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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]

Oral broad-spectrum antivirals are urgently needed for the treatment of many emerging and contemporary RNA viruses. We previously synthesized 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-RVn (ODBG-P-RVn, V2043), a phospholipid prodrug of GS-441524 (remdesivir nucleoside, RVn), and demonstrated its in vivo efficacy in a SARS-CoV-2 mouse model. Structure-activity relationship studies focusing on the prodrug scaffold identified two modifications, 3-fluoro-4-methoxy-benzyl (V2053) and 4-cyano-benzyl (V2067), that significantly enhanced the in vitro broad-spectrum antiviral activity against multiple RNA viruses when compared to V2043. Here, we demonstrate that V2043, V2053, and V2067 are all orally bioavailable, well-tolerated, and achieve high sustained plasma levels after single oral daily dosing. All three phospholipid prodrugs are significantly more active than RVn in vitro and significantly reduce SARS-CoV-2 lung titers in prophylaxis and treatment mouse models of SARS-CoV-2 B.1.351 infection. On a molar basis, V2043 and V2067 are substantially more active than obeldesivir/GS-5245 and molnupiravir in vivo. Together, these data support the continued development of phospholipid RVn prodrugs for the treatment of SARS-CoV-2 and other RNA viruses of clinical concern.

BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels

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]

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.

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.

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.

Simple Summary: This study explores Warburg's paradox, whereby cancer cells use both glucose and oxygen to survive, even though glucose is converted to lactate instead of being oxidized. By systematically investigating cellular metabolism during each phase of cell division and comparing the metabolic profiles of lymphoma cells and non-malignant lymphocytes, we discovered that pyruvate, the end-product of glucose metabolism, is converted into alanine. This conversion directs glutamine carbon, rather than glucose, into the TCA cycle. Furthermore, using fludarabine to selectively inhibit lymphoma cell proliferation, we showed that blocking the conversion of pyruvate to alanine disrupts the TCA cycle and interferes with the supply of nucleotides and the energy necessary for cancer cell growth. Our findings suggest that with the suppression of glucose oxidation, the conversion of pyruvate to alanine is the crucial metabolic link that connects glucose and oxygen metabolism and serves as a key component of Warburg's paradox. Background/Objectives: Warburg's metabolic paradox illustrates that malignant cells require both glucose and oxygen to survive, even after converting glucose into lactate. It remains unclear whether sparing glucose from oxidation intersects with TCA cycle continuity and if this confers any metabolic advantage in proliferating cancers. This study seeks to understand the mechanistic basis of Warburg's paradox and its overall implications for lymphomagenesis. Methods: Using metabolomics, we first examined the metabolomic profiles, glucose, and glutamine carbon labeling patterns in the metabolism during the cell cycle. We then investigated proliferation-specific metabolic features of malignant and nonmalignant cells. Finally, through bioinformatics and the identification of appropriate pharmacological targets, we established malignant-specific proliferative implications for the Warburg paradox associated with metabolic features in this study. Results: Our results indicate that pyruvate, lactate, and alanine levels surge during the S phase and are correlated with nucleotide synthesis. By using 13C1,2-Glucose and 13C6, 15N2-Glutamine isotope tracers, we observed that the transamination of pyruvate to alanine is elevated in lymphoma and coincides with the entry of glutamine carbon into the TCA cycle. Finally, by using fludarabine as a strong inhibitor of lymphoma, we demonstrate that disrupting the transamination of pyruvate to alanine correlates with the simultaneous suppression of glucose-derived nucleotide biosynthesis and glutamine carbon entry into the TCA cycle. Conclusions: We conclude that the transamination of pyruvate to alanine intersects with reduced glucose oxidation and maintains the TCA cycle as a critical metabolic feature of Warburg's paradox and lymphomagenesis. [ABSTRACT FROM AUTHOR]

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]

