernel model are determined using randomized linear algebra, leading to a runtime that scales linearly with the number of data points. In numerical experiments involving a triple-well potential and alanine dipeptide, the FCM yields higher accuracy and trains more quickly than a neural network with the same number of parameters. The FCM is also more interpretable than the neural net. [ABSTRACT FROM AUTHOR]

The dynamics of lysozyme is probed by attaching –SCN to all alanine residues. The one-dimensional infrared spectra exhibit frequency shifts in the position of the maximum absorption of 4 cm−1, which is consistent with experiments in different solvents and indicates moderately strong interactions of the vibrational probe with its environment. Isotopic substitution 12C → 13C leads to a redshift by −47 cm−1, which agrees quantitatively with experiments for CN-substituted copper complexes in solution. The low-frequency, far-infrared part of the protein spectra contains label-specific information in the difference spectra when compared with the wild type protein. Depending on the position of the labels, local structural changes are observed. For example, introducing the –SCN label at Ala129 leads to breaking of the α-helical structure with concomitant change in the far-infrared spectrum. Finally, changes in the local hydration of SCN-labeled alanine residues as a function of time can be related to the reorientation of the label. It is concluded that –SCN is potentially useful for probing protein dynamics, both in the high-frequency part (CN-stretch) and in the far-infrared part of the spectrum. [ABSTRACT FROM AUTHOR]

The present work shows that the free energy landscape associated with alanine dipeptide isomerization can be effectively represented by specific interatomic distances without explicit reference to dihedral angles. Conventionally, two stable states of alanine dipeptide in vacuum, i.e., C7eq (β-sheet structure) and C7ax (left handed α-helix structure), have been primarily characterized using the main chain dihedral angles, φ (C–N–Cα–C) and ψ (N–Cα–C–N). However, our recent deep learning combined with the "Explainable AI" (XAI) framework has shown that the transition state can be adequately captured by a free energy landscape using φ and θ (O–C–N–Cα) [Kikutsuji et al., J. Chem. Phys. 156, 154108 (2022)]. In the perspective of extending these insights to other collective variables, a more detailed characterization of the transition state is required. In this work, we employ interatomic distances and bond angles as input variables for deep learning rather than the conventional and more elaborate dihedral angles. Our approach utilizes deep learning to investigate whether changes in the main chain dihedral angle can be expressed in terms of interatomic distances and bond angles. Furthermore, by incorporating XAI into our predictive analysis, we quantified the importance of each input variable and succeeded in clarifying the specific interatomic distance that affects the transition state. The results indicate that constructing a free energy landscape based on the identified interatomic distance can clearly distinguish between the two stable states and provide a comprehensive explanation for the energy barrier crossing. [ABSTRACT FROM AUTHOR]

Several enhanced sampling techniques rely on the definition of collective variables to effectively explore free energy landscapes. The existing variables that describe the progression along a reactive pathway offer an elegant solution but face a number of limitations. In this paper, we address these challenges by introducing a new path-like collective variable called the "deep-locally non-linear-embedding," which is inspired by principles of the locally linear embedding technique and is trained on a reactive trajectory. The variable mimics the ideal reaction coordinate by automatically generating a non-linear combination of features through a differentiable generalized autoencoder that combines a neural network with a continuous k-nearest neighbor selection. Among the key advantages of this method is its capability to automatically choose the metric for searching neighbors and to learn the path from state A to state B without the need to handpick landmarks a priori. We demonstrate the effectiveness of DeepLNE by showing that the progression along the path variable closely approximates the ideal reaction coordinate in toy models, such as the Müller-Brown potential and alanine dipeptide. Then, we use it in the molecular dynamics simulations of an RNA tetraloop, where we highlight its capability to accelerate transitions and estimate the free energy of folding. [ABSTRACT FROM AUTHOR]

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimers disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1β2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brains endogenous γ-oscillations through enhancing the function of PV+INs.

Translation fidelity relies on accurate aminoacylation of transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases (AARSs). AARSs specific for alanine (Ala), leucine (Leu), serine, and pyrrolysine do not recognize the anticodon bases. Single nucleotide anticodon variants in their cognate tRNAs can lead to mistranslation. Human genomes include both rare and more common mistranslating tRNA variants. We investigated three rare human tRNALeu variants that mis-incorporate Leu at phenylalanine or tryptophan codons. Expression of each tRNALeu anticodon variant in neuroblastoma cells caused defects in fluorescent protein production without significantly increased cytotoxicity under normal conditions or in the context of proteasome inhibition. Using tRNA sequencing and mass spectrometry we confirmed that each tRNALeu variant was expressed and generated mistranslation with Leu. To probe the flexibility of the entire genetic code towards Leu mis-incorporation, we created 64 yeast strains to express all possible tRNALeu anticodon variants in a doxycycline-inducible system. While some variants showed mild or no growth defects, many anticodon variants, enriched with G/C at positions 35 and 36, including those replacing Leu for proline, arginine, alanine, or glycine, caused dramatic reductions in growth. Differential phenotypic defects were observed for tRNALeu mutants with synonymous anticodons and for different tRNALeu isoacceptors with the same anticodon. A comparison to tRNAAla anticodon variants demonstrates that Ala mis-incorporation is more tolerable than Leu at nearly every codon. The data show that the nature of the amino acid substitution, the tRNA gene, and the anticodon are each important factors that influence the ability of cells to tolerate mistranslating tRNAs.

ImpactFindings from this study provide further reassuring evidence that infant exposure through human milk received from lactating individuals who require treatment with remdesivir is negligible.

Ridomil Gold SL (45.3% a.i. mefenoxam) is a widely used chemical fungicide for the control of oomycetes. However, its impact on fungal communities remains unexplored. Therefore, the goal of this study was to examine the effects of mefenoxam on the temporal dynamics of fungal taxonomic and functional diversities during carrot cultivation under four treatment groups: mefenoxam application with and without Pythium inoculation, and untreated control groups with and without Pythium inoculation. Our in vitro sensitivity assay showed that the maximum recommended concentration of mefenoxam, 0.24 ppm, did not suppress the mycelial growth of P. irregulare. At 100 ppm, mycelial growth was only reduced by 11.4%, indicating that the isolate was resistant to mefenoxam. MiSeq sequencing data revealed transient taxonomic variations among treatments 2 weeks post-treatment. Mortierella dominated the fungal community in the mefenoxam-Pythium combination treatment, as confirmed through PCR using our newly designed Mortierella-specific primers. Conversely, mefenoxam-Pythium combination had adverse effects on Penicillium, Trichoderma, and Fusarium, and decrease the overall alpha diversity. However, these compositional changes gradually reverted to those observed in the control by the 12th week. The predicted ecological functions of fungal communities in all Pythium and mefenoxam treatments shifted, leading to a decrease in symbiotrophs and plant pathogen functional groups. Moreover, the community-level physiological profiling approach, utilizing 96-well Biolog FF microplates, showed discernible variations in the utilization of 95 diverse carbon sources among the treatments. Notably, arbutin, L-arabinose, Tween 80, and succinamic acid demonstrated a strong positive association with Mortierella. Our findings demonstrate that a single application of mefenoxam at its recommended rate triggers substantial taxonomic and functional shifts in the soil fungal community. Considering this impact, the conventional agricultural practice of repeated mefenoxam application is likely to exert considerable shifts on the soil ecosystem that may affect agricultural sustainability.

