A brain machine interface framework for exploring proactive control of smart environments.

Brain machine interfaces (BMIs) can substantially improve the quality of life of elderly or disabled people. However, performing complex action sequences with a BMI system is onerous because it requires issuing commands sequentially. Fundamentally different from this, we have designed a BMI system that reads out mental planning activity and issues commands in a proactive manner. To demonstrate this, we recorded brain activity from freely-moving monkeys performing an instructed task and decoded it with an energy-efficient, small and mobile field-programmable gate array hardware decoder triggering real-time action execution on smart devices. Core of this is an adaptive decoding algorithm that can compensate for the day-by-day neuronal signal fluctuations with minimal re-calibration effort. We show that open-loop planning-ahead control is possible using signals from primary and pre-motor areas leading to significant time-gain in the execution of action sequences. This novel approach provides, thus, a stepping stone towards improved and more humane control of different smart environments with mobile brain machine interfaces.

Metal-organic complex coating for enhanced corrosion control and biocompatibility on biodegradable magnesium alloy for orthopaedic implants.

Magnesium alloy is currently regarded as the most favourable biodegradable metal; however, obstacles remain to be overcome in terms of managing its corrosion and ensuring its biocompatibility. In this study, a metal-organic complex comprising Ca ions incorporated in tannic acid (TA) was prepared and used to coat magnesium alloy by chemical conversion and dipping processes, followed by modification with stearic acid (SA). This metal-organic complex coating was demonstrated to be homogeneous and compact, and it significantly improved the electrochemical corrosion resistance and long-term degradation behaviour of the coated samples. Consequently, the well-controlled release of Mg and Ca ions, as well as the osteo-compatible TA and SA molecules, promoted the proliferation of osteoblast cells. This metal-organic complex coating offers a promising modifying strategy for magnesium-based orthopaedic implants.

Comparison between different advanced cannulation techniques for difficult biliary cannulation: a systematic review with a meta-analysis.

Objective: This study aimed to systematically evaluate the efficacy and safety of the double-guidewire technique along with other methods (persistent standard cannulation techniques, transpancreatic sphincterotomy, and pancreatic stent-assisted technique) for difficult biliary cannulation. Methods: Two researchers searched for literature on the efficacy and safety of the double-guidewire technique and other techniques in difficult biliary cannulation in databases, including PubMed, Embase, Cochrane, China National Knowledge Infrastructure, and Wanfang Data, based on the inclusion and exclusion criteria. The success rate of cannulation, duration of cannulation, post-ERCP pancreatitis, and overall postoperative complications were also analyzed using RevMan 5.4 software. Results: In total, 20 randomized controlled trial (RCT) studies involving 2008 participants were identified. The success rate of cannulation in the double-guidewire technique was much higher than that in persistent standard cannulation techniques [RR = 1.37, 95%CI (1.05, 1.79), p = 0.02]. However, it was lower than the success rate observed with transpancreatic sphincterotomy [RR = 0.89, 95%CI (0.81, 0.97), p = 0.01]. There was no significance in post-ERCP pancreatitis [RR = 1.09, 95% CI (0.85, 1.40), p = 0.49], overall postoperative complications [RR = 0.90, 95% CI (0.56, 1.45), p = 0.66], and duration of cannulation [SMD = -0.14, 95%C I (-1.43, 1.15), p = 0.83] between the double-guidewire technique and other techniques. Conclusion: This study demonstrated that the success rate of cannulation ranged from transpancreatic sphincterotomy to the double-guidewire technique and then to persistent standard cannulation techniques.

Catalytic Enantioselective Electrophilic Difunctionalization of Unsaturated Sulfones.

An efficient protocol of enantioselective thiolative azidation of sulfone-tethered alkenes via a chiral chalcogenide catalyzed electrophilic reaction is disclosed. A series of enantioenriched sulfones bearing remote stereogenic centers was achieved with good yields and high enantioselectivities with linear unsaturated sulfones and cyclic unsaturated sulfones. Mechanistic studies revealed the importance of the sulfone group in the improvement of the reactivity and enantioselectivity of the reaction.

