Visible-Light-Promoted Enantioselective Acylation and Alkylation of Aldimines Enabled by 9-Fluorenone Electron-Shuttle Catalysis.

Chiral acyclic α-tertiary amino ketones are widely present in various natural products and pharmaceuticals; however, the direct synthesis of this pharmacophore through a robust strategy still presents significant challenges. The emerging photocatalysis provides a powerful approach to construct chemical bonds that are difficult to form via a traditional two-electron pathway. Herein, we developed visible-light-induced chiral Lewis acid-catalyzed highly enantioselective acylation/alkylation of aldimines enabled by cooperative FLN (9-fluorenone) electron-shuttle catalysis via radical addition. An array of α-tertiary amino ketones, ß-amino alcohols, and chiral amines were achieved with high yields and good to excellent stereocontrol (87 examples, up to 84% yield, 96% ee). These products can be easily transformed into valuable and bioactive skeletons. Extensive control experiments, detailed mechanism studies, and density functional theory calculations elucidated the reaction process and highlighted the crucial role played by FLN.

Role of Gpr124 in the Migration and Proliferation of Retinal Microvascular Endothelial Cells and Microangiopathies in Diabetic Retinopathy.

Retinal microangiopathies, such as neovascularization and preretinal and vitreous hemorrhages, are the primary pathological features of diabetic retinopathy (DR). These conditions can worsen visual impairment and may result in blindness. Furthermore, multiple metabolic pathways are associated with microangiopathy in DR. However, the specific underlying pathological mechanisms remain unclear. Several studies have demonstrated the important role of G protein-coupled receptor 124 (Gpr124) in cerebral vascular endothelial cells, but its effect on the retinal endothelium has not been elucidated. In this study, we found that Gpr124 is expressed in both pathological retinal fibrous vascular membranes of DR patients and retinal blood vessels of mice, with elevated protein expression specifically observed in the retinas of DR model mice. Furthermore, Gpr124 expression was elevated after high-glucose treatment of human retinal microvascular endothelial cells (HRMECs). Inhibition of Gpr124 expression affected the high glucose-induced proliferation, migration, and tube-forming ability of HRMECs. We concluded that Gpr124 expression was upregulated in DR and promoted HRMECs angiogenesis in a high-glucose environment. This finding may help to elucidate the pathogenesis of DR and provide a critical research basis for identifying effective treatments.

[Mechanism of Puerariae Thomsonii Radix in treatment of mild dyslipidemia: based on clinical metabolomics and proteomics].

This study aims to explore the potential metabolic pathways and targets of Puerariae Thomsonii Radix in the clinical treatment of mild dyslipidemia. UPLC-Q-TOF-MS and EASY-nLC-timsTOF-Pro2 were employed to perform metabolomic and proteomic analyses of the plasma samples collected from the patients with mild dyslipidemia at baseline and after 12 weeks of treatment with Puerariae Thomsonii Radix. The multivariate statistical analysis was carried out for comparison between groups, and the correlation analysis was performed for the metabolites and proteins closely related to mild dyslipidemia with the blood lipid indexes. The possible pathways and targets for mitigating mild dyslipidemia were screened out by the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. The results showed that 56 differential metabolites and 78 differential proteins in the plasma of patients were associated with Puerariae Thomsonii Radix treatment. In addition, changes were detected for the proteins or metabolites(ApoB-100, 9,10-DHOME, GAPDH, PGK1, PGAM1, ENO1, etc.) involved in lipoprotein, lipid, and glucose metabolism and the proteins or metabolites(oxidized phospholipid, PLA2G7, LTA4H, etc.) related to inflammation and oxidative stress. Puerariae Thomsonii Radix may down-regulate the overexpression of ApoB-100, activate the peroxisome proliferator-activated receptor α/γ(PPARα/γ), promote the catabolism of fat and glycerol, and alleviate the oxidative stress mediated by oxidized phospholipids and leukotriene B4(LTB4) in the treatment of mild dyslipidemia.

Decreasing circ_0014614 promotes the differentiation of bone marrow flineage cells into megakaryocytes in essential thrombocythemia via activiation of miR-138-5p/caspase3 axis.