Purpose: This study was motivated by the need for better positron emission tomography (PET)-compatible tools to image bacterial infection. Our previous efforts have targeted bacteria-specific metabolism via assimilation of carbon-11 labeled d-amino acids into the bacterial cell wall. Since the chemical determinants of this incorporation are not fully understood, we sought a high-throughput method to label d-amino acid derived structures with fluorine-18. Our strategy employed a chemical biology approach, whereby an azide (-N3) bearing d-amino acid is incorporated into peptidoglycan muropeptides, with subsequent "click" cycloaddition with an 18F-labeled strained cyclooctyne partner. Procedures: A water-soluble, 18F-labeled and dibenzocyclooctyne (DBCO)-derived radiotracer ([18F]FB-sulfo-DBCO) was synthesized. This tracer was incubated with pathogenic bacteria treated with azide-bearing d-amino acids, and incorporated 18F was determined via gamma counting. In vitro uptake in bacteria previously treated with azide-modified d-amino acids was compared to that in cultures treated with amino acid controls. The biodistribution of [18F]FB-sulfo-DBCO was studied in a cohort of healthy mice with implications for future in vivo imaging. Results: The new strain-promoted azide-alkyne cycloaddition (SPAAC) radiotracer [18F]FB-sulfo-DBCO was synthesized with high radiochemical yield and purity via N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB). Accumulation of [18F]FB-sulfo-DBCO was significantly higher in several bacteria treated with azide-modified d-amino acids than in controls; for example, we observed 7 times greater [18F]FB-sulfo-DBCO ligation in Staphylococcus aureus cultures incubated with 3-azido-d-alanine versus those incubated with d-alanine. Conclusions: The SPAAC radiotracer [18F]FB-sulfo-DBCO was validated in vitro via metabolic labeling of azide-bearing peptidoglycan muropeptides. d-Amino acid-derived PET radiotracers may be more efficiently screened via [18F]FB-sulfo-DBCO modification.

Aim: This observational study investigated the association between remdesivir treatment during hospitalization for COVID-19 and 30-day COVID-19-related and all-cause readmission across different variants time periods. Patients & methods: Hospitalization records for adult patients discharged from a COVID-19 hospitalization between 1 May 2020 to 30 April 2022 were extracted from the US PINC AI Healthcare Database. Likelihood of 30-day readmission was compared among remdesivir-treated and nonremdesivir-treated patients using multivariable logistic regression models adjusted for age, corticosteroid treatment, Charlson comorbidity index and intensive care unit stay during the COVID-19 hospitalization. Analyses were stratified by maximum supplemental oxygen requirement and variant time period (pre-Delta, Delta and Omicron). Results: Of the 440,601 patients discharged alive after a COVID-19 hospitalization, 248,785 (56.5%) patients received remdesivir. Overall, remdesivir patients had a 30-day COVID-19-related readmission rate of 3.0% and all-cause readmission rate of 6.3% compared with 5.4% and 9.1%, respectively, for patients who did not receive remdesivir during their COVID-19 hospitalization. After adjusting for demographics and clinical characteristics, remdesivir treatment was associated with significantly lower odds of 30-day COVID-19-related readmission (odds ratio 0.60 [95% confidence interval: 0.58-0.62]), and all-cause readmission (0.73 [0.72-0.75]). Significantly lower odds of 30-day readmission in remdesivir-treated patients was observed across all variant time periods. Conclusion: Treating patients hospitalized for COVID-19 with remdesivir is associated with a statistically significant reduction in 30-day COVID-19-related and all-cause readmission across variant time periods. These findings indicate that the clinical benefit of remdesivir may extend beyond the COVID-19 hospitalization.

Slow kinetic processes in molecular systems can be analyzed by computing the dominant eigenpairs of the Koopman operator or its generator. In this context, the Variational Approach to Markov Processes (VAMP) provides a rigorous way of discerning the quality of different approximate models. Kernel methods have been shown to provide accurate and robust estimates for slow kinetic processes, but they are sensitive to hyper-parameter selection and require the solution of large-scale generalized eigenvalue problems, which can easily become computationally demanding for large data sizes. In this contribution, we employ a stochastic approximation of the kernel based on random Fourier features (RFFs) to derive a small-scale dual eigenvalue problem that can be easily solved. We provide an interpretation of this procedure in terms of a finite, randomly generated basis set. By combining the RFF approach and model selection by means of the VAMP score, we show that kernel parameters can be efficiently tuned and accurate estimates of slow molecular kinetics can be obtained for several benchmarking systems, such as deca alanine and the NTL9 protein. [ABSTRACT FROM AUTHOR]

During exercise or stress, the sympathetic system stimulates cardiac contractility via β‐adrenergic receptor (β‐AR) activation, resulting in phosphorylation of the cardiac ryanodine receptor (RyR2). Three RyR2 phosphorylation sites have taken prominence in excitation–contraction coupling: S2808 and S2030 are described as protein kinase A specific and S2814 as a Ca2+/calmodulin kinase type‐2‐specific site. To examine the contribution of these phosphosites to Ca2+ signalling, we generated double knock‐in (DKI) mice in which Ser2808 and Ser2814 phosphorylation sites have both been replaced by alanine (RyR2‐S2808A/S2814A). These mice did not exhibit an overt phenotype. Heart morphology and haemodynamic parameters were not altered. However, they had a higher susceptibility to arrhythmias. We performed confocal Ca2+ imaging and electrophysiology experiments. Isoprenaline was used to stimulate β‐ARs. Measurements of Ca2+ waves and latencies in myocytes revealed an increased propensity for spontaneous Ca2+ releases in DKI myocytes, both in control conditions and during β‐AR stimulation. In DKI cells, waves were initiated from a lower threshold concentration of Ca2+ inside the sarcoplasmic reticulum, suggesting higher Ca2+ sensitivity of the RyRs. The refractoriness of Ca2+ spark triggering depends on the Ca2+ sensitivity of the RyR2. We found that RyR2‐S2808A/S2814A channels were more Ca2+ sensitive in control conditions. Isoprenaline further shortened RyR refractoriness in DKI cardiomyocytes. Together, our results suggest that ablation of both the RyR2‐Ser2808 and RyR2‐S2814 sites increases the propensity for pro‐arrhythmic spontaneous Ca2+ releases, as previously suggested for hyperphosphorylated RyRs. Given that the DKI cells present a full response to isoprenaline, the data suggest that phosphorylation of Ser2030 might be sufficient for β‐AR‐mediated sensitization of RyRs. Key points: Phosphorylation of cardiac sarcoplasmic reticulum Ca2+‐release channels (ryanodine receptors, RyRs) is involved in the regulation of cardiac function.Ablation of both the RyR2‐Ser2808 and RyR2‐Ser2814 sites increases the propensity for pro‐arrhythmic spontaneous Ca2+ releases, as previously suggested for hyperphosphorylated RyRs.The intra‐sarcoplasmic reticulum Ca2+ threshold for spontaneous Ca2+ wave generation is lower in RyR2‐double‐knock‐in cells.The RyR2 from double‐knock‐in cells exhibits increased Ca2+ sensitivity.Phosphorylation of Ser2808 and Ser2814 might be important for basal activity of the channel.Phosphorylation of Ser2030 might be sufficient for a β‐adrenergic response. [ABSTRACT FROM AUTHOR]

