Structural insights into the human D1 and D2 dopamine receptor signaling complexes.

The D1- and D2-dopamine receptors (D1R and D2R), which signal through Gs and Gi, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-Gs and D2R-Gi signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.

Leaf-Inspired Hetero-Structure WS2/WO3 In Situ Embedded on Pomelo Peel Derived Carbon for Supercapacitor and Capacitive Deionization.

Composite materials have occupied a reliable position in electrochemical energy storage and conversion due to their double electric layer and pseudocapacitance. In this work, a leaf-like heterostructure composite, obtained by peeling - carbonizing - in situ sulfuration/oxidation approach for the first time, is investigated as electrode material for electrochemical capacitance behavior. The thin and highly active transition metal WS2 acts as an energetic "blade" to trap free ions, which are then transported across the material through a strong "tendon skeleton" WO3. The derived carbon PPC with a large aspect ratio holds up the overall leaf structure, also as a "warehouse" for ion storage, thus enhancing the conductivity and wettability of the material. The above three (WS2+WO3+PPC) synergistically provide outstanding double-layer capacitance and pseudocapacitance. In particular, the vacancy defects, constructed at the heterogenous interface from WS2-WO3 in situ growth, can still achieve superior ion absorption/desorption ability even under large current density and high concentration brackish solution.

Phosphodiesterase 8 (PDE8): Distribution and Cellular Expression and Association with Alzheimer's Disease.

Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.

IAIH-PG consensus for histological criteria of AIH: Multicentre validation with focus on chronic liver diseases in China.

BACKGROUND AND AIMS: The International AIH Pathology Group (IAIH-PG) put forward the new histological criteria of autoimmune hepatitis (AIH) in 2022, which have not undergone adequate verification. In this study, we verified the applicability of the new histological criteria in the population of Chinese patients with chronic liver disease, comparing it with the simplified criteria. METHODS: The gold standard for diagnosis in all patients was based on histological findings, combined with clinical manifestations and laboratory tests and determined after a follow-up period of at least 3 years. A total of 640 patients with various chronic liver diseases from multiple centres underwent scoring using the new histological criteria and the simplified criteria, comparing their diagnostic performance. RESULTS: In this study, the new histological criteria showed a sensitivity of 73.6% and 100% for likely and possible AIH, with specificities of 100% and 69.0% respectively. The coincidence rates of possible AIH for the new histological criteria, simplified histological criteria and simplified score were 81.7%, 72.8% and 69.7% respectively. For likely AIH, the rates were 89.2%, 75.9% and 65.6% respectively. Based on the new histological criteria, all patients with AIH were correctly diagnosed. Specifically, 73.6% were diagnosed with likely AIH and 26.4% were possible AIH. Additionally, the simplified histological criteria achieved a diagnosis rate of 98.6% for AIH, while the simplified score could only diagnose 53.8% of AIH. CONCLUSIONS: Compared with the simplified score and simplified histological criteria, the sensitivity and specificity of the new histological criteria for AIH were significantly improved. The results indicate that the new histological criteria exhibit high sensitivity and specificity for diagnosing AIH in China.

Development and validation of a noninvasive prediction model of autoimmune hepatitis in patients with liver diseases.

BACKGROUND AND AIMS: There is no golden standard for the diagnosis of autoimmune hepatitis which still dependent on liver biopsy currently. So, we developed a noninvasive prediction model to help optimize the diagnosis of autoimmune hepatitis. METHODS: From January 2017 to December 2019, 1739 patients who had undergone liver biopsy were seen in the second hospital of Nanjing, of which 128 were here for consultation. Clinical, laboratory, and histologic data were obtained retrospectively. Multivariable logistic regression analysis was employed to create a nomogram model that predicting the risk of autoimmune hepatitis. Internal and external validation was both performed to evaluate the model. RESULTS: A total of 1288 patients with liver biopsy were enrolled (1184 from the second hospital of Nanjing, the remaining 104 from other centers). After the univariate and multivariate logistic regression analysis, nine variables including ALT, IgG, ALP/AST, ALB, ANA, AMA, HBsAg, age, and gender were selected to establish the noninvasive prediction model. The nomogram model exhibits good prediction in diagnosing autoimmune hepatitis with AUROC of 0.967 (95% CI: 0.776-0.891) in internal validation and 0.835 (95% CI: 0.752-0.919) in external validation. CONCLUSIONS: ALT, IgG, ALP/AST, ALB, ANA, AMA, HBsAg, age, and gender are predictive factors for the diagnosis of autoimmune hepatitis in patients with unexplained liver diseases. The predictive nomogram model built by the nine predictors achieved good prediction for diagnosing autoimmune hepatitis.

