Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life.

BACKGROUND: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively. METHODS: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. RESULTS: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. CONCLUSIONS: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play.

O-GlcNAcylation promotes the progression of nonalcoholic fatty liver disease by upregulating the expression and function of CD36.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) and its progressive variant, nonalcoholic steatohepatitis (NASH), constitute a burgeoning worldwide epidemic with no FDA-approved pharmacotherapies. The multifunctional immunometabolic receptor, fatty acid translocase CD36 (CD36), plays an important role in the progression of hepatic steatosis. O-GlcNAcylation is a crucial posttranslational modification that mediates the distribution and function of CD36, but its involvement in NAFLD remains poorly understood. METHODS: O-GlcNAcylation and CD36 expression were evaluated in human liver tissues obtained from NASH patients and normal control. Mice with hepatocyte-specific CD36 knockout were administered adeno-associated viral vectors expressing wild-type CD36 (WT-CD36) or CD36 O-GlcNAcylation site mutants (S468A&T470A-CD36) and were provided with a high-fat/high-cholesterol (HFHC) diet for 3 months. RT-qPCR analysis, immunoblotting, dual-luciferase reporter assays, chromatin immunoprecipitation, and coimmunoprecipitation were performed to explore the mechanisms by which O-GlcNAcylation regulates CD36 expression. Membrane protein extraction, immunofluorescence analysis, site-directed mutagenesis, and fatty acid uptake assays were conducted to elucidate the impact of O-GlcNAcylation on CD36 function. RESULTS: O-GlcNAcylation and CD36 expression were significantly increased in patients with NASH, mouse models of NASH, and palmitic acid-stimulated hepatocytes. Mechanistically, the increase in O-GlcNAcylation facilitated the transcription of CD36 via the NF-κB signalling pathway and stabilized the CD36 protein by inhibiting its ubiquitination, thereby promoting CD36 expression. On the other hand, O-GlcNAcylation facilitated the membrane localization of CD36, fatty acid uptake, and lipid accumulation. However, site-directed mutagenesis of residues S468 and T470 of CD36 reversed these effects. Furthermore, compared with their WT-CD36 counterparts, HFHC-fed S468A&T470A-CD36 mice exhibited decreases in systemic insulin resistance, steatosis severity, inflammation and fibrosis. Pharmacological inhibition of O-GlcNAcylation and CD36 also mitigated the progression of NASH. CONCLUSIONS: O-GlcNAcylation promotes the progression of NAFLD by upregulating CD36 expression and function. Inhibition of CD36 O-GlcNAcylation protects against NASH, highlighting a potentially effective therapeutic approach for individuals with NASH.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia.

OBJECTIVE: In B-cell acute lymphoblastic leukemia (B-ALL), current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50% of cases, underscoring the urgent need for new therapeutic regimens for this patient population. The present study aimed to determine whether HZX-02-059, a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) and tubulin, is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients. METHODS: Cell proliferation, vacuolization, apoptosis, cell cycle, and in-vivo tumor growth were evaluated. In addition, Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL. RESULTS: HZX-02-059 was found to inhibit cell proliferation, induce vacuolization, promote apoptosis, block the cell cycle, and reduce in-vivo tumor growth. Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations. CONCLUSION: Overall, these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Functional analysis of CYP71AV1 reveals the evolutionary landscape of artemisinin biosynthesis.