D-Alanine, a rare enantiomer of alanine, can potentially alleviate the worsening of viral infections and maintain circadian rhythm. This study aimed to analyze the kinetics of D-Alanine upon oral intake. Five healthy volunteers were administered D-Alanine as a single oral dose at 11,236 or 33,708 µmoL (1–3 g). Upon intake of the lower dose, the plasma level of D-Alanine reached its peak concentration of 588.4 ± 40.9 µM with a peak time of 0.60 ± 0.06 h. The compartment model estimated the clearance of D-Alanine at 12.5 ± 0.3 L/h, or 208 ± 5 mL/min, distribution volume of 8.3 ± 0.7 L and half-life of 0.46 ± 0.04 h, suggesting a rapid clearance of D-Alanine. The peak concentration and area under the curve increased proportionally upon intake of the higher dose, while the clearance, distribution volume and half-life did not. The urinary ratio of D-Alanine per sum of D- and L-Alanine reached its peak of nearly 100%, followed by a slow decline. The peak time of the urinary ratio was 1.15 ± 0.15 h, showing a time lag of blood to urine excretion. Fractional excretion, a ratio of the clearance of a substance per a standard molecule in kidney, of D-Alanine increased from 14.0 ± 5.8% to 64.5 ± 10.3%; the latter corresponded to the urinary clearance of D-Alanine as about 77 mL/min for an adult, with a peak time of 1.90 ± 0.56 h. D-Alanine was quickly absorbed and appeared in blood, followed by urinary excretion. This kinetic analysis increases our fundamental knowledge of the oral intake of D-Alanine for the chronic dosing. Trial number: #UMIN000050865. Date of registration: 2023/6/30. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction associated fatty liver disease (MAFLD) is a common cause of liver disease in children and adolescents. The relationship between insulin resistance (IR) and MAFLD in children with short stature remains largely unknown. The present study was to investigate the relationship between the triglyceride–glucose (TyG) index and alanine aminotransferase (ALT) levels in children with short stature. A total of 1754 children with short stature were enrolled. Anthropometric, biochemical and hormonal indexes were collected through physical measurement examinations and laboratory tests. A nonlinear association was found between the TyG index and ALT. The inflection point of the curve was at a TyG index of 8.24. In multivariate piecewise linear regression, only when the TyG index was greater than 8.24 was there a significant positive association between the TyG index and ALT (β 5.75, 95% CI 3.30, 8.19; P < 0.001). However, when the TyG index was less than 8.24, there was no significant association between the TyG index and ALT (β −0.57, 95% CI −1.84, 0.71; P = 0.382). This study demonstrated a nonlinear relationship between TyG index and ALT in children with short stature. This finding suggests that a high TyG index is associated with elevated ALT in children with short stature. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of different thermal reaction conditions (temperature, pH, reaction time and substrate molar ratio) on the simultaneous generation pattern of 3 important dicarbonyl compounds (DCs) and the corresponding flavor substances in the glucose-alanine model system. Methods: The contents of glyoxal (GO), methylglyoxal (MGO) and 3-deoxyglucuronide (3-DG) in the glucose-alanine system were determined synchronously using o-phenylenediamine derivatization coupled with HPLC, and 5 types of important flavor compounds in the system were determined using SPME-GC-MS. Results: Increasing temperature promoted the production of DCs. Alkaline conditions were unfavorable to 3-DG but favorable to GO and MGO. Increasing the proportion of reducing sugars favored the production of 3-DG, while increasing the proportion of amino acids favored the production of GO and MGO. Conclusion: During the thermal processing of sweet and aromatic foods, the MGO in the system should be focused on. When adjusting the processing technology to control the generation of DCs or the conversion to hazardous substances, it was necessary to focus on the impact on ketone and pyrazine flavor substances. [ABSTRACT FROM AUTHOR]

Malva parviflora has shown anti-inflammatory, antihypertensive, antihyperlipidemic, and hypoglycemic effects. This study is aimed to evaluate the anti-adipogenic effect of M. parviflora on 3T3-L1 adipocytes. Fibroblast differentiation was induced either in the absence or presence of M. parviflora fractions (F3, F4, F7, F12, F13, F17, F18 and F19) for 4 days; F17 and 18 were the most effective fractions in reducing intracellular lipid accumulation (by 25.6% and 23.1%, respectively). EC50 of F17 and F18 (14 μg/mL and 17 μg/mL, respectively) were used to evaluate their anti adipogenic effect. After 10 days of inducing differentiation in the absence or presence of the extracts at the EC50 of F17 and F18, lipid accumulation, the concentration of interleukin 6 (IL-6) were measured in the culture medium; the presence of PPAR-γ, AKT, and p-AKT was also determined. In differentiated adipocytes (C2), F17 maintained intracellular lipid concentration at levels comparable to metformin, while decreasing PPAR-γ and increasing p-AKT presence; it also prevented IL-6 expression. F17 consists of alanine, valine, phenylalanine, and proline. On the other hand, F18 reduced intracellular lipid concentrations, prevented the increase of PPAR-γ and p-AKT, and maintained IL-6 expression at similar levels as metformin. F18 is mainly constituted by alanine, valine, proline, and sucrose. In conclusion, M. parviflora fractions (F17 and F18) control the process of adipogenesis, lipogenesis, and cellular dysfunction. [ABSTRACT FROM AUTHOR]

Sphingolipids (SLs) constitute a discrete subdomain of metabolism, and they display both structural and signaling functions. Accumulating evidence also points to intimate connections between intermediary metabolism and SL metabolism. Given that many SLs exhibit bioactive properties (i.e. transduce signals), these raise the possibility that an important function of SLs is to relay information on metabolic changes into specific cell responses. This could occur at various levels. Some metabolites are incorporated into SLs, whereas others may initiate regulatory or signaling events that, in turn, modulate SL metabolism. In this review, we elaborate on the former as it represents a poorly appreciated aspect of SL metabolism, and we develop the hypothesis that the SL network is highly sensitive to several specific metabolic changes, focusing on amino acids (serine and alanine), various fatty acids, choline (and ethanolamine), and glucose. [ABSTRACT FROM AUTHOR]

Schiff bases exhibit many pharmacological and biological properties. Here, methyl silicon (IV) complexes are formed by reacting methyl silicon alkoxides with alanine based ligand. Later, the pharmacological characteristics of these ligand and associated methyl silicon (IV) Schiff base complexes were assessed. The ligand and methyl silicon (IV) complexes underwent physical and spectral characterization, including IR, ¹H-NMR, and 13C-NMR. Pharmacological activities show an increase in the number of organic groups as well as in the coordinating environment of silicon. All compounds exhibited antioxidant, anti-inflammatory, and anti-diabetic activities, but the methyl silicon (IV) Schiff base complexes demonstrated superior activities relative to the ligand. [ABSTRACT FROM AUTHOR]

The association of thyroid function with essential and non-essential amino acids is understudied, despite their common metabolic roles. Thus, our aim was to evaluate the association of thyroid function with the levels of branched-chain amino acids (BCAAs—leucine, isoleucine, and valine) and of alanine in the general population. We utilized data from the São Paulo research center of ELSA-Brasil, a longitudinal population-based cohort study. Thyroid parameters included thyroid stimulating hormone (TSH), free T4 and free T3 levels, and the FT4:FT3 ratio. BCAAs and alanine were analyzed on a fully automated NMR platform. The current analysis included euthyroid participants and participants with subclinical hyperthyroidism and hypothyroidism. We used Pearson's coefficient to quantify the correlation between thyroid-related parameters and amino acids. Linear regression models were performed to analyze whether thyroid parameters were associated with BCAAs and alanine levels. We included 4098 participants (51.3 ± 9.0 years old, 51.5% women) in this study. In the most adjusted model, higher levels of TSH were associated with higher levels of alanine, FT4 levels were inversely associated with isoleucine levels, FT3 levels were statistically significant and positively associated with valine and leucine, and the T3:T4 ratio was positively associated with all amino acids. We observed that subclinical hypothyroidism was positively associated with isoleucine and alanine levels in all models, even after full adjustment. Our findings highlight the association of subclinical hypothyroidism and thyroid-related parameters (including TSH, free T4, free T3, and FT4:FT3 ratio) with BCAAs and alanine. Further studies are needed to explore the mechanisms underlying this association. These insights contribute to our understanding of the influence of thyroid-related parameters on BCAA and alanine metabolism. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of different thermal reaction conditions (temperature, pH, reaction time and substrate molar ratio) on the simultaneous generation pattern of 3 important dicarbonyl compounds (DCs) and the corresponding flavor substances in the glucose-alanine model system. Methods: The contents of glyoxal (GO), methylglyoxal (MGO) and 3-deoxyglucuronide (3-DG) in the glucose-alanine system were determined synchronously using o-phenylenediamine derivatization coupled with HPLC, and 5 types of important flavor compounds in the system were determined using SPME-GC-MS. Results: Increasing temperature promoted the production of DCs. Alkaline conditions were unfavorable to 3-DG but favorable to GO and MGO. Increasing the proportion of reducing sugars favored the production of 3-DG, while increasing the proportion of amino acids favored the production of GO and MGO. Conclusion: During the thermal processing of sweet and aromatic foods, the MGO in the system should be focused on. When adjusting the processing technology to control the generation of DCs or the conversion to hazardous substances, it was necessary to focus on the impact on ketone and pyrazine flavor substances.