Individualized small bowel preparation for computed tomography enterography: A prospective randomized controlled trial.

BACKGROUND AND AIM: The study aims to evaluate the feasibility of body mass index (BMI)-based individualized small bowel preparation for computed tomography enterography (CTE). METHODS: In this prospective randomized controlled study, patients undergoing CTE were randomly assigned to the individualized group or standardized group. Those in individualized group were given different volumes of mannitol solution based on BMI (1000 mL for patients with BMI < 18.5 kg/m2, 1500 mL for patients with 18.5 kg/m2 ≤ BMI < 25 kg/m2 and 2000 mL for patients with BMI ≥ 25 kg/m2) while patients in the standardized group were all asked to consume 1500-mL mannitol solution. CTE images were reviewed by two experienced radiologists blindly. Each segment of the small bowel was assessed for small bowel image quality and disease detection rates. Patients were invited to record a diary regarding adverse events and acceptance. RESULTS: A total of 203 patients were enrolled and randomly divided into two groups. For patients with BMI < 18.5 kg/m2, 1000-mL mannitol solution permitted a significantly lower rate of flatulence (P = 0.045) and defecating frequency (P = 0.011) as well as higher acceptance score (P = 0.015), but did not affect bowel image quality and diseases detection compared with conventional dosage. For patients with BMI ≥ 25 kg/m2, 2000-mL mannitol solution provided better overall image quality (P = 0.033) but comparable rates of adverse events and patients' acceptance compared with conventional dosage. CONCLUSIONS: Individualized bowel preparation could achieve both satisfactory image quality and patients' acceptance thus might be an acceptable alternative in CTE.

Chinese Additive Anti-inflammatory Action for Aortopathy & Arteriopathy (5A) Registry protocol: rationale, design and methodology.

BACKGROUND: Acute aortic syndrome (AAS) is a life-threatening condition. Inflammation plays a key role in the pathogenesis, development and progression of AAS, and is associated with significant mortality and morbidity. Understanding the inflammatory responses and inflammation resolutions is essential for an appropriate management of AAS. METHOD: Thirty Chinese cardiovascular centers have collaborated to create a multicenter observational registry (named Chinese Additive Anti-inflammatory Action for Aortopathy & Arteriopathy [5A] registry), with consecutive enrollment of adult patients who underwent surgery for AAS that was started on Jan 1, 2016 and will be ended on December 31, 2040. Specially, the impact of inflammation and anti-inflammatory strategies on the early and late adverse events are investigated. Primary outcomes are severe systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), Sequential Organ Failure Assessment (SOFA) scores at 7 days following this current surgery. Secondary outcomes are SISR, 30-day mortality, operative mortality, hospital mortality, new-onset stroke, acute kidney injury, surgical site infection, reoperation for bleeding, blood transfusion and length of stay in the intensive care unit. DISCUSSION: The analysis of this multicenter registry will allow our better knowledge of the prognostic importance of preoperative inflammation and different anti-inflammatory strategies in adverse events after surgery for AAS. This registry is expected to provide insights into novel different inflammatory resolutions in management of AAS beyond conventional surgical repair. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04398992 (Initial Release: 05/19/2020).

Synthesis, structure, theoretical calculation and antibacterial property of two novel Zn(II)/Ni(II) compounds based on 3, 5-dichlorosalicylaldehyde thiocarbamide ligand.