Artemisinin biosynthesis, unique to Artemisia annua, is suggested to have evolved from the ancestral costunolide biosynthetic pathway commonly found in the Asteraceae family. However, the evolutionary landscape of this process is not fully understood. The first oxidase in artemisinin biosynthesis, CYP71AV1, also known as amorpha-4,11-diene oxidase (AMO), has specialized from ancestral germacrene A oxidases (GAOs). Unlike GAO, which exhibits catalytic promiscuity toward amorpha-4,11-diene, the natural substrate of AMO, AMO has lost its ancestral activity on germacrene A. Previous studies have suggested that the loss of the GAO copy in A. annua is responsible for the abolishment of the costunolide pathway. In the genome of A. annua, there are two copies of AMO, each of which has been reported to be responsible for the different product profiles of high- and low-artemisinin production chemotypes. Through analysis of their tissue-specific expression and comparison of their sequences with those of other GAOs, it was discovered that one copy of AMO (AMOHAP) exhibits a different transcript compared to the reported artemisinin biosynthetic genes and shows more sequence similarity to other GAOs in the catalytic regions. Furthermore, in a subsequent in vitro enzymatic assay, the recombinant protein of AMOHAP unequivocally demonstrated GAO activity. This result clearly indicates that AMOHAP is a GAO rather than an AMO and that its promiscuous activity on amorpha-4,11-diene has led to its misidentification as an AMO in previous studies. In addition, the divergent expression pattern of AMOHAP compared to that of the upstream germacrene A synthase may have contributed to the abolishment of costunolide biosynthesis in A. annua. Our findings reveal a complex evolutionary landscape in which the emergence of a new metabolic pathway replaces an ancestral one.

Ginsenoside Rc alleviates osteoporosis by the TGF-ß/Smad signaling pathway.

Osteoporosis is a common chronic bone disorder in postmenopausal women. Ginsenosides are primary active components in ginseng and the effects of various ginsenoside variants in osteoporosis treatment have been widely revealed. We planned to explore the impact of ginsenoside Rc on bone resorption in an osteoporosis rat model. We used ovariectomized rats to assess the potential impact of ginsenoside Rc on osteoporosis. µ-CT was implemented for analyzing the microstructure of the distal left femur in rats. H&E staining together with Masson staining were applied for bone histomorphometry evaluation. ELISA kits were implemented to detect serum concentrations of TRACP-5b, OCN, CTX, as well as PINP. Ginsenoside Rc treatment lessened the serum levels of TRACP-5b as well as CTX, while increasing serum levels of OCN, and PINP of OVX rats. Moreover, we found that ginsenoside Rc contributed to the synthesis of type I collagen via increasing Col1a1 and Col1a2 levels in femur tissues of ovariectomized rats. Our findings also revealed that ginsenoside Rc activated the TGF-ß/Smad pathway by increasing TGF-ß as well as phosphorylated Smad2/3 protein levels. Ginsenoside Rc alleviates osteoporosis in rats through promoting the TGF-ß/Smad pathway.

Arene-Arene Coupled Disulfamethazines (or Sulfadiazine)-Phenanthroline-Metal(II) Complexes were Synthesized by In Situ Reactions and Inhibited the Growth and Development of Triple-Negative Breast Cancer through the Synergistic Effect of Antiangiogenesis, Anti-Inflammation, Pro-Apoptosis, and Cuproptosis.

The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.

Quercetin attenuates lipopolysaccharide-induced hepatic inflammation by modulating autophagy and necroptosis.

Lipopolysaccharide (LPS) from Gram-negative bacteria initially induces liver inflammation with proinflammatory cytokines expressions. However, the underlying hepatoprotective mechanism of quercetin on LPS-induced hepatic inflammation remains unclear. Specific pathogen-free chicken embryos (n = 120) were allocated control vehicle, PBS with or without ethanol vehicle, LPS (125 ng/egg) with or without quercetin treatment (10, 20, or 40 nmol/egg, respectively), quercetin groups (10, 20, or 40 nmol/egg). Fifteen-day-old embryonated eggs were inoculated abovementioned solutions via the allantoic cavity. At embryonic d 19, the livers of the embryos were collected for histopathological examination, RNA extraction, real-time polymerase chain reaction, and immunohistochemistry investigation. We found that the liver presented inflammatory response (heterophils infiltration) after LPS induction. The LPS-induced mRNA expressions of inflammation-related factors (TLR4, TNFα, IL-1ß, IL-10, IL-6, MYD88, NF-κB1, p38, and MMP3) were upregulated after LPS induction when compared with the PBS group, while quercetin could downregulate these expressions as compared with the LPS group. Quercetin significantly decreased the immunopositivity to TLR4 and MMP3 in the treatment group when compared with the LPS group. Quercetin could significantly downregulate the mRNA expressions of autophagy-related genes (ATG5, ATG7, Beclin-1, LC3A, and LC3B) and necroptosis-related genes (Fas, Bcl-2, Drp1, and RIPK1) after LPS induction. Quercetin significantly decreased the immunopositivity to LC3 in the treatment group when compared with the LPS group; meanwhile, quercetin significantly decreased the protein expressions of LC3-I, LC3-II, and the rate of LC3-II/LC3-I. In conclusions, quercetin can alleviate hepatic inflammation induced by LPS through modulating autophagy and necroptosis.