BACKGROUND: Circular RNAs (circRNA) are pivotal in hematological diseases. Previous study showed that circ_0014614 (circDAP3) was significantly underexpressed in bone marrow-derived exosomes from essential thrombocythemia (ET) patients, affecting the differentiation of bone marrow lineage cells into megakaryocytes. METHODS: Fluorescence in situ hybridization (FISH) was used to display circ_0014614's primary cytoplasmic location in K562 cells. Cytoscape software was used to predict the circRNA-miRNA-mRNA networks, and their expression at the cellular level was detected by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR). qRT-PCR was utilized to detect the expression levels of circ_0014614，miR-138-5p and caspase3 mRNA. Western blot was used to determine the protein levels of GATA-1, RUNX-1, NF-E2, CD41 and caspase3. The proliferation of K562 cells was assessed using the Cell Counting Kit-8 (CCK-8) Assay. Furthermore, the interplay between miR-138-5p and circ_0014614 or caspase3 was elucidated through a Dual-luciferase reporter assay. RESULTS: FISH assay indicated circ_0014614's primary cytoplasmic location in K562 cells. In ET bone marrow and K562 cells, circ_0014614 and caspase3 were down-regulated, whereas miR-138-5p saw a significant surge. Overexpressing circ_0014614 curtailed K562 cells' proliferation and differentiation. Further, circ_0014614 targeted miR-138-5p, with heightened miR-138-5p levels counteracting circ_0014614's inhibition. MiR-138-5p further targeted caspase3, and caspase3 silencing neutralized suppressed miR-138-5p's effects on K562 cell differentiation. CONCLUSION: Circ_0014614 was down-regulated in ET bone marrow and bone marrow lineage cells, and upregulating circ_0014614 can inhibit bone marrow lineage cells' proliferation and differentiation into megakaryocytes. Mechanistically, circ_0014614 functioned as ceRNA via sponging miR-138-5p and alleviated the inhibitory effect of miR-138-5p on its target caspase3, which potentially deters tumor activity in ET.

Garlic oil supplementation blocks inflammatory pyroptosis-related acute lung injury by suppressing the NF-κB/NLRP3 signaling pathway via H2S generation.

Acute lung injury (ALI) is a major cause of acute respiratory failure with a high morbidity and mortality rate, and effective therapeutic strategies for ALI remain limited. Inflammatory response is considered crucial for the pathogenesis of ALI. Garlic, a globally used cooking spice, reportedly exhibits excellent anti-inflammatory bioactivity. However, protective effects of garlic against ALI have never been reported. This study aimed to investigate the protective effects of garlic oil (GO) supplementation on lipopolysaccharide (LPS)-induced ALI models. Hematoxylin and eosin staining, pathology scores, lung myeloperoxidase (MPO) activity measurement, lung wet/dry (W/D) ratio detection, and bronchoalveolar lavage fluid (BALF) analysis were performed to investigate ALI histopathology. Real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to evaluate the expression levels of inflammatory factors, nuclear factor-κB (NF-κB), NLRP3, pyroptosis-related proteins, and H2S-producing enzymes. GO attenuated LPS-induced pulmonary pathological changes, lung W/D ratio, MPO activity, and inflammatory cytokines in the lungs and BALF. Additionally, GO suppressed LPS-induced NF-κB activation, NLRP3 inflammasome expression, and inflammatory-related pyroptosis. Mechanistically, GO promoted increased H2S production in lung tissues by enhancing the conversion of GO-rich polysulfide compounds or by increasing the expression of H2S-producing enzymes in vivo. Inhibition of endogenous or exogenous H2S production reversed the protective effects of GO on ALI and eliminated the inhibitory effects of GO on NF-κB, NLRP3, and pyroptotic signaling pathways. Overall, these findings indicate that GO has a critical anti-inflammatory effect and protects against LPS-induced ALI by suppressing the NF-κB/NLRP3 signaling pathway via H2S generation.

[Research progress on active ingredients of Coicis Semen].

