Unraveling the Unique Strong Metal-Support Interaction in Titanium Dioxide Supported Platinum Clusters for the Hydrogen Evolution Reaction.

Strong metal-support interaction (SMSI) is crucial to modulating the nature of metal species, yet the SMSI behaviors of sub-nanometer metal clusters remain unknown due to the difficulties in constructing SMSI at cluster scale. Herein, we achieve the successful construction of the SMSI between Pt clusters and amorphous TiO2 nanosheets by vacuum annealing, which required a relatively low temperature that avoids the aggregation of small clusters. In situ scanning transmission electron microscopy observation is employed to explore the SMSI behaviors, and the results reveal the dynamic rearrangement of Pt atoms upon annealing for the first time. The originally disordered Pt atoms become ordered as the crystallizing of the amorphous TiO2 support, forming an epitaxial interface between Pt and TiO2. Such SMSI state can remain stable in oxidation environment even at 400 °C. Further investigations prove that the electron transfer from TiO2 to Pt occupies the Pt 5d orbitals, which is responsible for the disappeared CO adsorption ability of Pt/TiO2 after forming SMSI. This work not only opens a new avenue for constructing SMSI at cluster scale but also provides in-depth understanding on the unique SMSI behavior, which would stimulate the development of supported metal clusters for catalysis applications.

Heterogenetic mechanism in high-temperature Daqu fermentation by traditional craft and mechanical craft: From microbial assembly patterns to metabolism phenotypes.

The mechanical process has a widely usage in large-scale high-temperature Daqu (HTD) enterprises, however, the quality of the mechanical HTD is gapped with the HTD by traditional process. Currently, the understanding of the mechanism behind this phenomenon is still over-constrained. To this end, the discrepancies in fermentation parameters, enzymatic characteristics, microbial assembly and succession patterns, metabolic phenotypes were compared between traditional HTD and mechanical HTD in this paper. The results showed that mechanical process altered the temperature ramping procedure, resulting in a delayed appearance of the peak temperature. This alteration shifted the assembly pattern of the initial bacterial community from determinism to stochasticity, while having no impact on the stochastic assembly pattern of the fungal community. Concurrently, mechanical pressing impeded the accumulation of arginase, tetramethylpyrazine, trimethylpyrazine, 2-methoxy-4-vinylphenol, and butyric acid, as the target dissimilarities in metabolism between traditional HTD and mechanical HTD. Pearson correlation analysis combined with the functional prediction further demonstrated that Bacillus, Virgibacillus, Oceanobacillus, Kroppenstedtia, Lactobacillus, and Monascus were mainly contributors to metabolic variances. The Redundancy analysis (RDA) of fermented environmental factors on functional ASVs indicated that high temperature, high acid and low moisture were key positive drivers on the microbial metabolism for the characteristic flavor in HTD. Based on these results, heterogeneous mechanisms between traditional HTD and mechanical HTD were explored, and controllable metabolism targets were as possible strategies to improve the quality of mechanical HTD.

Ten-year observation of corneal densitometry and associated factors following small incision lenticule extraction.

AIM: To investigate the long-term changes of corneal densitometry (CD) and its contributing elements after small incision lenticule extraction (SMILE). METHODS: Totally 31 eyes of 31 patients with mean spherical equivalent of -6.46±1.50 D and mean age 28.23±7.38y were enrolled. Full-scale examinations were conducted on all patients preoperatively and during follow-up. Visual acuity, manifest refraction, axial length, corneal thickness, corneal higher-order aberrations, and CD were evaluated. RESULTS: All surgeries were completed successfully without complications or adverse events. Ten-year safety index was 1.17±0.20 and efficacy 1.04±0.28. CD value of 0-6 mm zones in central layer was statistically significantly lower 10y postoperatively, compared with preoperative values (0-2 mmΔ=-1.62, 2-6 mmΔ=-1.24, P<0.01). There were no correlations between CD values and factors evaluated. CONCLUSION: SMILE is a safe and efficient procedure for myopia on a long-term basis. CD values get lower 10y postoperatively, whose mechanism is to be further discussed.

The mechanisms of natural products for eye disorders by targeting mitochondrial dysfunction.