We present a time-dependent variational method to learn the mechanisms of equilibrium reactive processes and efficiently evaluate their rates within a transition path ensemble. This approach builds off of the variational path sampling methodology by approximating the time-dependent commitment probability within a neural network ansatz. The reaction mechanisms inferred through this approach are elucidated by a novel decomposition of the rate in terms of the components of a stochastic path action conditioned on a transition. This decomposition affords an ability to resolve the typical contribution of each reactive mode and their couplings to the rare event. The associated rate evaluation is variational and systematically improvable through the development of a cumulant expansion. We demonstrate this method in both over- and under-damped stochastic equations of motion, in low-dimensional model systems, and in the isomerization of a solvated alanine dipeptide. In all examples, we find that we can obtain quantitatively accurate estimates of the rates of the reactive events with minimal trajectory statistics and gain unique insights into transitions through the analysis of their commitment probability. [ABSTRACT FROM AUTHOR]

A novel chiroptical sensing technique was recently introduced that utilized the helical phase of the structured light as a chiral reagent instead of polarization of light to differentiate enantiopure chiral liquids. The unique advantage of this non-resonant, nonlinear technique is that the chiral signal can be scaled and tuned. In this paper, we extend this technique to enantiopure powders of alanine and camphor by dissolving them in solvents of varying concentrations. We show the differential absorbance of helical light to be an order of magnitude higher relative to conventional resonant linear techniques and is comparable to nonlinear techniques that use circularly polarized light. The origin of helicity dependent absorption is discussed in terms of induced multipole moments in nonlinear light–matter interaction. These results opens up new opportunities in using helical light as a primary chiral reagent in nonlinear spectroscopic techniques. [ABSTRACT FROM AUTHOR]

β-Alanine (BA) is one of the most widely used sport supplements, due to its capacity to improve high-intensity exercise performance by increasing muscle carnosine (MCarn) content, and consequently, the buffering capacity of the muscle. BA is also available in a variety of animal foods, but little is currently known about the influence of dietary BA intake on MCarn. The aim of the current study was to compile a detailed summary of available data on the BA content of commonly consumed foods, and to explore whether associations could be detected between self-reported dietary BA intake and skeletal MCarn in a group of 60 healthy, active, omnivorous men and women. Dietary BA intake was assessed via 3-day food records, and MCarn content assessed by high-performance liquid chromatography. A series of univariate and multivariate linear regression models were used to explore associations between estimated dietary BA and MCarn. No evidence of associations between dietary BA intake and MCarn were identified, with effect sizes close to zero calculated from models accounting for key demographic variables (f² ≤ 0.02 for all analyses). These findings suggest that capacity to increase MCarn via dietary strategies may be limited, and that supplementation may be required to induce increases of the magnitude required to improve performance. [ABSTRACT FROM AUTHOR]

How does a single amino acid mutation occurring in the blinding disease, Lebers hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutations replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.

Aim: The aim of this study is to determine the albumin/bilirubin ratio index and the aspartate aminotransferase (AST)/alanine aminotransferase ratio (ALT) index in patients diagnosed with cholestasis during pregnancy, and to demonstrate their correlation with liver damage. Additionally, potential strategies to prevent liver damage will be elucidated. Materials and method: Our study is a retrospective study. A total of 4019 pregnant women aged between 18 and 40 years, presenting with itching complaints at 32–36 weeks of gestation, were screened at the Department of Obstetrics and Gynecology, Istanbul Training and Research Hospital of Health Sciences University between January 1, 2018, and December 31, 2023. Among them, 104 pregnant women without any other accompanying diseases were diagnosed with Gestational Cholestasis. Among the 104 diagnosed women, 78 met the inclusion criteria and were included in the study. Twenty-six women were excluded from the study due to missing albumin and total bilirubin values or due to blood samples being taken at different times. The serum albumin/bilirubin ratio index and the alanine aminotransferase/aspartate aminotransferase ratio index were calculated and statistically compared between pregnant women diagnosed with cholestasis and healthy pregnant women at the same gestational week. Findings: We found that AST, ALT, albumin, and total bilirubin levels were significantly higher in pregnant women diagnosed with cholestasis compared to the control group (p < 0.05). The AST/ALT index in the case group was significantly lower compared to the control group. However, there were no significant differences found between the case and control groups regarding the albumin/total bilirubin index and ALBI grade. When comparing ALBI grades in cases, no significant differences were found in terms of patients' age, gestational week, AST, ALT, and AST/ALT index. When compared according to ALBI grades, the albumin level was higher in patients with ALBI grade I compared to grade II, and in patients with grade II compared to grade III. The total bilirubin level was significantly higher in patients with ALBI grade III compared to grades I and II, but there was no significant difference between grades I and II. No significant differences were found among the groups separated according to ALBI grades when FBA values were compared. Conclusion: In this study, the negative correlation between lower AST/ALT ratio and FBA values in patients with severe cholestasis suggests the need for careful consideration regarding future liver damage. The lack of difference in ALBI score between the case and control groups, as well as the absence of correlation with FBA values, indicates the necessity to evaluate ALBI score based on patients' long-term prognosis. [ABSTRACT FROM AUTHOR]

The vibrational spectrum of the alanine amino acid was computationally determined in the infrared range 1000–2000 cm−1, under various environments encompassing the gas, hydrated, and crystalline phases, by means of classical molecular dynamics trajectories, carried out with the Atomic Multipole Optimized Energetics for Biomolecular Simulation polarizable force field. An effective mode analysis was performed, in which the spectra are optimally decomposed into different absorption bands arising from well-defined internal modes. In the gas phase, this analysis allows us to unravel the significant differences between the spectra obtained for the neutral and zwitterionic forms of alanine. In condensed phases, the method provides invaluable insight into the molecular origins of the vibrational bands and further shows that peaks with similar positions can be traced to rather different molecular motions. [ABSTRACT FROM AUTHOR]

Alanine hydrochloride was prepared from alanine, then its derivative was synthesized by amidation. The structure of the synthesized product was characterized by infrared and 1H nuclear magnetic resonance. The corrosion inhibition effect of alanine and alanine derivative on carbon steel at 30 ℃ in 0.5 mol/L sulfuric acid medium was studied by weight loss method, electrochemical method and scanning electron microscope. The results showed that alanine derivative had better corrosion inhibition than alanine due to the hydrophobic alkane long chain. The weight loss method and electrochemistry showed that the corrosion inhibition rate reached more than 90% at the alanine derivative dosage of 300 mg/L. The adsorption of corrosion inhibitor on carbon steel surface conformed to Langmuir adsorption model. Alanine derivative at low mass concentrations(50-100 mg/L) could inhibit the oxidation of anode metal,which was anode corrosion inhibitor. At higher mass concentrations(200-500 mg/L), the rate of hydrogen evolution reaction at the cathode and metal oxidation reaction at the anode was reduced at the same time, thus reducing the overall corrosion reaction rate, so alanine derivative was a mixed corrosion inhibitor.

Abstract Background Zymomonas mobilis is well known for its outstanding ability to produce ethanol with both high specific productivity and with high yield close to the theoretical maximum. The key enzyme in the ethanol production pathway is the pyruvate decarboxylase (PDC) which is converting pyruvate to acetaldehyde. Since it is widely considered that its gene pdc is essential, metabolic engineering strategies aiming to produce other compounds derived from pyruvate need to find ways to reduce PDC activity. Results Here, we present a new platform strain (sGB027) of Z. mobilis in which the native promoter of pdc was replaced with the IPTG-inducible PT7A1, allowing for a controllable expression of pdc. Expression of lactate dehydrogenase from E. coli in sGB027 allowed the production of D-lactate with, to the best of our knowledge, the highest reported specific productivity of any microbial lactate producer as well as with the highest reported lactate yield for Z. mobilis so far. Additionally, by expressing the L-alanine dehydrogenase of Geobacillus stearothermophilus in sGB027 we produced L-alanine, further demonstrating the potential of sGB027 as a base for the production of compounds other than ethanol. Conclusion We demonstrated that our new platform strain can be an excellent starting point for the efficient production of various compounds derived from pyruvate with Z. mobilis and can thus enhance the establishment of this organism as a workhorse for biotechnological production processes.