As a common medicinal and edible resource in China, Coicis Semen has a long history of cultivation and medicinal use. Traditional Chinese medicine(TCM) clinically believes that Coicis Semen has the effect of strengthening the spleen and tonifying the lungs, clearing heat and dampness, removing pus and paralysis, and stopping diarrhea. Therefore, it is used to treat edema, foot odor, spleen deficiency, diarrhea, and other symptoms. The above effects are closely related to the active ingredients of Coicis Semen, such as esters, fatty acids, polysaccharides, proteins, as well as phenolic acids, sterols, flavonoids, lactams, triterpenes, alkaloids, and adenosine. Modern research has found that Coicis Semen also has anti-cancer, anti-inflammatory, antioxidant, hypoglycemic, and hypotensive effects and other pharmacological activities, and it can improve immunity and regulate lipid metabolism. Coicis Semen is widely distributed in China, mainly produced in Guizhou, Yunnan, Fujian, Sichuan, and other places, and the quality of Coicis Semen from different origins varies. From ancient times to the present, Coicis Semen processing methods have experienced the process from simple to complex, and the types of auxiliary materials are more extensive, such as soil, bran, and river sand. These processing methods have been inherited from generation to generation. Nowadays, the commonly used methods are bran-fried, stir-fried, sand-fried, etc. In this paper, by reviewing the relevant literature in China and abroad in recent years, the main active ingredients and related pharmacological effects of Coicis Semen are sorted out, and the effects of different origins and processing methods on the chemical composition of Coicis Semen are summarized, with a view to providing references for the comprehensive development and utilization of Coicis Semen and the further study of its mechanism of action.

NR5A2 gene affects the overall survival of LUAD patients by regulating the activity of CSCs through SNP pathway by OCLR algorithm and immune score.

Objective: Differentially expressed genes (DEGs) in lung adenocarcinoma (LUAD) tumor stem cells were screened, and the biological characteristics of NR5A2 gene were investigated. Methods: The expression and prognosis of NR5A2 in human LUAD were predicted and analyzed through bioinformatics analysis from a human cancer database. Gene expression and clinical data of LUAD tumor and normal lung tissues were obtained from The Cancer Genome Atlas (TCGA) database, and DEGs associated with lung cancer tumor stem cells (CSCs) were screened. Univariate and multivariate Cox regression models were used to screen and establish prognostic risk prediction models. The immune function of the patients was scored according to the model, and the relative immune functions of the high- and low-risk groups were compared to determine the difference in survival prognosis between the two groups. In addition, we calculated the index of stemness based on the transcriptome of the samples using one-class linear regression (OCLR). Results: Bioinformatics analysis of a clinical cancer database showed that NR5A2 was significantly decreased in human LUAD tissues than in normal lung tissues, and the decrease in NR5A2 gene expression shortened the overall survival and progression-free survival of patients with LUAD. Conclusion: The NR5A2 gene may regulate LUAD tumor stem cells through selective splicing mutations, thereby affecting the survival and prognosis of patients with lung cancer, and the NR5A2 gene may regulate CSCs through single nucleotide polymorphism.

Corrigendum: OPN promotes pro-inflammatory cytokine expression via ERK/JNK pathway and M1 macrophage polarization in Rosacea.

[This corrects the article DOI: 10.3389/fimmu.2023.1285951.].

Phase Behavior of Hydrocarbon Fluids in Shale Reservoirs, Considering Pore Geometries, Adsorption, and Water Film.

Phase behavior of hydrocarbon fluids in nanopores is different from that observed in a PVT cell due to the confinement effect. While scholars have established various models for studying the phase behavior in nanopores, the authors often ignore the effect of pore geometries, which can significantly affect the critical fluid properties in shale nanopores. In this study, we extend the Soave-Redlich-Kwong equation of state (SRK EOS) using potential theory and establish models of critical property shift, considering pore geometries, adsorption, and water film. Our research shows that the critical property shifts, considering fluid adsorption, begin at rp ≤ 10 nm and are seriously strengthened with nanopore radius reduction. The extended SRK EOS is applied to compute phase diagrams of the 50% C1-50% nC10 mixture at different pore sizes and find that the thickness of adsorption and water film causes a depression in the P-T diagram and that the bubble point pressure is lower in cylindrical pores. At pressures above 6 MPa, the irreducible water saturation and pore geometries greatly impact the vapor-liquid ratio. This study is significant for evaluating residual oil distribution and studying fluid flow laws in shale reservoirs.

Patterns of Structural Changes in the Fundus Measured by Optical Coherence Tomography Angiography as Potential Markers of Acute Mountain Sickness.