The human eye is susceptible to various disorders that affect its structure or function, including glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitochondrial dysfunction has been identified as a critical factor in the pathogenesis and progression of eye disorders, making it a potential therapeutic target in the clinic. Natural products have been used in traditional medicine for centuries and continue to play a significant role in modern drug development and clinical therapeutics. Recently, there has been a surge in research exploring the efficacy of natural products in treating eye disorders and their underlying physiological mechanisms. This review aims to discuss the involvement of mitochondrial dysfunction in eye disorders and summarize the recent advances in the application of natural products targeting mitochondria. In addition, we describe the future perspective and challenges in the development of mitochondria-targeting natural products.

Human amniotic mesenchymal stem cells-derived conditioned medium and exosomes alleviate oxidative stress-induced retinal degeneration by activating PI3K/Akt/FoxO3 pathway.

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly, which is primarily attributed to oxidative stress-induced damage to the retinal pigment epithelium (RPE). Human amniotic mesenchymal stem cells (hAMSC) were considered to be one of the most promising stem cells for clinical application due to their low immunogenicity, tissue repair ability, pluripotent potential and potent paracrine effects. The conditional medium (hAMSC-CM) and exosomes (hAMSC-exo) derived from hAMSC, as mediators of intercellular communication, play an important role in the treatment of retinal diseases, but their effect and mechanism on oxidative stress-induced retinal degeneration are not explored. Here, we reported that hAMSC-CM alleviated H2O2-induced ARPE-19 cell death through inhibiting mitochondrial-mediated apoptosis pathway in vitro. The overproduction of reactive oxygen species (ROS), alteration in mitochondrial morphology, loss of mitochondrial membrane potential and elevation of Bax/Bcl2 ratio in ARPE-19 cells under oxidative stress were efficiently reversed by hAMSC-CM. Moreover, it was found that hAMSC-CM protected cells against oxidative injury via PI3K/Akt/FoxO3 signaling. Intriguingly, exosome inhibitor GW4869 alleviated the inhibitory effect of hAMSC-CM on H2O2-induced decrease in cell viability of ARPE-19 cells. We further demonstrated that hAMSC-exo exerted the similar protective effect on ARPE-19 cells against oxidative damage as hAMSC-CM. Additionally, both hAMSC-CM and hAMSC-exo ameliorated sodium iodate-induced deterioration of RPE and retinal damage in vivo. These results first indicate that hAMSC-CM and hAMSC-exo protect RPE cells from oxidative damage by regulating PI3K/Akt/FoxO3 pathway, suggesting hAMSC-CM and hAMSC-exo will be a promising cell-free therapy for the treatment of AMD in the future.

The present state and future outlook of pectin-based nanoparticles in the stabilization of Pickering emulsions.

The stabilization of Pickering emulsions using micro/nanoparticles has gained significant attention due to their wide range of potential applications in industries such as cosmetics, food, catalysis, tissue engineering, and drug delivery. There is a growing demand for the development of environmentally friendly micro/nanoparticles to create stable Pickering emulsions. Naturally occurring polysaccharides like pectin offer promising options as they can assemble at oil/water interfaces. This polysaccharide is considered a green candidate because of its biodegradability and renewable nature. The physicochemical properties of micro/nanoparticles, influenced by fabrication methods and post-modification techniques, greatly impact the characteristics and applications of the resulting Pickering emulsions. This review focuses on recent advancements in Pickering emulsions stabilized by pectin-based micro/nanoparticles, as well as the application of functional materials in delivery systems, bio-based films and 3D printing using these emulsions as templates. The effects of micro/nanoparticle properties on the characteristics of Pickering emulsions and their applications are discussed. Additionally, the obstacles that currently hinder the practical implementation of pectin-based micro/nanoparticles and Pickering emulsions, along with future prospects for their development, are addressed.

Single-Cell Transcriptome Landscape and Cell Fate Decoding in Human Brain Organoids after Transplantation.