The role and mechanism of TXNDC5 in disease progression.

Thioredoxin domain containing protein-5 (TXNDC5), also known as endothelial protein-disulfide isomerase (Endo-PDI), is confined to the endoplasmic reticulum through the structural endoplasmic reticulum retention signal (KDEL), is a member of the PDI protein family and is highly expressed in the hypoxic state. TXNDC5 can regulate the rate of disulfide bond formation, isomerization and degradation of target proteins through its function as a protein disulfide isomerase (PDI), thereby altering protein conformation, activity and improving protein stability. Several studies have shown that there is a significant correlation between TXNDC5 gene polymorphisms and genetic susceptibility to inflammatory diseases such as rheumatoid, fibrosis and tumors. In this paper, we detail the expression characteristics of TXNDC5 in a variety of diseases, summarize the mechanisms by which TXNDC5 promotes malignant disease progression, and summarize potential therapeutic strategies to target TXNDC5 for disease treatment.

Palladium/XuPhos-catalyzed enantioselective cascade Heck/intermolecular C(sp2)-H alkylation reaction.

Palladium-catalyzed enantioselective domino Heck/intramolecular C-H functionalization reaction, as a valuable strategy for creating molecular diversity, has remained a prominent challenge. Here, we describe a Pd/XuPhos catalyst for asymmetric domino Heck/intermolecular C-H alkylation of unactivated alkenes with diverse polyfluoro- and heteroarenes in a highly chemo- and enantioselective manner. This process enables efficient synthesis of various dihydrobenzofurans, indolines and indanes, which are of interest in pharmaceutical research and other areas. Late-stage modifications of the core structures of natural products are also well showcased. Moreover, synthetic transformations create a valuable platform for preparing a series of functionalized molecules. Several control experiments for mechanistic study are conducted to pursue a further understanding of the reaction.

A Prolonged Artificial Nighttime-light Dataset of China (1984-2020).

Nighttime light remote sensing has been an increasingly important proxy for human activities. Despite an urgent need for long-term products and pilot explorations in synthesizing them, the publicly available long-term products are limited. A Night-Time Light convolutional LSTM network is proposed and applied the network to produce a 1-km annual Prolonged Artificial Nighttime-light DAtaset of China (PANDA-China) from 1984 to 2020. Assessments between modeled and original images show that on average the RMSE reaches 0.73, the coefficient of determination (R2) reaches 0.95, and the linear slope is 0.99 at the pixel level, indicating a high confidence in the quality of generated data products. Quantitative and visual comparisons witness PANDA-China's superiority against other NTL datasets in its significantly longer NTL dynamics, higher temporal consistency, and better correlations with socioeconomics (built-up areas, gross domestic product, population) characterizing the most relevant indicator in different development phases. The PANDA-China product provides an unprecedented opportunity to trace nighttime light dynamics in the past four decades.

The effectiveness of instrument-assisted soft tissue mobilization on range of motion: a meta-analysis.