Purpose: Reprogramming of amino acid metabolism is relevant for initiating and fueling tumor formation and growth. Therefore, there has been growing interest in anticancer therapies targeting amino acid metabolism. While developing personalized therapeutic approaches to glioma, in vivo proton magnetic resonance spectroscopy (MRS) is a valuable tool for non-invasive monitoring of tumor metabolism. Here, we evaluated MRS-detected brain amino acids and myo-inositol as potential diagnostic and prognostic biomarkers in glioma. Method: We measured alanine, glycine, glutamate, glutamine, and myo-inositol in 38 patients with MRI-suspected glioma using short and long echo-time single-voxel PRESS MRS sequences. The detectability of alanine, glycine, and myo-inositol and the (glutamate + glutamine)/total creatine ratio were evaluated against the patients' IDH mutation status, CNS WHO grade, and overall survival. Results: While the detection of alanine and non-detection of myo-inositol significantly correlated with IDH wildtype (p = 0.0008, p = 0.007, respectively) and WHO grade 4 (p = 0.01, p = 0.04, respectively), glycine detection was not significantly associated with either. The ratio of (glutamate + glutamine)/total creatine was significantly higher in WHO grade 4 than in 2 and 3. We found that the overall survival was significantly shorter in glioma patients with alanine detection (p = 0.00002). Conclusion: Focusing on amino acids in MRS can improve its diagnostic and prognostic value in glioma. Alanine, which is visible at long TE even in the presence of lipids, could be a relevant indicator for overall survival. [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]

Background: The high global prevalence of prediabetes requires its early identification. Amino acids (AAs) have emerged as potential predictors of prediabetes. This study investigates the association between amino acids and prediabetes in the Kazakh population. Materials and Methods: In this case-control study, serum AAs levels were measured using the Trace GC 1310 gas chromatography system coupled with the TSQ 8000 triple quadrupole mass spectrometer (Thermo Scientific, Austin, TX, USA) followed by silylation with the BSTFA + 1% TMCS derivatization method. Biochemical parameters, including total cholesterol, HDL-C, LDL-C, triglycerides, fasting glucose, HbA1c, and Creatinine, were assessed for each participant. Trained professionals conducted anthropometric and physical examinations (which included taking blood pressure and heart rate measurements) and family history collection. Results: A total of 112 Kazakh individuals with prediabetes and 55 without prediabetes, aged 36–65 years, were included in the study. Only Alanine and valine showed a significant association with prediabetes risk among the 13 AAs analyzed. Our findings revealed an inverse relationship between Alanine and Valine and prediabetes in individuals of Kazakh ethnicity. Conclusion: A lower serum level of Alanine and Valine may serve as a predictive biomarker for prediabetes in the Kazakh population. [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]

The formation of mononuclear complexes and a heterovalent compound in the FeII—FeIII—l-Ala—H2O system was observed when using the Clark—Nikolsky oxidation potential at a temperature of 298.15 K and an ionic strength of the (Na(H)ClO4) solution equal to 0.75 mol L−1. The method of successive approximations (iteration) of the Yusupov oxidation function was used to calculate the stability and the model parameters of the mononuclear coordination compounds [FeHL(H2O)5]3+, [Fe(HL)2(H2O)4]3+, [Fe2(HL)2(OH)4(H2O)6]2+, [FeIIIFeII(HL)2(OH)4(H2O)6]+, [FeHL(H2O)5]2+, [Fe(HL)(OH)(H2O)4]+, and [Fe(HL)(OH)2(H2O)3]0 (L is an alanine ligand), the formation constants of these complexes, to determine the regions where they are dominant and their maximum degrees of accumulation, as well as to plot the diagrams of their distribution as a function of pH. It was determined that the heterovalent complex is the most stable and dominates up to pH 9.5. [ABSTRACT FROM AUTHOR]

The formation of mononuclear complexes and a heterovalent compound in the FeII—FeIII—l-Ala—H2O system was observed when using the Clark—Nikolsky oxidation potential at a temperature of 298.15 K and an ionic strength of the (Na(H)ClO4) solution equal to 0.75 mol L−1. The method of successive approximations (iteration) of the Yusupov oxidation function was used to calculate the stability and the model parameters of the mononuclear coordination compounds [FeHL(H2O)5]3+, [Fe(HL)2(H2O)4]3+, [Fe2(HL)2(OH)4(H2O)6]2+, [FeIIIFeII(HL)2(OH)4(H2O)6]+, [FeHL(H2O)5]2+, [Fe(HL)(OH)(H2O)4]+, and [Fe(HL)(OH)2(H2O)3]0 (L is an alanine ligand), the formation constants of these complexes, to determine the regions where they are dominant and their maximum degrees of accumulation, as well as to plot the diagrams of their distribution as a function of pH. It was determined that the heterovalent complex is the most stable and dominates up to pH 9.5. [ABSTRACT FROM AUTHOR]

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]

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]

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.

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]

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]

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.

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.

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]

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: 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]

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]

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]

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]

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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 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]