Human stem cells and derivatives transplantation are widely used to treat nervous system diseases, while the fate determination of transplanted cells is not well elucidated. To explore cell fate changes of human brain organoids before and after transplantation, human brain organoids are transplanted into prefrontal cortex (PFC) and hippocampus (HIP), respectively. Single-cell sequencing is then performed. According to time-series sample comparison, transplanted cells mainly undergo neural development at 2 months post-transplantation (MPT) and then glial development at 4MPT, respectively. A different brain region sample comparison shows that organoids grafted to PFC have obtained cell fate close to those of host cells in PFC, other than HIP, which may be regulated by the abundant expression of dopamine (DA) and acetylcholine (Ach) in PFC. Meanwhile, morphological complexity of human astrocyte grafts is greater in PFC than in HIP. DA and Ach both activate the calcium activity and increase morphological complexity of astrocytes in vitro. This study demonstrates that human brain organoids receive host niche factor regulation after transplantation, resulting in the alignment of grafted cell fate with implanted brain regions, which may contribute to a better understanding of cell transplantation and regenerative medicine.

Comprehensive comparison between conservative therapy and surgical management for completely displaced and comminuted mid-shaft clavicle fractures.

PURPOSE: It is still controversial whether complete displaced mid-shaft clavicle fractures should be treated with internal fixation or conservative therapy. This retrospective study aims to compare clinical outcomes of two treatment protocols. MATERIALS AND METHODS: 105 patients with displaced and comminuted mid-shaft clavicle fractures were included in this study, among which 55 patients were treated conservatively and 50 patients accepted surgical fixation and were followed up for over 20 months on average. Rate of union, malunion, time taken for union, functional outcome, self-reported satisfaction and complications were compared. RESULTS: Union rate of operative group (n=49, 98.0%) was higher than the non-operative group (n=48, 87.3%). Time taken for union in operative group (2.37±1.06 months) was shorter than the non-operative group (3.69±1.01 months). Malunion and asymmetric were only seen in the conservative group. Numbness of the shoulder was only reported in the operative group (n=23, 46.0%). Most of patients in the operative group (n=45, 90%) accepted a second operation to remove the implant. No statistically difference was found in self-reported satisfaction, Quick-DASH and Constant-Murley score. The operative group returned to work faster (1.47±0.89 to 3.34±1.37 months), regained full range of motion earlier (1.66±0.78 to 3.83±1.24 months) and regained strength faster (3.86±2.45 to 8.03±2.78 months) than the non-operative group. CONCLUSION: Complete displaced and comminuted mid-shaft clavicle fractures treated surgically have more reliable union and faster recovery when compared to conservatively treated fractures.

Sarcocinerenolides A, an open-loop decarbonizing cembranolide, and sarcocinerenolides B-I, eight polyoxygenated cembranolides with anti-thrombotic activity from the South China Sea soft coral Sarcophyton cinereum.

A previously undescribed open-loop decarbonizing cembranolide, sarcocinerenolide A, and eight undescribed cembranolides, sarcocinerenolides B-I, characterized by poly-membered oxygen ring fragments were isolated from the soft coral Sarcophyton cinereum collected from the South China Sea. The structures and absolute configurations of these previously undescribed compounds were precisely determined by analysis of NMR data, DP4+ and ECD spectra. The bioactivities of the compounds were evaluated using zebrafish models and sarcocinerenolides C and H exhibited anti-thrombotic activity.

Construction of human 3D striato-nigral assembloids to recapitulate medium spiny neuronal projection defects in Huntington's disease.

The striato-nigral (Str-SN) circuit is composed of medium spiny neuronal projections that are mainly sent from the striatum to the midbrain substantial nigra (SN), which is essential for regulating motor behaviors. Dysfunction of the Str-SN circuitry may cause a series of motor disabilities that are associated with neurodegenerative disorders, such as Huntington's disease (HD). Although the etiology of HD is known as abnormally expanded CAG repeats of the huntingtin gene, treatment of HD remains tremendously challenging. One possible reason is the lack of effective HD model that resembles Str-SN circuitry deficits for pharmacological studies. Here, we first differentiated striatum-like organoids from human pluripotent stem cells (hPSCs), containing functional medium spiny neurons (MSNs). We then generated 3D Str-SN assembloids by assembling striatum-like organoids with midbrain SN-like organoids. With AAV-hSYN-GFP-mediated viral tracing, extensive MSN projections from the striatum to the SN are established, which formed synaptic connection with GABAergic neurons in SN organoids and showed the optically evoked inhibitory postsynaptic currents and electronic field potentials by labeling the striatum-like organoids with optogenetic virus. Furthermore, these Str-SN assembloids exhibited enhanced calcium activity compared to that of individual striatal organoids. Importantly, we further demonstrated the reciprocal projection defects in HD iPSC-derived assembloids, which could be ameliorated by treatment of brain-derived neurotrophic factor. Taken together, these findings suggest that Str-SN assembloids could be used for identifying MSN projection defects and could be applied as potential drug test platforms for HD.