BACKGROUND: To evaluate the effectiveness of instrument-assisted soft tissue mobilization (IASTM) on range of motion (ROM). METHODS: We performed a literature search of the PubMed, Embase, Web of Science, and Cochrane Library databases from inception to December 23, 2023. Randomized controlled trials that compared treatment groups receiving IASTM to controls or IASTM plus another treatment(s) to other treatment(s) among healthy individuals with or without ROM deficits, or patients with musculoskeletal disorders were included. The Cochrane risk of bias tool was used to assess the risk of bias. RESULTS: Nine trials including 450 participants were included in the quantitative analysis. The IASTM was effective in improving ROM in degree in healthy individuals with ROM deficits and patients with musculoskeletal disorders (n=4) (MD = 4.94, 95% CI: 3.29 to 6.60), and in healthy individuals without ROM deficits (n=4) (MD = 2.32, 95% CI: 1.30 to 3.34), but failed to improve ROM in centimeter in healthy individuals with ROM deficits (n=1) (MD = 0.39, 95% CI: -1.34 to 2.11, p=0.66, I2 = 88%). CONCLUSIONS: IASTM can improve ROM in degree in healthy individuals with or without ROM deficits, or in patients with musculoskeletal disorders (with very low to low certainty). TRIAL REGISTRATION: The PROSPERO registration ID is CRD42023425200.

Structure and dynamics determine G protein coupling specificity at a class A GPCR.

G protein coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The ß2-adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase. By developing a new Gαi-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Gαs and Gαi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways.

Consistent efficacy outcomes between phase 2 and phase 3 trials in Crohn's disease or ulcerative colitis in adults: a meta-analysis.

INTRODUCTION: The approval of novel biologic agents and small molecules for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) is dependent on phase 3 randomized controlled trials (RCTs). However, these trials sometimes fail to achieve the expected efficacy outcomes observed in phase 2 trials. METHODS: We conducted a systematic review of RCTs that evaluated biologic agents and small molecules using paired regimens in both phase 2 and phase 3. We searched Medline, EMBASE, and Cochrane databases up until February 13, 2024. The revised Cochrane tool was utilized to assess the risk of bias. A generalized linear mixed-effects model (GLMM) was employed to estimate the odds ratios (ORs) for efficacy outcomes in phase 2 trials compared to phase 3. RESULTS: We identified a total of 23 trials with 10 paired regimens for CD and 30 trials with 11 paired regimens for UC. The GLMM analysis revealed that phase 2 CD trials had higher outcomes measured by the Crohn's Disease Activity Index (CDAI) by 9-13% without statistical significance: CDAI-150: OR, 1.12 (95% CI 0.83-1.51, p = 0.41); CDAI-100: OR, 1.09 (95% CI 0.88-1.35, p = 0.40); or CDAI-70: OR, 1.13 (95% CI 0.61-2.08, p = 0.66). For UC, two efficacy outcomes were estimated to be equally reported in phase 2/phase 3 pairs: clinical remission: OR, 1.00 (95% CI 0.83-1.20, p = 0.96); endoscopic improvement: OR, 0.98 (95% CI 0.83-1.15, p = 0.79). However, the rate of clinical response was underestimated in phase 2 by 19%: OR, 0.81 (95% CI 0.70-0.95, p = 0.03). The inclusion criterion for the type of Mayo score for UC had a significant interaction with the study phase to influence the difference in clinical response (p = 0.002). CONCLUSIONS: Our findings suggest that the main efficacy outcomes for CD and UC remain consistent between phase 2 and phase 3 trials, except for UC response rates. The efficacy data obtained from phase 2 trials can be considered reliable for the design of subsequent phase 3 trials. REGISTRATION: PROSPERO (CRD42023407947).

Blood MALT1 expression could help predict treatment outcomes in psoriasis patients, especially in those receiving biologics.