Sepsis is characterized by a metabolic disorder of amino acid occurs in the early stage; however, the profile of serum amino acids and their alterations associated with the onset of sepsis remain unclear. Thus, our objective is to identify the specific kinds of amino acids as diagnostic biomarkers in pediatric patients with sepsis. Serum samples were collected from patients with sepsis admitted to the pediatric intensive care unit (PICU) between January 2019 and December 2019 on the 1st, 3rd and 7th day following admission. Demographic and laboratory variables were also retrieved from the medical records specified times. Serum amino acid concentrations were detected by UPLC-MS/MS system. PLS-DA (VIP > 1.0) and Kruskal-Wallis test (p < 0.05) were employed to identify potential biomarkers. Spearman's rank correlation analysis was conducted to find the potential association between amino acid levels and clinical features. The diagnostic utility for pediatric sepsis was assessed using receiver operating characteristic (ROC) curve analysis. Most of amino acid contents in serum were significantly decreased in patients with sepsis, but approached normal levels by the seventh day post-diagnosis. Threonine (THR), lysine (LYS), valine (VAL) and alanine (ALA) emerged as potential biomarkers related for sepsis occurrence, though they were not associated with PELOD/PELOD-2 scores. Moreover, alterations in serum THR, LYS and ALA were linked to complications of brain injury, and serum ALA levels were also related to sepsis-associated acute kidney injury. Further analysis revealed that ALA was significantly correlated with the Glasgow score, serum lactate and glucose levels, C-reactive protein (CRP), and other indicators for liver or kidney dysfunction. Notably, the area under the ROC curve (AUC) for ALA in distinguishing sepsis from healthy controls was 0.977 (95% CI: 0.925-1.000). The serum amino acid profile of children with sepsis is significantly altered compared to that of healthy controls. Notably, ALA shows promise as a potential biomarker for the early diagnosis in septic children. [ABSTRACT FROM AUTHOR]

The waning potency of antibiotics against resilient bacterial strains highlights the imperative demand for nanomaterial approaches in addressing bacterial infections. However, the creation of a nanostructure in the post-antibiotic era has necessitated not only exceptional antibacterial activity but also high accessibility endowed with compatible natural molecules. By using a type of biomolecule-derived ionic liquid phases as the passivating ligands, we showcase a simple synthetic route to flower-shaped gold nanoparticles (AuNPs) of over 100 nm in diameter, which represent a class of large antibacterial nanostructures against both Gram-positive and Gram-negative bacteria. The hierarchical growth of the gold nanoflowers (AuNFs) achieved within minutes relies on the competition between individual domain particle growth and thermodynamic particle coalescence, which is thought to be driven by large reaction kinetics and nanoparticle passivation. Insights into the antibacterial activity reveal that the positively charged AuNFs with many protrusions cause enhanced membrane permeability and disruption of the bacterial membrane while boosting the level of intracellular reactive oxygen species (ROS). The minimum inhibitory concentration (MIC) of the AuNFs can be as low as 16 μg/mL, outperforming most of the reported AuNPs. Our findings present a general approach to hierarchical nanomaterials with antibacterial properties achievable without the need for a professional background, suggesting a potential solution to antibacterial resistance and reduced reliance on antibiotics. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysregulation represents a defining characteristic of Type 2 diabetes (T2DM). Nevertheless, there remains an absence of substantial evidence establishing a direct causal link between circulating blood metabolites and the promotion or prevention of T2DM. In addressing this gap, we employed Mendelian randomization (MR) analysis to investigate the potential causal association between 1,091 blood metabolites, 309 metabolite ratios, and the occurrence of T2DM. Methods: Data encompassing single-nucleotide polymorphisms (SNPs) for 1,091 blood metabolites and 309 metabolite ratios were extracted from a Canadian Genome-wide association study (GWAS) involving 8,299 participants. To evaluate the causal link between these metabolites and Type 2 diabetes (T2DM), multiple methods including Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Weighted Mode, and Simple Mode were employed. p-values underwent correction utilizing False Discovery Rates (FDR). Sensitivity analyses incorporated Cochran's Q test, MR-Egger intercept test, MRPRESSO, Steiger test, leave-one-out analysis, and single SNP analysis. The causal effects were visualized via Circos plot, forest plot, and scatter plot. Furthermore, for noteworthy, an independent T2DM GWAS dataset (GCST006867) was utilized for replication analysis. Metabolic pathway analysis of closely correlated metabolites was conducted using MetaboAnalyst 5.0. Results: The IVW analysis method utilized in this study revealed 88 blood metabolites and 37 metabolite ratios demonstrating a significant causal relationship with T2DM (p < 0.05). Notably, strong causal associations with T2DM were observed for specific metabolites: 1-linoleoyl-GPE (18:2) (IVW: OR:0.930, 95% CI: 0.899-0.962, p = 2.16 × 10-5), 1,2-dilinoleoyl-GPE (18:2/18:2) (IVW: OR:0.942, 95% CI: 0.917-0.968, p = 1.64 × 10-5), Mannose (IVW: OR: 1.133, 95% CI: 1.072-1.197, p = 1.02 × 10-5), X-21829 (IVW: OR:1.036, 95% CI: 1.036-1.122, p = 9.44 × 10-5), and Phosphate to mannose ratio (IVW: OR:0.870, 95% CI: 0.818-0.926, p = 1.29 × 10-5, FDR = 0.008). Additionally, metabolic pathway analysis highlighted six significant pathways associated with T2DM development: Valine, leucine and isoleucine biosynthesis, Phenylalanine metabolism, Glycerophospholipid metabolism, Alpha-Linolenic acid metabolism, Sphingolipid metabolism, and Alanine, aspartate, and glutamate metabolism. Conclusion: This study identifies both protective and risk-associated metabolites that play a causal role in the development of T2DM. By integrating genomics and metabolomics, it presents novel insights into the pathogenesis of T2DM. These findings hold potential implications for early screening, preventive measures, and treatment strategies for T2DM. [ABSTRACT FROM AUTHOR]

Background: Schisanlactone E, also known as XueTongSu (XTS), is an active compound extracted from the traditional Tujia medicine Kadsura heteroclita ("XueTong"). Recent studies highlight its anti-inflammatory and antioxidant properties, yet the mechanisms of XTS's therapeutic effects on Alzheimer's disease (AD) are unclear. This study aims to elucidate the therapeutic efficacy and mechanisms of XTS in AD. Methods: Ten C57BL/6 mice were assigned to the control group (NC), and twenty APP/PS1 transgenic mice were randomly divided into the model group (M) (10 mice) and the XTS treatment group (Tre) (10 mice). After an acclimatization period of 7 days, intraperitoneal injections were administered over a 60-day treatment period. The NC and M groups received saline, while the Tre group received XTS at 2 mg/kg. Learning and memory abilities were assessed using the Morris Water Maze (MWM) test. Histopathological changes were evaluated using hematoxylin and eosin (HE) and Nissl staining, and immunofluorescence was used to assess pathological products and glial cell activation. Cytokine levels (IL-1β, IL-6, TNF-α) in the hippocampus were quantified by qPCR. 16S rDNA sequencing analyzed gut microbiota metabolic alterations, and metabolomic analysis was performed on cortical samples. The KEGG database was used to analyze the regulatory mechanisms of XTS in AD treatment. Results: XTS significantly improved learning and spatial memory in APP/PS1 mice and ameliorated histopathological changes, reducing Aβ plaque aggregation and glial cell activation. XTS decreased the expression of inflammatory cytokines IL-1β, IL-6, and TNF-α. It also enhanced gut microbiota diversity, notably increasing Akkermansia species, and modulated levels of metabolites such as isosakuranetin, 5-KETE, 4-methylcatechol, and sphinganine. Pathway analysis indicated that XTS regulated carbohydrate metabolism, neuroactive ligand-receptor interactions, and alanine, aspartate, and glutamate metabolism, mitigating gut microbiota dysbiosis and metabolic disturbances. Conclusion: XTS ameliorates cognitive deficits, pathological changes, and inflammatory responses in APP/PS1 mice. It significantly modulates the gut microbiota, particularly increasing Akkermansia abundance, and influences levels of key metabolites in both the gut and brain. These findings suggest that XTS exerts anti-AD effects through the microbial-gut-brain axis (MGBA). [ABSTRACT FROM AUTHOR]