A combined model of serum neutrophil extracellular traps, CD8+ T cells, and tumor proportion score provides better prediction of PD-1 inhibitor efficacy in patients with NSCLC.

Immune checkpoint inhibitors provide a definite survival benefit for patients with driver-negative advanced non-small cell lung cancer (NSCLC), but predictors of efficacy are still lacking. There may be a relationship between immune inflammatory state and tumor immune response. We explored the relationship of serum neutrophil extracellular traps (NETs) with infiltrating cells in the tumor tissues of patients with NSCLC as well as their relationship with the therapeutic efficacy of programmed cell death protein 1 (PD-1) inhibitors. Serum myeloperoxidase (MPO)-double-stranded DNA (dsDNA) was detected as a marker of NET serum concentration. T cells were detected by immunohistochemical staining, and neutrophils were counted by MPO immunofluorescence staining. Of the 31 patients with NSCLC, a longer progression-free survival after PD-1 inhibitor treatment was associated with higher levels of CD3+ T cells, a lower neutrophil : CD3+-T-cell ratio (NEU/CD3+) and lower neutrophil : CD8+-T-cell ratio (NEU/CD8+) in tumor tissues. Patients with higher serum NETs were more likely to develop progressive disease after treatment (P = 0.003) and to have immune-related adverse events (IrAEs) as well as higher NEU/CD3+ and NEU/CD8+. The combined model of serum NETs, CD8+ T cells, and tumor proportion score (TPS) significantly improved the prediction of PD-1 inhibitor efficacy [P = 0.033; area under the curve (AUC) = 0.881]. Our results indicate that serum NETs are effective predictors of PD-1 inhibitor response and reflect the tissue neutrophil-to-lymphocyte ratio and IrAE levels. The combined model of serum NETs, CD8+ T cells, and TPS is a powerful tool for predicting the efficacy of PD-1 inhibitor treatment in patients with NSCLC.

Causal Relationship Between Immune Cells/Cytokines and Dilated Cardiomyopathy.

To date, whether there is any causal relationship between dilated cardiomyopathy (DCM) and the changes in the levels/expression of immune cells/cytokines is still unclear. This study aimed to investigate the causal relationship between the levels of various types of immune cells/cytokines and DCM. Herein, two-sample Mendelian randomization (MR) (TSMR) using R software was conducted. Single nucleotide polymorphisms (SNPs) related to the levels of various types of immune cells/cytokines and DCM were screened based on the genome-wide association studies (GWAS) obtained from open-source databases. The TSMR was conducted using inverse variance weighted (IVW), method, MR-Egger regression, weighted median method, and simple estimator based on mode to explore the causal association between the levels of each immune cell/cytokine and DCM. Sensitivity analysis was conducted using MR-Egger regression and a leave-one-out sensitivity test. A total of 1816 SNPs related to host immune status and DCM were identified. The IVW results showed a relationship between DCM and the circulating levels of basophils/eosinophils, total eosinophils-basophils, lymphocytes, and C-reactive protein (CRP). Increased lymphocytes levels (odds ratio (OR) = 0.91, 95% confidence interval (CI): 0.84-0.97, P = 0.005) were seen as protective against DCM, whereas increased basophil (OR = 1.18, 95% CI: 1.04-1.33, P = 0.022), eosinophil (OR = 1.1, 95% CI: 1.03-1.17, P = 0.007), eosinophil-basophil (OR = 1.09, 95% CI: 1.02-1.17, P = 0.014), and CRP (OR = 1.1, 95% CI: 1.03-1.18, P = 0.013) levels were associated with an increased risk of DCM. These analyses revealed that there may be a relationship between immune cells/select cytokine status and the onset of DCM. Future studies are required to further validate these outcomes in animal models and clinical trials.

Genome-wide identification of dysregulated alternative splicing and RNA-binding proteins involved in atopic dermatitis.