INTRODUCTION: Mucosa-associated lymphoid tissue 1 (MALT1) modulates T helper cell differentiation, pro-inflammatory cytokine production, and epidermal hyperplasia to participate in the pathology of psoriasis. This study aimed to explore the correlation of blood MALT1 with treatment outcomes in psoriasis patients. METHODS: MALT1 was detected in peripheral blood mononuclear cells by reverse transcription-quantitative polymerase chain reaction in 210 psoriasis patients before starting or converting to a new therapy, 50 disease controls, and 50 healthy controls. The psoriasis area severity index (PASI) score was evaluated at month (M)1, M3, and M6 in psoriasis patients. RESULTS: MALT1 was increased in psoriasis patients versus disease controls and healthy controls (both p < .001); and positively related to body mass index (p = .019) and PASI score (p < .001) in psoriasis patients. PASI75 rate at M1, M3, and M6 was 22.9%, 46.2%, and 71.0%, respectively; while PASI90 rate at M1, M3, and M6 was 3.8%, 29.0%, and 50.5%, respectively, in psoriasis patients. PASI75/90 rates at M1, M3, and M6 were increased in psoriasis patients receiving biologics versus those without (all p < .05). Pretreatment MALT1 was higher in psoriasis patients who achieved PASI75 (p = .001) and PASI90 (p < .001) at M6 compared to those who did not achieve that. Subgroup analyses discovered that pretreatment MALT1 had a stronger ability to predict PASI75 and 90 realizations in psoriasis patients receiving biologics (area under the curve [AUC]: 0.723 and 0.808) versus those without (AUC: 0.594 and 0.675). CONCLUSION: Blood MALT1 measurement may assist in predicting outcomes in psoriasis patients, especially in those receiving biologics.

Effect of prior lenalidomide or daratumumab exposure on hematopoietic stem cell collection and reconstitution in multiple myeloma.

BACKGROUND: The roles of Lenalidomide (Len) and Daratumumab (Dara) in multiple myeloma treatment are well-established, yet their influences on hematopoietic stem cell harvesting and reconstitution remain disputed. METHODS: We conducted a systematic database review to identify cohort studies or RCTs evaluating the effect of the use of Len or Dara on hematopoietic stem cell collection and peripheral blood count recovery in multiple myeloma patients. Effects on hematopoietic collection or reconstitution were estimated by comparing standardized mean differences (SMD) and mean differences (MD), or median differences. RESULTS: Eighteen relevant studies were identified, summarizing mobilization results. For Len, data from 13 studies were summarized, including total CD34+ cell yield, collection failure rate, and time to neutrophil and platelet engraftment. Results indicated that Len exposure led to decreased stem cell collection [SMD=-0.23, 95% CI (-0.34, -0.12)]. However, collection failure (<2×106) could be mitigated by plerixafor [OR=2.14, 95% CI (0.96, 4.77)]. For Dara, two RCTs and three cohort studies were included, showing that Dara exposure resulted in a reduction in total stem cells even with optimized plerixafor mobilization [SMD=-0.75, 95% CI (-1.26, -0.23)], and delayed platelet engraftment recovery [MD=1.20, 95% CI (0.73, 1.66)]. CONCLUSIONS: Our meta-analysis offers a comprehensive view of Len and Dara's impacts on hematopoietic stem cell collection and reconstitution in multiple myeloma. Len usage could lead to reduced stem cell collection, counteracted by plerixafor mobilization. Dara usage could result in diminished stem cell collection and delayed platelet engraftment.

Auto-Cleaving Bond for Better Drugs.

While bond formation has historically been the mainstay of medicinal chemistry, the phenomenon of bond cleavage has received less focus. However, the success of numerous oral medications demonstrates the importance of controlled cleavage in prodrugs to achieve desired therapeutic outcomes. Nevertheless, effective strategies to control this cleavage remain limited. This concept article introduces a novel approach: employing peptides as conjugates to drugs to modulate the hydrolysis of these conjugates and enhance drug efficacy. The article begins by briefly outlining common prodrug strategies, followed by a few representative examples of how peptides can be leveraged to control the autohydrolysis of peptide-conjugated prodrugs for bacterial and cancer cell inhibition. Finally, it provides a brief outlook on the future potential of this promising new research direction in molecular medicine.

Exosomes and exosomal miRNAs: A new avenue for the future treatment of rheumatoid arthritis.