Purpose: To use optical coherence tomography angiography (OCTA) to assess the pattern of changes in retinal and choroidal blood flow and structure in healthy volunteers who quickly went from sea level to a plateau and to determine the parameters associated with acute mountain sickness (AMS). Methods: Forty-five individuals (89 eyes) were examined by OCTA and filled out the AMS questionnaire. One baseline examination was performed on the plain, followed by examinations at days 1, 3, and 5 after entering the plateau. Parameters were self-controlled to explore patterns of change, analyzed for correlation with AMS score, and modeled as a nomogram of AMS risk. Results: On the plateau compared to the plain, vascular morphology showed dilated superficial macular retinal vessels and constricted deeper layers with increased vessel length density and fractal dimension; vessel density increased in all retinal strata and decreased in the choroidal macrovascular layer; and thickness increased except for a decrease in mean retinal thickness in the central macular sulcus. The rate of increase in retinal nerve fiber layer (RNFL) thickness in the inner and outer macular rings correlated with AMS score (r = -0.211). The nomogram showed moderate accuracy (AUC = 0.672) and consistency (C-index = 0.659) in assessing AMS risk. Conclusions: In high-altitude hypoxia, retinal vessels dilate and distort, resulting in increased blood flow density and thickness. Increased RNFL thickness in the paracentral macula may be a marker of low AMS risk. Translational Relevance: The changes in the retinal structure of the fundus can be used to assess the risk of developing AMS.

GSTM2 alleviates heart failure by inhibiting DNA damage in cardiomyocytes.

BACKGROUND: Heart failure (HF) seriously threatens human health worldwide. However, the pathological mechanisms underlying HF are still not fully clear. RESULTS: In this study, we performed proteomics and transcriptomics analyses on samples from human HF patients and healthy donors to obtain an overview of the detailed changes in protein and mRNA expression that occur during HF. We found substantial differences in protein expression changes between the atria and ventricles of myocardial tissues from patients with HF. Interestingly, the metabolic state of ventricular tissues was altered in HF samples, and inflammatory pathways were activated in atrial tissues. Through analysis of differentially expressed genes in HF samples, we found that several glutathione S-transferase (GST) family members, especially glutathione S-transferase M2-2 (GSTM2), were decreased in all the ventricular samples. Furthermore, GSTM2 overexpression effectively relieved the progression of cardiac hypertrophy in a transverse aortic constriction (TAC) surgery-induced HF mouse model. Moreover, we found that GSTM2 attenuated DNA damage and extrachromosomal circular DNA (eccDNA) production in cardiomyocytes, thereby ameliorating interferon-I-stimulated macrophage inflammation in heart tissues. CONCLUSIONS: Our study establishes a proteomic and transcriptomic map of human HF tissues, highlights the functional importance of GSTM2 in HF progression, and provides a novel therapeutic target for HF.

Pseudorabies gD protein protects mice and piglets against lethal doses of pseudorabies virus.

Introduction: Pseudorabies (PR) is a highly contagious viral disease caused by the pseudorabies virus (PRV), which can cause disease in a wide range of domestic and wild animals. Studies have shown that new mutant strains have emerged in pig farms in many regions and that commercial inactivated and live attenuated vaccines are becoming less effective at protecting pigs. Methods: Porcine pseudorabies glycoprotein D (gD) gene (GenBank: QEY95774.1) with hexa-His tag to the C terminus for further purification processes was cloned into the lentiviral expression plasmid pLV-CMV-eGFP by restriction enzyme, the resulting plasmid was designated as pLV-CMV-gD. HEK-293T cells with robust and stable expression of recombinant gD protein was established by infection with recombinant lentivirus vector pLV-CMV-gD. We expressed porcine pseudorabies virus gD protein using HEK-293T cells. Results: We describe in this study that individual gD proteins produced by a mammalian cell expression system are well immunogenic and stimulate high levels of PRV-specific and neutralizing antibodies in mice and piglets. All mice and piglets survived lethal doses of PRV, significantly reducing the amount of PRV virus in piglets' lymph nodes, lungs, spleen, and other tissues. It also significantly reduced the time cycle and amount of viral excretion from piglets to the environment through the nasal and anal cavities. Discussion: The results suggest that PRV gD protein is expected to be a potential candidate for the preparation of genetically engineered PR vaccines for the prevention of PRV infection and the control of PR epidemics.