Objectives: We explored the role and molecular mechanisms of RNA-binding proteins (RBPs) and their regulated alternative splicing events (RASEs) in the pathogenesis of atopic dermatitis (AD). Methods: We downloaded RNA-seq data (GSE121212) from 10 healthy control skin samples (healthy, Ctrl), 10 non-lesional skin samples with AD damage (non-lesional, NL), and 10 lesional skin samples with AD damage (lesional, LS). We performed the analysis of differentially expressed genes (DEGs), differentially expressed RBPs (DE-RBPs), alternative splicing (AS), functional enrichment, the co-expression of RBPs and RASEs, and quantitative polymerase chain reaction (qPCR). Results: We identified 60 DE-RBP genes by intersecting 2141 RBP genes from existing reports with overall 2697 DEGs. Most of the DE-RBP genes were found to be upregulated in the AD LS group and related to immune and apoptosis pathways. We observed different ASEs and RASEs among the healthy, AD NL, and AD LS groups. In particular, alt3p and alt5p were the main ASEs and RASEs in AD NL and AD LS groups, compared to the healthy group. Furthermore, we constructed co-expression networks of DE-RBPs and RAS, with particular enrichment in biological pathways including cytoskeleton organization, inflammation, and immunity. Subsequently, we selected seven genes that are commonly present in these three pathways to assess their expression levels in the peripheral blood mononuclear cells (PBMCs) from both healthy individuals and AD patients. The results demonstrated the upregulation of four genes (IFI16, S100A9, PKM, and ENO1) in the PBMCs of AD patients, which is highly consistent with DE-RBP genes analysis. Finally, we selected four RAS genes regulated by RBPs that were related to immune pathways and examined their RASEs in PBMCs from both AD patients and healthy controls. The results revealed an increased percentage of RASEs in the DDX60 gene in AD, which is highly consistent with AS analysis. Conclusion: Dysregulated RBPs and their associated RASEs may have a significant regulatory role in the development of AD and could be potential therapeutic targets in the future.

Catalytic Enantioselective Aminative Difunctionalization of Alkenes.

Enantioselective difunctionalization of alkenes offers a straightforward means for the rapid construction of enantioenriched complex molecules. Despite the tremendous efforts devoted to this field, enantioselective aminative difunctionalization remains a challenge, particularly through an electrophilic addition fashion. Herein, we report an unprecedented approach for the enantioselective aminative difunctionalization of alkenes via copper-catalyzed electrophilic addition with external azo compounds as nitrogen sources. A series of valuable cyclic hydrazine derivatives via either [3 + 2] cycloaddition or intramolecular cyclization have been achieved in high chemo-, regio-, enantio-, and diastereoselectivities. In this transformation, a wide range of functional groups, such as carboxylic acid, hydroxy, amide, sulfonamide, and aryl groups, could serve as nucleophiles. Importantly, a new cyano oxazoline chiral ligand was found to play a crucial role in the control of enantioselectivity.

Differences in physiology and behavior between male winner and loser mice in the tube test.

Social hierarchy is a crucial element for survival, reproduction, fitness, and the maintenance of a stable social group in social animals. This study aimed to investigate the physiological indicators, nociception, unfamiliar female mice preference, spatial learning memory, and contextual fear memory of male mice with different social status in the same cage. Our findings revealed significant differences in the trunk temperature and contextual fear memory between winner and loser mice. However, there were no major discrepancies in body weight, random and fasting blood glucose levels, whisker number, frontal and perianal temperature, spleen size, mechanical and thermal pain thresholds, preference for unfamiliar female mice, and spatial memory. In conclusion, social status can affect mice in multiple ways, and, therefore, its influence should be considered when conducting studies using these animals.

A survey on prevalence and parents' perceptions of food allergy in 3- to 16-year-old children in Wuhan, China.