Targeted inhibition of branched-chain amino acid metabolism drives apoptosis of glioblastoma by facilitating ubiquitin degradation of Mfn2 and oxidative stress.

Glioblastoma is one of the most challenging malignancies with high aggressiveness and invasiveness and its development and progression of glioblastoma highly depends on branched-chain amino acid (BCAA) metabolism. The study aimed to investigate effects of inhibition of BCAA metabolism with cytosolic branched-chain amino acid transaminase (BCATc) Inhibitor 2 on glioblastoma, elucidate its underlying mechanisms, and explore therapeutic potential of targeting BCAA metabolism. The expression of BCATc was upregulated in glioblastoma and BCATc Inhibitor 2 precipitated apoptosis both in vivo and in vitro with the activation of Bax/Bcl2/Caspase-3/Caspase-9 axis. In addition, BCATc Inhibitor 2 promoted K63-linkage ubiquitination of mitofusin 2 (Mfn2), which subsequently caused lysosomal degradation of Mfn2, and then oxidative stress, mitochondrial fission and loss of mitochondrial membrane potential. Furthermore, BCATc Inhibitor 2 treatment resulted in metabolic reprogramming, and significant inhibition of expression of ATP5A, UQCRC2, SDHB and COX II, indicative of suppressed oxidative phosphorylation. Moreover, Mfn2 overexpression or scavenging mitochondria-originated reactive oxygen species (ROS) with mito-TEMPO ameliorated BCATc Inhibitor 2-induced oxidative stress, mitochondrial membrane potential disruption and mitochondrial fission, and abrogated the inhibitory effect of BCATc Inhibitor 2 on glioblastoma cells through PI3K/AKT/mTOR signaling. All of these findings indicate suppression of BCAA metabolism promotes glioblastoma cell apoptosis via disruption of Mfn2-mediated mitochondrial dynamics and inhibition of PI3K/AKT/mTOR pathway, and suggest that BCAA metabolism can be targeted for developing therapeutic agents to treat glioblastoma.

Mitigating dengue incidence through advanced Aedes larval surveillance and control: A successful experience from Pakistan.

Dengue fever is a viral disease caused by one of four dengue stereotypes (Flavivirus: Flaviviridae) that are primarily transmitted by Aedes albopictus (Skuse) and Aedes aegypti (L.). To safeguard public health, it is crucial to conduct surveys that examine the factors favouring the presence of these species. Our study surveyed 42 councils across four towns within the Bhakkar district of Punjab Province, by inspecting man-made or natural habitats containing standing water. First, door-to-door surveillance teams from the district health department were assigned to each council to surveillance Aedes species and dengue cases. Second, data collection through surveillance efforts, and validation procedures were implemented, and the verified data was uploaded onto the Dengue Tracking System by Third Party Validation teams. Third, data were analysed to identify factors influencing dengue fever cases. The findings demonstrated the following: (1) Predominantly, instances were discerned among individuals who had a documented history of having travelled beyond the confines of the province. (2) Containers associated with evaporative air coolers and tyre shops were responsible for approximately 30% of the Aedes developmental sites. (4) Variability in temperature was responsible for approximately 45% of the observed differences in the quantity of recorded Aedes mosquito developmental sites. (5) Implementation of dengue prevention initiatives precipitated a 50% reduction in Aedes-positive containers, alongside a notable 70% decline in reported cases of dengue fever during the period spanning 2019 to 2020, while the majority of reported cases were of external origin. Aedes control measures substantially curtailed mosquito populations and lowered vector-virus interactions. Notably, local dengue transmission was eliminated through advanced and effective Aedes control efforts, emphasising the need for persistent surveillance and eradication of larval habitats in affected regions.

PPA1 promotes adipogenesis by regulating the stability of C/EBPs.