Maintaining skeletal muscle mass is important for improving muscle strength and function. Hence, maximizing lean body mass (LBM) is the primary goal for both elite athletes and fitness enthusiasts. The use of amino acids as dietary supplements is widespread among athletes and physically active individuals. Extensive literature analysis reveals that branched-chain amino acids (BCAA), creatine, glutamine and β-alanine may be beneficial in regulating skeletal muscle metabolism, enhancing LBM and mitigating exercise-induced muscle damage. This review details the mechanisms of these amino acids, offering insights into their efficacy as supplements. Recommended dosage and potential side effects are then outlined to aid athletes in making informed choices and safeguard their health. Lastly, limitations within the current literature are addressed, highlighting opportunities for future research. [ABSTRACT FROM AUTHOR]

Paraphenylenediamine is the main component in many commercial hair dyes, and can produce severe local and systemic toxicity reactions after acute ingestion or dermal absorption. The aim of this study was to assess the factors contributing to morbidity and mortality in cases of acute paraphenylenediamine poisoning, with a focus on evaluating the resultant hepatic and cardiac toxicity. This observational study was conducted on patients with acute paraphenylenediamine poisoning presenting to Sohag University Hospitals, and included a retrospective part from February 2021 to January 2022 and a prospective part from February 2022 to July 2022. Clinical data were extracted and receiver operating characteristic curves created to identify prognostic markers. Among 50 eligible patients 39 (78 percent) recovered, and 11 (22 percent) died or had permanent complications. Angioedema and anuria were the most frequent features in complicated cases. By receiver operating characteristic analysis, either an increase in aspartate aminotransferase activity greater than 644 IU/L or alanine aminotransferase activity greater than 798 IU/L, a time delay to presentation of greater than 4.5 hours, and a pH of less than 7.32 were associated with a significant increase in morbidity and mortality. While cardiac enzyme activities, and concentrations of blood urea nitrogen and creatinine increased in most cases, they were not associated with mortality. Management of patients with paraphenylenediamine poisoning is mainly supportive, as there is no specific antidote. Respiratory failure and kidney failure are the most life threatening complications. Hepatoxicity and cardiotoxicity also occur. The ability to predict the events can help guide patient disposition and care. Elevated liver enzyme activities, increased time delay to admission, decreased pH, and the presence of angioedema and anuria can be used as predictors of morbidity and mortality in patients with acute paraphenylenediamine poisoning. [ABSTRACT FROM AUTHOR]

The dystrophin gene (Dmd) is recognized for its significance in Duchenne muscular dystrophy (DMD), a lethal and progressive skeletal muscle disease. Some patients with DMD and model mice with muscular dystrophy (mdx) spontaneously develop various types of tumors, among which rhabdomyosarcoma (RMS) is the most prominent. By contrast, spindle cell sarcoma (SCS) has rarely been reported in patients or mdx mice. In this study, we aimed to use metabolomics to better understand the rarity of SCS development in mdx mice. Gas chromatography-mass spectrometry was used to compare the metabolic profiles of spontaneously developed SCS and RMS tumors from mdx mice, and metabolite supplementation assays and silencing experiments were used to assess the effects of metabolic differences in SCS tumor-derived cells. The levels of 75 metabolites exhibited differences between RMS and SCS, 25 of which were significantly altered. Further characterization revealed downregulation of nonessential amino acids, including alanine, in SCS tumors. Alanine supplementation enhanced the growth, epithelial mesenchymal transition, and invasion of SCS cells. Reduction of intracellular alanine via knockdown of the alanine transporter Slc1a5 reduced the growth of SCS cells. Lower metabolite secretion and reduced proliferation of SCS tumors may explain the lower detection rate of SCS in mdx mice. Targeting of alanine depletion pathways may have potential as a novel treatment strategy. NEW & NOTEWORTHY: To the best of our knowledge, SCS has rarely been identified in patients with DMD or mdx mice. We observed that RMS and SCS tumors that spontaneously developed from mdx mice with the same Dmd genetic background exhibited differences in metabolic secretion. We proposed that, in addition to dystrophin deficiency, the levels of secreted metabolites may play a role in the determination of tumor-type development in a Dmd-deficient background. [ABSTRACT FROM AUTHOR]

Embryonic transfer of bovine blastocysts produced by in vitro fertilization is widely utilized-despite a compromised conception rate. It has been suggested that a set of four evaluation criteria for judging the quality of embryos, based on the timing of early cleavages and proper morphologies of embryos, can effectively predict pregnancy success. These blastocysts are hereafter referred to as four-criteria-compliant blastocysts. The same criteria should be used to modify the culture media to improve embryo quality. For example, culture media is often supplemented with nonessential amino acids (NEAA) at a uniform concentration despite the major variation in their concentration in the oviductal fluid. In the present study, the effects of the embryo culture medium, namely CR1, supplemented with all seven MEM NEAA or six of them, excluding one at a time, were examined. All media, except for the medium that did not contain proline and serine, tended to improve the efficiency of producing four-criteria-compliant blastocysts, and excluding alanine was particularly effective. The absence of alanine resulted in the rapid occurrence of the first cleavage and pronuclear formation of fertilized oocytes in the alanine-free medium compared to that in the medium containing alanine. These results suggested that alanine hinders certain events involved in the progression of early embryogenesis, which is necessary to achieve the four criteria that provide a benchmark for pregnancy. Therefore, a significantly higher percentage of embryos satisfied the recommended criteria and developed into four-criteria-compliant blastocysts when developed in alanine-free medium than in alanine-containing medium. [ABSTRACT FROM AUTHOR]

The efficacy and mechanisms of probiotic fermented tomato juice (PFTJ) in mitigating the impact of alcohol, and its ability to protect the liver were examined. The effects of different doses of PFTJ on the time taken by mice to sober up and on the activity of alcohol dehydrogenase (ADH) in mice were analyzed using mouse models of acute alcohol intoxication. In the meantime, models of chronic alcohol intoxication were established to investigate the effects of PFTJ on the liver function indicators and lipid metabolism indicators in serum as well as the antioxidant indicators in liver tissue of mice. In addition, histopathological analysis was conducted. The results showed that PFTJ significantly shortened the time taken by mice to sober up and improved ADH activity in acute alcohol intoxication models. Compared with those of the model group, the activities of aspartate transaminase (AST) and alanine aminotransferase (ALT) decreaseds by 24.87% and 26.65%, respectively (P<0.05), and the levels of triglyceride (TG) and total cholesterol (TC) reduced to 0.58 mmol/L and 1.21 mmol/L, respectively, in the high-dose group (15 mL/kg). The activities of catalase (CAT) and superoxide dismutase (SOD) in liver tissue increased by 17.05% and 22.91%, respectively (P<0.05), while the content of malondialdehyde (MDA) declined by 34.69% (P<0.05). The administration of 15 mL/kg PFTJ remarkably relieved liver cell swelling and steatosis in the mouse models. In conclusion, PFTJ can increase ADH activity to accelerate ethanol metabolism and enhance activities of antioxidant enzymes to eliminate free radicals in the liver and restore lipid metabolism. Therefore, PFTJ has the potential to become a new functional food for sobering up and liver protection. [ABSTRACT FROM AUTHOR]