Vtc4 Promotes the Entry of Phagophores into Vacuoles in the Saccharomyces cerevisiae Snf7 Mutant Cell.

Endocytosis and autophagy are the main pathways to deliver cargoes in vesicles and autophagosomes, respectively, to vacuoles/lysosomes in eukaryotes. Multiple positive regulators but few negative ones are reported to regulate the entry of vesicles and autophagosomes into vacuoles/lysosomes. In yeast, the Rab5 GTPase Vps21 and the ESCRT (endosomal sorting complex required for transport) are positive regulators in endocytosis and autophagy. During autophagy, Vps21 regulates the ESCRT to phagophores (unclosed autophagosomes) to close them. Phagophores accumulate on vacuolar membranes in both vps21∆ and ESCRT mutant cells under a short duration of nitrogen starvation. The vacuolar transport chaperon (VTC) complex proteins are recently found to be negative regulators in endocytosis and autophagy. Phagophores in vps21∆ cells are promoted to enter vacuoles when the VTC complex proteins are absent. Phagophores are easily observed inside vacuoles when any of these VTC complex proteins (Vtc1, 2, 4, 5) are removed. However, it is unknown whether the removal of VTC complex proteins will also promote the entry of phagophores into vacuoles in ESCRT mutant cells under the same conditions. Snf7 is a core subunit of ESCRT subcomplex III (ESCRT-III), and phagophores accumulate in snf7∆ cells under a short duration of nitrogen starvation. We used green fluorescence protein (GFP) labeled Atg8 to display phagophores and FM4-64-stained or Vph1-GFP-labeled membrane structures to show vacuoles, then examined fluorescence localization and GFP-Atg8 degradation in snf7∆ and snf7∆vtc4∆ cells. Results showed that Vtc4 depletion promoted the entry of phagophores in snf7∆ cells into vacuoles as it did for vps21∆ cells, although the promotion level was more obvious in vps21∆ cells. This observation indicates that the VTC complex proteins may have a widespread role in negatively regulating cargos to enter vacuoles in yeast.

Association Between Nasal Colonization of Staphylococcus aureus and Eczema of Multiple Body Sites.

PURPOSE: Staphylococcus aureus is the critical pathogenic bacterium of eczema. The relationship between nasal colonization by S. aureus and eczema has not been well studied. We aimed to evaluate the associations between nasal colonization by S. aureus and eczema of multiple body sites, including persistent and ever-reported eczema. We further examined the associations between eczema and different subtypes of S. aureus, that is, methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA). METHODS: The real-world data from the US National Health and Nutrition Examination Survey were used. The associations were calculated using survey-weighted multinomial logistic regression models and further calculated in subgroups stratified by demographic factors. RESULTS: In total, 2,941 adults were included. The prevalence rate of S. aureus nasal carriage was significantly higher in adults with persistent hand eczema (51.0%) than in those with ever-reported hand eczema (23.3%) and never eczema (26.9%). S. aureus nasal colonization was associated with an approximately two-fold increased risk of persistent hand eczema (odds ratios ranges in different models: 2.86-3.06) without significant heterogeneity in the association by demographic factors. No significant associations between S. aureus nasal colonization and persistent eczema of other body sites or ever-reported eczema of multiple body sites (including hands) were observed. Furthermore, similar significant association between nasal colonization of MSSA and persistent hand eczema was seen; the association was much stronger (odds ratios ranges in different models: 4.64-6.54) for MRSA, although with borderline significant. CONCLUSIONS: Nasal colonization of S. aureus was associated with increased risk of persistent hand eczema. Our findings imply that preventive measures targeting S. aureus for the anterior nares should be considered in preventing and treating eczema.

[Research progress in gut-skin axis and its association with traditional Chinese medicine theory].