Adipogenesis significantly contributes to healthy adipose tissue expansion in obesity. Increasing adipocyte number or function to alleviate adipose tissue overload could serve as a therapeutic strategy for both lipodystrophy and obesity-related metabolic syndrome. Inorganic pyrophosphatase (PPA1) is an enzyme that catalyzes the hydrolysis of pyrophosphate (PPi) and is involved in many biochemical reactions, but its function in adipose tissue has not been studied previously. In this study, we demonstrated that adipose-specific PPA1 knockout (PPA1AKO) mice showed lipodystrophy and spontaneously developed hepatic steatosis and severe insulin resistance under normal chow diet feeding. PPA1 deficiency suppressed the differentiation of primary adipocyte precursors and 3T3-L1 cells. Notably, PPA1 overexpression can restore inhibited adipogenesis in preadipocytes isolated from db/db mice and type 2 diabetes patients. Mechanistic studies have revealed that PPA1 acts as a positive regulator of early adipocyte differentiation by promoting CCAAT/enhancer-binding proteinß and δ (C/EBPß and δ) protein stability. Moreover, the function of PPA1 in adipogenesis is independent of its PPi catalytic activity. Collectively, our in vivo and in vitro findings demonstrated that PPA1 is a novel critical upstream regulator of adipogenesis, controlling adipose tissue development and whole-body metabolic homeostasis.

Cannabidiol ameliorates PTSD-like symptoms by inhibiting neuroinflammation through its action on CB2 receptors in the brain of male mice.

Post-traumatic stress disorder (PTSD) is a debilitating mental health disease related to traumatic experience, and its treatment outcomes are unsatisfactory. Accumulating research has indicated that cannabidiol (CBD) exhibits anti-PTSD effects, however, the underlying mechanism of CBD remains inadequately investigated. Although many studies pertaining to PTSD have primarily focused on aberrations in neuronal functioning, the present study aimed to elucidate the involvement and functionality of microglia/macrophages in PTSD while also investigated the modulatory effects of CBD on neuroinflammation associated with this condition. We constructed a modified single-prolonged stress (SPS) mice PTSD model and verified the PTSD-related behaviors by various behavioral tests (contextual freezing test, elevated plus maze test, tail suspension test and novel object recognition test). We observed a significant upregulation of Iba-1 and alteration of microglial/macrophage morphology within the prefrontal cortex and hippocampus, but not the amygdala, two weeks after the PTSD-related stress, suggesting a persistent neuroinflammatory phenotype in the PTSD-modeled group. CBD (10 mg/kg, i.p.) inhibited all PTSD-related behaviors and reversed the alterations in both microglial/macrophage quantity and morphology when administered prior to behavioral assessments. We further found increased pro-inflammatory factors, decreased PSD95 expression, and impaired synaptic density in the hippocampus of the modeled group, all of which were also restored by CBD treatment. CBD dramatically increased the level of anandamide, one of the endocannabinoids, and cannabinoid type 2 receptors (CB2Rs) transcripts in the hippocampus compared with PTSD-modeled group. Importantly, we discovered the expression of CB2Rs mRNA in Arg-1-positive cells in vivo and found that the behavioral effects of CBD were diminished by CB2Rs antagonist AM630 (1 mg/kg, i.p.) and both the behavioral and molecular effects of CBD were abolished in CB2Rs knockout mice. These findings suggest that CBD would alleviate PTSD-like behaviors in mice by suppressing PTSD-related neuroinflammation and upregulation and activation of CB2Rs may serve as one of the underlying mechanisms for this therapeutic effect. The present study offers innovative experimental evidence supporting the utilization of CBD in PTSD treatment from the perspective of its regulation of neuroinflammation, and paves the way for leveraging the endocannabinoid system to regulate neuroinflammation as a potential therapeutic approach for psychiatric disorders.

Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer.

Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.

Construction of a stable radical hydrogen-bonded metal-organic framework with functionalized tetrathiafulvalene linkers.

A stable two-dimensional radical hydrogen-bonded metal-organic framework, constructed using a modified tetrathiafulvalene-tetrabenzoate ((2-Me)-H4TTFTB) linker and Cd2+ ions, exhibits a high electrical conductivity of 4.1 × 10-4 S m-1 and excellent photothermal conversion with a temperature increase of 137 °C in 15 s under the irradiation of a 0.7 W cm-2 808 nm laser.

Artificial intelligence enhances whole-slide interpretation of PD-L1 CPS in triple-negative breast cancer: A multi-institutional ring study.