Background: The prevalence of food allergy (FA) has risen in recent decades, yet there is limited data on the cognition and beliefs of FA among the parents of FA children. Objective: To investigate the prevalence of FA and assess the knowledge and perception of FA among parents of FA children in Wuhan, China. Methods: Online questionnaires were conducted for the parents of 3- to 16-year-old children. They reported symptoms of suspected FA in the screening questionnaire were interviewed for further diagnostic evaluation. All the parents of the suspected FA children completed the subsequent assessments of the knowledge and perception on FA as well as their attitude towards the current online platforms. Results: A total of 1963 children were recruited. The prevalence of self-reported FA was 10.2% (95% CI: 8.1-12.4%) and the physician-diagnosed FA was 6.2% (95% CI: 5.1-7.2%) in 3- to 16-year-olds in Wuhan. And the children with family history (57.9%) were predisposed to developing FA (P＜0.001). The total Brief Illness Perception Questionnaire (B-IPQ) score was 41.3 ± 10.0 among the parents. The B-IPQ scores correlated with symptom onset, but not with family history or other atopic comorbidities. The parents who never sought treatments obtained lower B-IPQ scores on most items compared to those who received treatments. The accuracy rate of the FA knowledge questionnaire was 56.7%. 11.6% of participants reported that children's FA had an impact on their lives. 67.2% of participants had searched information of FA online, among whom 80% expected to obtain professional suggestions on management and prevention strategies of FA from online platform. Conclusion: In 3- to 16-year-old children in Wuhan, the prevalence of self-reported and physician-diagnosed FA was 10.2% and 6.2% respectively. Parents' knowledge of FA was insufficient and only a small proportion of parents perceived that their lives and careers have been affected considerably by FA of their children. Patient education and current online platforms should be improved among parents of FA children.

The individualized delineation of clinical target volume for primary nasopharyngeal carcinoma based on invasion risk of substructures: A prospective, real-world study with a large population.

BACKGROUND AND PURPOSE: The delineation of clinical target volume (CTV) for primary nasopharyngeal carcinoma (NPC) is currently controversial and the international guideline still recommend a uniform border for CTV regardless of the tumor extent. We conducted this prospective, real-world study to evaluate the clinical outcomes of our individualized CTV delineation method based on distance plus substructures. MATERIALS AND METHODS: We preliminarily investigated the local extension patterns of NPC on 354 newly diagnosed patients and defined the structures surrounding the nasopharynx as Level-1 to Level-4 substructures stratified by the risk of invasion. We then enrolled patients with newly diagnosed NPC without distant metastasis to investigate our individualized CTV delineation protocol. All patients received intensity modulated radiotherapy. CTV1 and CTV2 were prescribed doses of 60 Gy and 54 Gy in 30 âˆ¼ 33 fractions. The primary endpoint was local recurrence-free survival (LRFS); secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method. The local failure patterns were also analyzed. RESULTS: From January 2008 to December 2012 and from January 2013 to September 2019, 356 and 648 patients were enrolled, named as training set and validation set, respectively. With a median follow-up of 104.6 (interquartile, 73.1-126.9) and 51.4 (39.5-78.5) months, 31 (8.7 %) and 38 (5.9 %) patients in training and validation sets experienced local recurrence, and the 5-year LRFS was 93.0 % and 93.2 %, respectively; 63 (17.7 %) and 39 (6 %) patients died in training and validation sets, and the 5-year overall survival (OS) was 88.5 % and 93.4 %, respectively. For the whole study cohort (N = 1004) with a median follow-up of 66.6 (41.5-98.0) months, the 5-year LRFS and OS was 93.2 % and 91.5 %. The grade 3 late toxicities included xerostomia, subcutaneous fibrosis, hearing impairment, trismus, visuality impairment and skin atrophy, with a total incidence of 1.5 %. Sixty-seven of 69 (97.1 %) local recurrence was in high-dose area. CONCLUSION: Our individualized CTV delineation method can achieve favorable local tumor control and long-term survival outcomes with acceptable late toxicities.

Vascular stent with immobilized anti-inflammatory chemerin 15 peptides mitigates neointimal hyperplasia and accelerates vascular healing.