Currently, the gut-organ axis has become a hot research topic. As increasing attention has been paid to the role of gut microbiota in the health of organs, the complex and integrated dialogue mechanism between the gastrointestinal tract and the associated microbiota has been demonstrated in more and more studies. Skin as the largest organ in the human body serves as the primary barrier protecting the human body from damage. The proposal of the gut-skin axis has established a bidirectional link between the gut and the skin. The disturbance of gut microbiota can lead to the occurrence of skin diseases, the mechanism of which is complex and may involve multiple pathways in immunity, metabolism, and internal secretion. According to the theory of traditional Chinese medicine(TCM), the connection between the intestine and the skin can be established through the lung, and the interior disorders will definitely cause symptoms on the exterior. This paper reviews the research progress in the gut-skin axis and its correlation with TCM theory and provides ideas and a basis for cli-nical treatment and drug development of skin and intestinal diseases.

Effects of Implant Diameter on Implant Stability and Osseointegration in the Early Stage in a Dog Model.

Purpose: To determine the optimal implant diameter under limited bone width by comparing the effects of implants with different diameters on implant stability, peri-implant bone stability, and osseointegration. In addition, to evaluate the reliability of resonance frequency analysis (RFA) in detecting osseointegration and marginal bone level (MBL). Materials and Methods: Mandibular premolars and first molars of seven beagle dogs were extracted. After 8 weeks, their mandibular models and radiographic information were collected to fabricate implant templates. Implant sites were randomly divided into three groups according to diameter: Ø3.3, Ø4.1, and Ø4.8 mm. Implant stability quotient (ISQ) measurement and radiographic evaluation were performed after surgery (baseline) and at 4, 8, and 12 weeks. Three dogs were euthanized at 4 weeks to observe osteogenesis and implant-tissue interface biology. Four dogs were euthanized at 12 weeks to observe osseointegration. Hard tissue sections were prepared to analyze osteogenesis (fluorescence double labeling) and osseointegration (methylene blue-acid fuchsin staining). Results: At baseline and at 4, 8, and 12 weeks, the ISQ values of Ø4.1- and Ø4.8-mm implants did not differ (P > .05), but both had higher values than the Ø3.3-mm implants (P < .05). The mean marginal bone resorption (MBR) associated with Ø3.3-, Ø4.1-, and Ø4.8-mm implants was 0.65 ± 0.58 mm, 0.37 ± 0.28 mm, and 0.73 ± 0.37 mm, respectively. The buccal MBR of Ø4.8-mm implants was significantly higher than that of Ø4.1-mm implants (P < .05). The bone-to-implant contact (BIC) percentage at 12 weeks did not differ for any group (P > .05). The correlation coefficients between the ISQ and MBL of the Ø3.3-, Ø4.1-, and Ø4.8-mm implants were -0.84 (P < .01), -0.90 (P < .001), and -0.93 (P < .001), respectively, while that between the ISQ and BIC was 0.15 (P > .05). Conclusions: During the early healing stage, the performance of Ø4.1- and Ø4.8-mm implants in terms of implant stability was better than that of Ø3.3-mm implants. Implant diameter may not influence BIC percentage. RFA can be used to evaluate implant stability and MBL but is not suitable to assess the degree of osseointegration.

Identifying prognostic biomarker related to immune infiltration in acute myeloid leukemia.

The immune cells of tumor microenvironment (TME) constitute a vital element of the tumor tissue. There is increasing evidence for their clinical significance in predicting prognosis and therapeutic outcomes. However, the TME immune cell infiltrating pattern of the bone marrow in acute myeloid leukemia (AML) patients remains unclear. Here, RNA-sequencing results of AML patients from TCGA database were used to quantify the abundance of 28 types of immune cells in the TME using the single-sample gene set enrichment analysis algorithm. We comprehensively evaluated the immune infiltration status in the TCGA-LAML cohort and defined two immunophenotypes: the immune hot and immune cold subtypes. Additionally, we constructed a TME score reflecting the immune infiltrating pattern of the patients using Cox regression algorithm. Subtypes with high TME score were characterized by over-activation of immune inflammation-related pathways, release of inflammatory factors, T-cell dysfunction, and poor prognosis. Subtypes with a low TME score were characterized by relatively low immune infiltration and immune exclusion. Our analysis indicated that patients in the low TME score group were more sensitive to chemotherapeutic drugs, and those in high TME score were more likely to respond to immunotherapy. Our study provides a new direction to evaluate anti-tumor therapy from immune infiltration of the TME, and the individualized scoring system in this study has important clinical significance in identifying patients who respond to immunotherapy.