The analysis of dietary supplements is far less regulated than pharmaceuticals, leading to potential quality issues. Considering their positive effect, many athletes consume supplements containing l-histidine and β-alanine. A new microfluidic method for the determination of l-histidine and β-alanine in dietary supplement formulations has been developed. For the first time, capacitively coupled contactless conductivity detection was employed for the microchip electrophoresis of amino acids in real samples. A linear relationship between detector response and concentration was observed in the range of 10–100 µmol L–1 for l-histidine (R2 = 0.9968) and β-alanine (R2 = 0.9954), while achieved limits of detection (3 × S/N ratio) were 4.2 µmol L–1 and 5.2 µmol L–1, respectively. The accuracy of the method was confirmed using recovery experiments as well as CE-UV-VIS and HPLC-UV-VIS techniques. The developed method allows unambiguous identification of amino acids in native form without chemical derivatization and with the possibility of simultaneous analysis of amino acids with metal cations. [ABSTRACT FROM AUTHOR]

This study aims to explore the development of sustainable fertilizers from waste materials of a biogas plant and a brewery. These wastes, rich in organic carbon and nitrogen, were processed with sulfuric(VI) and phosphoric(V) acid mixture, facilitating the production of free amino acids and achieving waste sanitization. This treatment produced by-products, which extended the range of possible applications. The highest concentration of free amino acids (360 mg/l) was achieved through hydrolyzing with a 40% concentration medium over 24 h. In this case, the maximum levels were recorded for beta-alanine (69.3 mg/l), glycine (46.8 mg/l), isoleucine (43.5 mg/l), proline (36.2 mg/l), and valine (31.5 mg/l). The study presents two fertilizer technologies, with and without micronutrients, that satisfy European Parliament Regulation 2019/1009 (Ntot > 2%, Norg > 0.5%, Corg > 3%). Bioavailability of nutrients in the formulations ranged from 60 to 100%. The efficacies of these fertilizers were evaluated in 30-day pot trials with various plant species, with both single application and fertigation tested. Multielement analysis confirmed high nutrient transfer in the soil-plant system, and the inclusion of micronutrients led to biofortification of plant biomass in Cu (48.3 ± 7.2 mg/kg), Mn (249 ± 37 mg/kg), Zn (164 ± 25 mg/kg), and Fe (211 ± 32 mg/kg). These sustainable fertilizers present an alternative to traditional, non-renewable fertilizers and offer promising solutions for precision agriculture and environmentally conscious production. [ABSTRACT FROM AUTHOR]

Six differently charged amphoteric polyamidoamines, synthesized by the polyaddition of N,N′-methylenebisacrylamide to alanine, leucine, serine, arginine (M-ARG), glutamic acid (M-GLU) and a glycine/cystine mixture, were screened for their short-term phytotoxicity using a seed germination test. Lepidium sativum L. seeds were incubated in polyamidoamine water solutions with concentrations ranging from 0.156 to 2.5 mg mL−1 at 25 ± 1 °C for 120 h. The seed germination percentage (SG%), an indicator of acute toxicity, and both root and shoot elongation, related to plant maturation, were the considered endpoints. The germination index (GI) was calculated as the product of relative seed germination times relative radical growth. The SG% values were in all cases comparable to those obtained in water, indicating no detectable acute phytotoxicity of the polyamidoamines. In the short term, the predominantly positively charged M-ARG proved to be phytotoxic at all concentrations (GI < 0.8), whereas the predominantly negatively charged M-GLU proved to be biostimulating at intermediate concentrations (GI > 1) and slightly inhibitory at 2.5 mg mL−1 (0.8 < GI < 1). Overall, polyamidoamine phytotoxicity could be correlated to charge distribution, demonstrating the potential of the test for predicting and interpreting the eco-toxicological behavior of water-soluble polyelectrolytes. [ABSTRACT FROM AUTHOR]

Bacterial contamination is a hazard in many industries, including food, pharmaceuticals, and healthcare. The availability of a rapid and simple method for detecting this type of contamination in sterile areas enables immediate intervention to avoid or reduce detrimental effects. Among these methods, colorimetric indicators are becoming increasingly popular due to their affordability, ease of use, and quick visual interpretation of the signal. In this article, a bacterial contamination indicator system was designed by incorporating MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) into an electrospun PADAS matrix, which is a biodegradable poly(ester amide) synthesized from L-alanine, 1,12-dodecanediol, and sebacic acid. Uniaxial stress testing, thermogravimetric analysis and scanning electron microscopy were used to examine the mechanical properties, thermal stability, and morphology of the mats, respectively. The capacity for bacterial detection was not only analyzed with agar and broth assays but also by replicating important environmental conditions. Among the MTT concentrations tested in this study (0.2%, 2%, and 5%), it was found that only with a 2% MTT content the designed system produced a color response visible to the naked eye with optimal intensity, a sensitivity limit of 104 CFU/mL, and 86% cell viability, which showed the great potential for its use to detect bacterial contamination. In summary, by means of the process described in this work, it was possible to obtain a simple, low-cost and fast-response bacterial contamination indicator that can be used in mask filters, air filters, or protective clothing. [ABSTRACT FROM AUTHOR]

Imidazole dipeptides (IDPs) and taurine (Tau) have several health benefits and are known to be contained in natural seafoods. However, their levels vary widely in different natural seafoods, making their simultaneous determination desirable. Herein, we employ a liquid chromatography–tandem mass spectrometry approach using a novel amino group derivatization reagent, succinimidyl 2-(3-((benzyloxy)carbonyl)-1-methyl-5-oxoimidazolidin-4-yl) acetate ((R)-CIMa-OSu), for the simultaneous quantification of IDPs (carnosine (Car) and anserine (Ans)), their related amino acids, and Tau in natural seafoods. Each seafood sample contained different concentrations of IDPs (Car: ND to 1.48 mmol/100 g-wet, Ans: ND to 4.67 mmol/100 g-wet). The Car levels were considerably higher in eel, while Tau was more abundant in squid, boiled octopus, and scallop. Thus, the derivatization reagent (R)-CIMa-OSu provides a new approach to accurately assess the nutritional composition of seafoods, thereby providing valuable insight into its dietary benefits. [ABSTRACT FROM AUTHOR]

Oncometabolites refer to pro-oncogenic metabolites that are aberrantly accumulated due to distorted metabolic pathways in cancer cells, and play a crucial role in promoting cancer malignancy. In recent years, the concept of oncometabolites has been broadened beyond their original definition. Emerging evidence has suggested that oncometabolites also exert crucial functions in non-cancer cells within the tumor microenvironment, and can even be produced by these cells. In this review, we summarize the expanded understanding of oncometabolites by presenting an overview of their functions and mechanisms in oncogenesis and cancer progression from the viewpoint of the tumor microenvironment, with a special attention to metabolite-mediated cell-cell crosstalk in promoting cancer progression. With this review, we hope to gain a better understanding of roles and the regulation of the rewired metabolism in cancer and inspire novel therapeutic avenues for treating oncometabolite-driven cancers. [ABSTRACT FROM AUTHOR]

The electrochemical synthesis of α ${\alpha }$ ‐amino acids at room temperature and pressure is a sustainable alternative to conventional methods like microbial fermentation and Strecker synthesis. A custom‐built zero‐gap flow electrolyzer was used to study the electrosynthesis of alanine via the electrocatalytic reductive amination (ERA) of the corresponding biomass‐derivable α ${\alpha }$ ‐keto acid precursor – pyruvic acid (PA), and hydroxylamine (NH2OH) at very low pH. Non‐toxic, abundant, and easy to prepare TiO2/Ti electrocatalysts were utilized as the cathode. Three TiO2/Ti felt electrodes with different oxide thicknesses were prepared and their characterization results were correlated with their respective electrochemical performance in terms of Faradaic efficiency η ${\eta }$ , and partial current density j‾ ${\left|\overline{j}\right|}$. Cyclic voltammetry indicated a different electrocatalytic reduction process on hydrothermally treated electrodes, compared to thermally oxidized ones. Hydrothermally treated electrodes were also found to have the thickest porous anatase layer and achieved 50–75 % alanine conversion efficiencies. Optimization showed that the cell potential, reactant flow rate and the PA: NH2OH ratio were crucial parameters in determining the conversion efficiency. η ${\eta }$ and j‾ ${\left|\overline{j}\right|}$ were found to significantly decrease when an excess of is used and, an optimal alanine η ${\eta }$ of 75 % was achieved at 2.0 V applied cell potential and 10 mL/h reactant flow rate. [ABSTRACT FROM AUTHOR]