Endovascular stenting is a safer alternative to open surgery for use in treating cerebral arterial stenosis and significantly reduces the recurrence of ischemic stroke, but the widely used bare-metal stents (BMSs) often result in in-stent restenosis (ISR). Although evidence suggests that drug-eluting stents are superior to BMSs in the short term, their long-term performances remain unknown. Herein, we propose a potential vascular stent modified by immobilizing clickable chemerin 15 (C15) peptides on the stent surface to suppress coagulation and restenosis. Various characterization techniques and an animal model were used to evaluate the surface properties of the modified stents and their effects on endothelial injury, platelet adhesion, and inflammation. The C15-immobilized stent could prevent restenosis by minimizing endothelial injury, promoting physiological healing, restraining the platelet-leukocyte-related inflammatory response, and inhibiting vascular smooth muscle cell proliferation and migration. Furthermore, in vivo studies demonstrated that the C15-immobilized stent mitigated inflammation, suppressed neointimal hyperplasia, and accelerated endothelial restoration. The use of surface-modified, anti-inflammatory, endothelium-friendly stents may be of benefit to patients with arterial stenosis. STATEMENT OF SIGNIFICANCE: Endovascular stenting is increasingly used for cerebral arterial stenosis treatment, aiming to prevent and treat ischemic stroke. But an important accompanying complication is in-stent restenosis (ISR). Persistent inflammation has been established as a hallmark of ISR and anti-inflammation strategies in stent modification proved effective. Chemerin 15, an inflammatory resolution mediator with 15-aa peptide, was active at picomolar through cell surface receptor, no need to permeate cell membrane and involved in resolution of inflammation by inhibiting inflammatory cells adhesion, modulating macrophage polarization into protective phenotype, and reducing inflammatory factors release. The implications of this study are that C15 immobilized stent favors inflammation resolution and rapid re-endothelialization, and exhibits an inhibitory role of restenosis. As such, it helps the decreased incidence of ISR.

A Highly Active Porous Mo2C-Mo2N Heterostructure on Carbon Nanowalls/Diamond for a High-Current Hydrogen Evolution Reaction.

Developing non-precious metal-based electrocatalysts operating in high-current densities is highly demanded for the industry-level electrochemical hydrogen evolution reaction (HER). Here, we report the facile preparation of binder-free Mo2C-Mo2N heterostructures on carbon nanowalls/diamond (CNWs/D) via ultrasonic soaking followed by an annealing treatment. The experimental investigations and density functional theory calculations reveal the downshift of the d-band center caused by the heterojunction between Mo2C/Mo2N triggering highly active interfacial sites with a nearly zero ∆GH* value. Furthermore, the 3D-networked CNWs/D, as the current collector, features high electrical conductivity and large surface area, greatly boosting the electron transfer rate of HER occurring on the interfacial sites of Mo2C-Mo2N. Consequently, the self-supporting Mo2C-Mo2N@CNWs/D exhibits significantly low overpotentials of 137.8 and 194.4 mV at high current densities of 500 and 1000 mA/cm2, respectively, in an alkaline solution, which far surpass the benchmark Pt/C (228.5 and 359.3 mV) and are superior to most transition-metal-based materials. This work presents a cost-effective and high-efficiency non-precious metal-based electrocatalyst candidate for the electrochemical hydrogen production industry.

Design and Fabrication of Environmentally Responsive Nanoparticles for the Diagnosis and Treatment of Atherosclerosis.

Cardiovascular disease poses a significant threat to human health in today's society. A major contributor to cardiovascular disease is atherosclerosis (AS). The development of plaque in the affected areas involves a complex pathological environment, and the disease progresses rapidly. Nanotechnology, combined with emerging diagnostic and treatment methods, offers the potential for the management of this condition. This paper presents the latest advancements in environment-intelligent responsive controlled-release nanoparticles designed specifically for the pathological environment of AS, which includes characteristics such as low pH, high reactive oxygen species levels, high shear stress, and multienzymes. Additionally, the paper summarizes the applications and features of nanotechnology in interventional therapy for AS, including percutaneous transluminal coronary angioplasty and drug-eluting stents. Furthermore, the application of nanotechnology in the diagnosis of AS shows promising real-time, accurate, and continuous effects. Lastly, the paper explores the future prospects of nanotechnology, highlighting the tremendous potential in the diagnosis and treatment of atherosclerotic diseases, especially with the ongoing development in nano gas, quantum dots, and Metal-Organic Frameworks materials.