Rheumatoid arthritis is a chronic systemic autoimmune disease that involves mainly synovitis and joint injury and is one of the main causes of disability. The pathogenesis of rheumatoid arthritis is complicated, and the treatment cycle is long. The traditional methods of inhibiting inflammation and immunosuppression are no longer sufficient for treatment of the disease, so there is an urgent need to seek new treatments. The exocrine microenvironment is a kind of microvesicle with a lipid bilayer membrane structure that can be secreted by most cells in the body. This structure contains cell-specific proteins, lipids and nucleic acids that can transmit this information from one cell to another. To achieve cell-to-cell communication. Exocrine microRNAs can be contained in exocrine cells and can be selectively transferred to target receptor cells via exocrine signaling, thus regulating the physiological function of target cells. This article focuses on the pathological changes that occur during the development of rheumatoid arthritis and the biological regulation of exocrine and exocrine microRNAs in rheumatoid joints. Research on the roles of exocrine and exocrine microRNAs in regulating the inflammatory response, cell proliferation/apoptosis, autophagy, effects on fibroblast-like synoviocytes and immune regulation in rheumatoid arthritis was reviewed. In addition, the challenges faced by this new treatment are discussed.

Concurrent Ammonia Synthesis and Alcohol Oxidation Boosted by Glutathione-Capped Quantum Dots under Visible Light.

Mother nature accomplishes efficient ammonia synthesis via cascade N2 oxidation by lightning strikes followed with enzyme-catalyzed nitrogen oxyanion (NOx -, x = 2,3) reduction. The protein environment of enzymatic centers for NOx --to-NH4 + process greatly inspires the design of glutathione-capped (GSH) quantum dots (QDs) for ammonia synthesis under visible light (440 nm) in tandem with plasma-enabled N2 oxidation. Mechanistic studies reveal that GSH induces positive shift of surface charge to strengthen the interaction between NOx - and QDs. Upon visible light irradiation of QDs, the balanced and rapid hole and electron transfer furnish GS·radicals for 2e-/2H+ alcohol oxidation and H·for 8e-/10H+ NO3 --to-NH4 + reduction simultaneously. For the first time, mmol-scale ammonia synthesis is realized with apparent quantum yields of 5.45% ± 0.64%, and gram-scale synthesis of value-added acetophenone and NH4Cl proceeds with 1:4 stoichiometry and stability, demonstrating promising multielectron and multiproton ammonia synthesis efficiency and sustainability with nature-inspired artificial photocatalysts.

Lactate acid promotes PD-1+ Tregs accumulation in the bone marrow with high tumor burden of Acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) displayed poor response to programmed death-1 (PD-1) blockade therapy. Regulatory T cells (Tregs) was one of major immunosuppressive components in Tumor microenvironment and plays a vital role in the resistance of immunotherapy. Coinhibitory receptors regulate function of regulatory Tregs and are associated with resistance of PD-1 blockade. However, the coinhibitory receptors expression and differentiated status of Tregs in AML patients remain to be unclear. METHODS: Phenotypic determination of Tregs and CD8+ T cells in bone marrow of healthy donors and AML patients was performed by flow cytometry. Coculture experiments of AML and Tregs in vitro were performed and the concentrations of lactate acid (LA) in the supernatant were examined by ELISA. RESULTS: More Tregs differentiated into effector subsets in AML patients. However, PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression on Tregs were comparable in healthy donors and AML patients. Further analysis showed that PD-1+ and PD-1+TIGIT+Tregs are more abundant in the bone marrow of patients with higher leukemic load. Moreover, PD-1+ Tregs accumulation was associated with higher level of senescent CD4+ T cells and increased frequencies of exhausted CD4+ as well as CD8+ T cells. Notably, neither Tregs nor their effector subsets were decreased among patients in complete remission. PD-1 expression was significantly downregulated in Tregs after achieving complete remission. Mechanistically, both AML cell line (KG-1α) and primary AML blasts produced high concentration of LA. Blockade of LA by lactate transporter inhibitor abrogated the upregulation of PD-1 by AML cells. CONCLUSION: PD-1+ Tregs accumulation in bone marrow in higher leukemic burden setting was linked to lactate acid secreted by AML blasts and decreased after disease remission. Our findings provided a novel insight into Tregs in AML and possible mechanism for resistance of PD-1 blockade in AML.