Background: Increased waist/hip ratio (WHR) contributes to type 2 diabetes, fatty liver, dyslipidaemia, hypertension and coronary artery disease, with potential sex‐differential effects. Postulated mediators include increased lipid flux, branched‐chain amino acids, glycine and glycoprotein acetyl, but their relative contributions and sex‐specific impact on WHR‐associated cardiometabolic disease (CMD) are not established. Methods: We therefore undertook combined and sex‐stratified Mendelian randomization (MR) to assess the relative causal contributions of these mediators to WHR‐associated CMD using summary statistics from the largest genome‐wide association studies in European ancestries. Results: In sex‐combined MR analyses, increased WHR significantly reduces high‐density lipoprotein (beta = −0.416, SE = 0.029, p = 2.87E‐47), increases triglyceride (beta = 0.431, SE = 0.029, p = 1.87E‐50), type 2 diabetes (odds ratio = 2.747, SE = 0.09, p = 26E‐23), coronary artery disease (odds ratio = 1.478, SE = 0.045, p = 6.96E‐18), alanine transaminase (beta = 0.062, SE = 0.004, p = 6.88E‐67), and systolic (beta = 0.134, SE = 0.022, p = 7.81E‐10) and diastolic blood pressure (beta = 0.162, SE = 0.026, p = 5.38E‐10). Adjustment for the mediators attenuated WHR's effects, but the associations remained significant with concordant results in females. In males, a similar pattern was seen, except after adjusting for the effect of the ratio of monounsaturated fatty acid to total free fatty acid, the potential causal effect of WHR was no longer significant: high‐density lipoprotein (beta = −0.117, SE = 0.069, p =.09) and triglyceride (beta = 0.051, SE = 0.068, p =.459). Conclusions: MR suggests WHR increases the risk of CMD independent of these mediators, with the exception of dyslipidaemia in males, which is largely driven by the monounsaturated fatty acid to total free fatty acid ratio. [ABSTRACT FROM AUTHOR]

Microorganisms in the rhizosphere, particularly arbuscular mycorrhiza, have a broad symbiotic relationship with their host plants. One of the major fungi isolated from the rhizosphere of Peucedanum praeruptorum is Penicillium restrictum. The relationship between the metabolites of P. restrictum and the root exudates of P. praeruptorum is being investigated. The accumulation of metabolites in the mycelium and fermentation broth of P. restrictum was analysed over different fermentation periods. Non‐targeted metabolomics was used to compare the differences in intracellular and extracellular metabolites over six periods. There were significant differences in the content and types of mycelial metabolites during the incubation. Marmesin, an important intermediate in the biosynthesis of coumarins, was found in the highest amount on the fourth day of incubation. The differential metabolites were screened to obtain 799 intracellular and 468 extracellular differential metabolites. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the highly enriched extracellular metabolic pathways were alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, and terpenoid backbone biosynthesis. In addition, the enrichment analysis associated with intracellular and extracellular ATP‐binding cassette transporter proteins revealed that some ATP‐binding cassette transporters may be involved in the transportation of certain amino acids and carbohydrates. Our results provide some theoretical basis for the regulatory mechanisms between the rhizosphere and the host plant and pave the way for the heterologous production of furanocoumarin. [ABSTRACT FROM AUTHOR]

ASCT2 (alanine serine cysteine transporter 2), a member of the solute carrier 1 family, mediates Na+-dependent exchange of small neutral amino acids across cell membranes. ASCT2 was shown to be highly expressed in tumor cells, making it a promising target for anticancer therapies. In this study, we explored the binding mechanism of the high-affinity competitive inhibitor L-cis hydroxyproline biphenyl ester (Lc-BPE) with ASCT2, using electrophysiological and rapid kinetic methods. Our investigations reveal that Lc-BPE binding requires one or two Na+ ions initially bound to the apo-transporter with high affinity, with Na1 site occupancy being more critical for inhibitor binding. In contrast to the amino acid substrate bound form, the final, third Na+ ion cannot bind, due to distortion of its binding site (Na2), thus preventing the formation of a translocation-competent complex. Based on the rapid kinetic analysis, the application of Lc-BPE generated outward transient currents, indicating that despite its net neutral nature, the binding of Lc-BPE in ASCT2 is weakly electrogenic, most likely because of asymmetric charge distribution within the amino acid moiety of the inhibitor. The preincubation with Lc-BPE also led to a decrease of the turnover rate of substrate exchange and a delay in the activation of substrate-induced anion current, indicating relatively slow Lc-BPE dissociation kinetics. Overall, our results provide new insight into the mechanism of binding of a prototypical competitive inhibitor to the ASCT transporters. [ABSTRACT FROM AUTHOR]

(1) Background: Intraperitoneal injections of the endogenous N-acyl amino acid N-Oleoyl alanine (OlAla) effectively reduces both the affective and somatic responses produced by opioid withdrawal in preclinical models. To increase the translational appeal of OlAla in clinical drug applications, the current experiments tested whether oral OlAla pretreatment also attenuates opioid withdrawal in rats. (2) Methods: In Experiment 1, to assess its impact on affective withdrawal behavior, OlAla (0, 5, 20 mg/kg) was orally administered during the conditioning phase of an acute naloxone-precipitated morphine withdrawal conditioned place avoidance task. In Experiment 2, to assess its impact on somatic withdrawal behavior, OlAla (5–80 mg/kg) was orally administered prior to naloxone-precipitated withdrawal from chronic heroin exposure. (3) Results: Pretreatment with oral OlAla at the higher (20 mg/kg), but not lower (5 mg/kg) dose, reduced the establishment of an acute morphine withdrawal-induced conditioned place aversion. Instead, the lower dose of oral OlAla (5 mg/kg) reduced heroin withdrawal-induced abdominal contractions and diarrhea, whereas higher doses were without effect. (4) Conclusions: The results suggest a dose-dependent reduction of opioid withdrawal responses by orally administered OlAla, and further highlight the potential utility of this compound for opioid withdrawal in clinical populations. [ABSTRACT FROM AUTHOR]

Several crustaceans including shrimps change the amount of specific free amino acids to regulate the osmotic pressure in their bodies. Kuruma shrimp Penaeus japonicus also increases the concentration of alanine (Ala) in the abdominal muscle following the increase of environmental salinity. In the present study, to elucidate the mechanisms of changes in Ala accumulation of kuruma shrimp depending on salinity, we cloned the gene encoding alanine aminotransferase (ALT), an enzyme involved in Ala biosynthesis, and examined its expression profile. It was found that the full‐length kuruma shrimp ALT1 cDNA consisted of 3,301 bp, encoding 514 amino acids, and that all amino acid residues important for ALT activity were conserved. Phylogenetic analysis also indicated that the ALT gene cloned in this study was classified as ALT1. Moreover, we examined the expression levels of the ALT1 gene in the abdominal muscle and the hepatopancreas of kuruma shrimp acclimated at 17‰, 34‰, and 40‰ salinities, resulting that the mRNA levels of the ALT1 genes in both tissues of the shrimp acclimated at 40‰ were significantly higher than those at 17‰ for 12 h (p < 0.05). The mRNA levels of the ALT1 gene in the abdominal muscle of the shrimp acclimated for more than 24 h tended to increase following the increase of environmental salinity. These results indicate that ALT1 is responsible for the increase of free Ala concentration in the abdominal muscle of kuruma shrimp to regulate osmotic pressure at high salinity. [ABSTRACT FROM AUTHOR]