Paxbp1 is indispensable for the survival of CD4 and CD8 double-positive thymocytes.

The lifespan of double-positive (DP) thymocytes is critical for intrathymic development and shaping the peripheral T cell repertoire. However, the molecular mechanisms that control DP thymocyte survival remain poorly understood. Paxbp1 is a conserved nuclear protein that has been reported to play important roles in cell growth and development. Its high expression in T cells suggests a possible role in T cell development. Here, we observed that deletion of Paxbp1 resulted in thymic atrophy in mice lacking Paxbp1 in the early stages of T cell development. Conditional loss of Paxbp1 resulted in fewer CD4+CD8+ DP T cells, CD4 and CD8 single positive (SP) T cells in the thymus, and fewer T cells in the periphery. Meanwhile, Paxbp1 deficiency had limited effects on the CD4-CD8- double negative (DN) or immature single-positive (ISP) cell populations. Instead, we observed a significant increase in the susceptibility of Paxbp1-deficient DP thymocytes to apoptosis. Consistent with this, RNA-Seq analysis revealed a significant enrichment of the apoptotic pathway within differentially expressed genes in Paxbp1-deficient DP cells compared to control DP cells. Together, our results suggest a new function for Paxbp1, which is an important mediator of DP thymocyte survival and critical for proper thymic development.

Visible-light-induced chemo-, diastereo- and enantioselective α-C(sp3)-H functionalization of alkyl silanes.

A catalytic asymmetric α-C(sp3)-H functionalization of alkyl silanes with benzosultams was realized by merging photoredox and chiral Lewis acid catalysis. The key to success was the choice of photocatalyst with an appropriate redox potential and non-nucleophilic solvent, providing a novel entry to chiral organosilanes containing two adjacent tri- and tetra-substituted stereocenters with high to efficient diastereo- and enantioselectivity (up to 99% ee, 94 : 6 dr) under mild reaction conditions. Based on the control experiment and spectral analysis, an initial single electron transfer reduction of a benzosultam-triggered simultaneous or stepwise electron transfer/proton transfer process was proposed to rationalize the favored C(sp3)-H functionalization rather than desilylation.

The evidence framework of traditional Chinese medicine injection (Aidi injection) in controlling malignant pleural effusion: A clustered systematic review and meta-analysis.

INTRODUCTION: Aidi injection (Aidi), a traditional Chinese medicine injection, is often practiced to control malignant pleural effusion (MPE). OBJECTIVES: We performed a registered systematic review and meta-analysis (PROSPERO: CRD42022337611) to clarify the clinical role of Aidi in MPE, reveal optimal combinations of Aidi and chemical agents, their indications, therapeutic route and usage, and demonstrate their clinical effectiveness and safety. METHODOLOGY: All randomized controlled trials (RCTs) about Aidi in controlling MPE were collected from Chinese and English databases (up to October 2022). We clustered them into multiple homogenous regimens, evaluated the risk-of-bias at outcome level using a RoB 2, extracted and pooled the data using meta-analysis or descriptive analysis, and finally summarized their evidence quality. RESULTS: All 56 studies were clustered into intrapleural administration with Aidi alone or plus chemical agents, and intravenous administration with Aidi for MPE. Intrapleural administration with Aidi alone displayed similar clinical responses on Cisplatin (DDP) alone. Only administration with Aidi plus DDP significantly improved complete response and quality of life, and displayed a low pleurodesis failure, disease progression, hematotoxicity, gastrointestinal and hepatorenal toxicity. For patients with moderate to massive effusion, Karnofsky Performance Status score ≥ 50 or anticipated survival time ≥3 months, Aidi (50 ml to 80 ml each time, one time each week and three to eight times) plus DDP (20 to 30 mg, 40 to 50 mg, or 60 to 80 mg each time) significantly improved clinical responses. Most results had moderate to low quality. CONCLUSIONS: Current evidences indicate that Aidi, a pleurodesis agent, plays an interesting clinical role in controlling MPE. Aidi plus DDP perfusion is a most commonly used regimen, which shows a significant improvement in clinical responses. These findings also provide an indication and possible optimal usage for rational drug use.