BACKGROUND AND AIMS: Evaluation of the programmed cell death ligand-1 (PD-L1) combined positive score (CPS) is vital to predict the efficacy of the immunotherapy in triple-negative breast cancer (TNBC), but pathologists show substantial variability in the consistency and accuracy of the interpretation. It is of great importance to establish an objective and effective method which is highly repeatable. METHODS: We proposed a model in a deep learning-based framework, which at the patch level incorporated cell analysis and tissue region analysis, followed by the whole-slide level fusion of patch results. Three rounds of ring studies (RSs) were conducted. Twenty-one pathologists of different levels from four institutions evaluated the PD-L1 CPS in TNBC specimens as continuous scores by visual assessment and our artificial intelligence (AI)-assisted method. RESULTS: In the visual assessment, the interpretation results of PD-L1 (Dako 22C3) CPS by different levels of pathologists have significant differences and showed weak consistency. Using AI-assisted interpretation, there were no significant differences between all pathologists (P = 0.43), and the intraclass correlation coefficient (ICC) value was increased from 0.618 [95% confidence interval (CI) = 0.524-0.719] to 0.931 (95% CI = 0.902-0.955). The accuracy of interpretation result is further improved to 0.919 (95% CI = 0.886-0.947). Acceptance of AI results by junior pathologists was the highest among all levels, and 80% of the AI results were accepted overall. CONCLUSION: With the help of the AI-assisted diagnostic method, different levels of pathologists achieved excellent consistency and repeatability in the interpretation of PD-L1 (Dako 22C3) CPS. Our AI-assisted diagnostic approach was proved to strengthen the consistency and repeatability in clinical practice.

Proteinase­3­antineutrophil cytoplasmic antibody­associated vasculitis secondary to subacute infective endocarditis: A case report.

A 58-year-old male patient was admitted to Peking University First Hospital (Beijing, China) due to recurrent hematuria, proteinuria and kidney dysfunction. The patient was positive for proteinase-3 (PR3)-antineutrophil cytoplasmic antibody (ANCA). Pathology of the kidney showed focal proliferative necrotizing glomerulonephritis with crescent formation and immune complex-mediated glomerulonephritis. The patient was diagnosed with PR3-ANCA-associated vasculitis (AAV), received intensive immunosuppressive therapy and experienced two relapses within 1 year. After admission, aortic valve vegetation was observed via echocardiography. The patient subsequently received antibiotic treatment and valve replacement, and achieved complete remission of kidney and cardiac function. The present case emphasized the importance of identifying secondary reasons for ANCA formation, especially infective endocarditis in patients with PR3-AAV.

Vineyard microclimate alterations induced by black inter-row mulch through transcriptome reshaped the flavoromics of cabernet sauvignon grapes.

BACKGROUND: Weed control is essential for agricultural floor management in vineyards and the inter-row mulching is an eco-friendly practice to inhibit weed growth via filtering out photosynthetically active radiation. Besides weed suppression, inter-row mulching can influence grapevine growth and the accumulation of metabolites in grape berries. However, the complex interaction of multiple factors in the field challenges the understanding of molecular mechanisms on the regulated metabolites. In the current study, black geotextile inter-row mulch (M) was applied for two vintages (2016-2017) from anthesis to harvest. Metabolomics and transcriptomics analysis were conducted in two vintages, aiming to provide insights into metabolic and molecular responses of Cabernet Sauvignon grapes to M in a semi-arid climate. RESULTS: Upregulation of genes related to photosynthesis and heat shock proteins confirmed that M weakened the total light exposure and grapes suffered heat stress, resulting in lower sugar-acid ratio at harvest. Key genes responsible for enhancements in phenylalanine, glutamine, ornithine, arginine, and C6 alcohol concentrations, and the downward trend in ε-viniferin, anthocyanins, flavonols, terpenes, and norisoprenoids in M grapes were identified. In addition, several modules significantly correlated with the metabolic biomarkers through weighted correlation network analysis, and the potential key transcription factors regulating the above metabolites including VviGATA11, VviHSFA6B, and VviWRKY03 were also identified. CONCLUSION: This study provides a valuable overview of metabolic and transcriptomic responses of M grapes in semi-arid climates, which could facilitate understanding the complex regulatory network of metabolites in response to microclimate changes.