Transcriptomic effects of paternal cocaine-seeking on the reward circuitry of male offspring.

It has been previously established that paternal development of a strong incentive motivation for cocaine can predispose offspring to develop high cocaine-seeking behavior, as opposed to sole exposure to the drug that results in drug resistance in offspring. However, the adaptive changes of the reward circuitry have not been fully elucidated. To infer the key nuclei and possible hub genes that determine susceptibility to addiction in offspring, rats were randomly assigned to three groups, cocaine self-administration (CSA), yoked administration (Yoke), and saline self-administration (SSA), and used to generate F1. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naïve conditions and after cocaine self-administration. Pairwise differentially expressed gene analysis revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine exposure, while the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) exhibited changes that were more closely associated with the paternal voluntary cocaine-seeking behavior. Consistently, these nuclei showed decreased dopamine levels, elevated neuronal activation, and elevated between-nuclei correlations, indicating dopamine-centered rewiring of the midbrain circuit in the CSA offspring. To determine if possible regulatory cascades exist that drive the expression changes, we constructed co-expression networks induced by paternal drug addiction and identified three key clusters, primarily driven by transcriptional factors such as MYT1L, POU3F4, and NEUROD6, leading to changes of genes regulating axonogenesis, synapse organization, and membrane potential, respectively. Collectively, our data highlight vulnerable neurocircuitry and novel regulatory candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.

Paternal cocaine-seeking motivation defines offspring's vulnerability to addiction by down-regulating GABAergic GABRG3 in the ventral tegmental area.

Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.

Photoredox-Mediated Aerobic Oxidative Cleavage of 1,3-Diketones to Access 1,2-Diketones and (Z)-1,4-Enediones.

An aerobic oxidative cleavage of 1,3-diketones under visible light irradiation using an organic dye as a photocatalyst is disclosed. The newly developed reaction provides practical access to 1,2-diketones and (Z)-1,4-enediones in moderate to good yields with absolute regio- and stereoselectivity. Mechanistic studies of the reaction suggest that tetraketone intermediates might undergo a photocatalytic energy transfer from the excited photocatalyst to form biradical-like (n,π*) states of ketones.

Topical glutathione amino acid precursors protect skin against environmental and oxidative stress.

BACKGROUND: Although glutathione (GSH) has long been considered a master antioxidant, poor stability and bioavailability limit its application in skin protection. To overcome the challenges, Unilever R&D formulated a Glutathione Amino acid Precursors blend (named GAP) to boost GSH de novo synthesis. OBJECTIVE: Determine whether GAP can boost GSH levels and provide skin protection against stressors. METHODS: Normal human epidermal keratinocytes were treated with GAP, with or without stressors, namely, menadione, blue light or pollutants. Ascorbic acid was used as a benchmark. The levels of GSH, glutathione disulfide (GSSG), adenosine triphosphate (ATP) and reactive oxygen species (ROS) were quantified. A placebo-controlled clinical study was conducted on 21 female subjects who received product applications and subsequent UV radiation. Tape strip samples were collected from the subjects for GSH and GSSG quantification using ultra-performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS). The UV-protective effect of GAP was investigated using ex vivo skin. Biomarkers related to DNA damage and the skin barrier were analysed using immunohistochemistry. RESULTS: Glutathione amino acid precursors significantly increased the GSH levels and GSH/GSSG ratio in normal human epidermal keratinocytes. Menadione treatment resulted in excessive ROS production and a decline in ATP levels, which were effectively abrogated by GAP. The protective effects of GAP against menadione-induced oxidative stress were superior to those of ascorbic acid. In addition, GAP effectively protected the cells against blue light-induced ROS production and pollutant-induced ATP depletion. Topical application of the GAP formulation significantly elevated the skin GSH/GSSG ratio in a clinical study. Ex vivo skin treated with the GAP formulation displayed a reduction in DNA damage and high levels of barrier proteins after UV exposure. CONCLUSIONS: Glutathione amino acid precursors effectively increases cellular GSH levels to protect the skin from oxidative and environmental stresses.