Two new compounds namely [Zn(L1)phen]31 and Ni(L1)phen(MeOH) 2 (L1 = 3, 5-dichlorosalicylaldehyde thiosemicarbazone) were synthesized by the slow evaporation method at room temperature. The structure of ligand L1 was determined using 1H NMR and 13C NMR spectra. X-ray single crystal diffraction analysis revealed that compounds 1-2 can form 3D supramolecular network structures through π···π stacking and hydrogen bonding interactions. The DFT calculation shows that the coordination of ligand and metal is in good agreement with the experimental results. Hirshfeld surface analysis revealed that H…H and Cl…H interactions were the predominant interactions in compounds 1-2. Energy framework analysis indicated that dispersion energy played a dominant role in the energy composition of compounds 1-2. The inhibitory effects of compounds 1-2 against Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA) were tested using the paper disk diffusion method (1: E. coli: 18 mm, MRSA: 17 mm, 2: E. coli: 15 mm, MRSA: 16 mm). Ion releasing experiments were conducted to assess the ion release capacity of compounds 1-2 (Zn2+, 4 days, 38.33 µg/mL; Ni2+, 4 days, 29.12 µg/mL). Molecular docking demonstrated the interaction modes of compounds 1-2 with UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) and dihydrofolate reductase (DHFR) in bacteria, involving hydrophobic, stacking, hydrogen bonding and halogen bonding interactions. The generation of reactive oxygen species (ROS) in bacteria under the presence of compounds 1-2 were evaluated using a fluorescent dye known as dichlorodihydrofluorescein diacetate (DCFH-DA). Potential antibacterial mechanisms of compounds 1-2 were proposed.

Carbon tax and low-carbon credit: Which policy is more beneficial to the capital-constrained manufacturer's remanufacturing activities?

Remanufacturing has attracted much attention for its enormous potential in resource recycling and low-carbon emission reduction. To investigate the effects of different government intervention policies on remanufacturing and carbon emissions, two profit maximization models of the capital-constrained manufacturer under carbon tax and low-carbon credit policies are constructed respectively. Then, through theoretical and numerical analyses, some significant findings are drawn: (1) Both carbon tax and low-carbon credit policies can encourage capital-constrained manufacturers to produce more remanufactured products, but which intervention policy is more advantageous also depends on the carbon emission cost of new products or financing cost of the remanufactured products. (2) Although carbon tax policy can effectively control carbon emissions, it is always at the expense of both capital-constrained manufacturers and consumers; while low-carbon credit policy can help capital-constrained manufacturers achieve the goal of win-win economic and environmental benefits when the remanufacturing carbon savings advantages are more apparent. (3) From the perspective of consumer benefits, carbon tax is more advantageous when the consumer willingness to pay for remanufactured products is higher; otherwise, low-carbon credit policy should be implemented. (4) The higher the environmental damage coefficient is, the more it can highlight the advantages of the two intervention policies in social welfare enhancement, especially the carbon tax policy; and when the environmental damage coefficient is given, the stronger the consumers' willingness to pay for remanufactured products is, the more it is conducive to reducing the negative effects caused by the carbon tax or low-carbon credit policy in social welfare enhancement, or increasing the corresponding positive effects. Based on above findings, some managerial insights and policy implications are provided to capital-constrained manufacturers and policy-makers.

The relationship between cardiometabolic index and pulmonary function among U.S. adults: insights from the National Health and Nutrition Examination Survey (2007-2012).

BACKGROUND: Previous findings have revealed that disorders of lipid metabolism may be a risk factor for pulmonary function damage; however, the combined effect of dyslipidemia and central obesity on pulmonary function is unclear. The cardiometabolic index (CMI) is a composite of serum lipids (triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C)) and visceral fat parameters (waist-to-height ratio (WHtR)). This research aimed to investigate the link between CMI and pulmonary function, employing large-scale demographic data sourced from the National Health and Nutrition Examination Survey (NHANES) database. METHODS: This cross-sectional study used data involving 4125 adults aged 20 and above collected by NHANES between 2007 and 2012. We defined CMI as the exposure variable and measured outcomes using forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC to evaluate pulmonary function. Weighted multiple linear regression models and subgroup analyses were employed to investigate separate relationships between CMI and pulmonary function. In addition, to investigate variations across different strata and evaluate the robustness of the findings, interaction tests and sensitivity analyses were conducted. RESULTS: Results from the weighted multiple linear regression analysis indicated a unit increase in log2-CMI was associated with a reduction of 82.63 mL in FEV1 and 112.92 mL in FVC. The negative association remained significant after transforming log2-CMI by quartile (Q). When the log2-CMI level reached Q4, ß coefficients (ß) were -128.49 (95% CI: -205.85, -51.13), -169.01 (95% CI: -266.72, -71.30), respectively. According to the interaction test findings, the negative association linking log2-CMI with FEV1 and FVC persists regardless of confounding factors including age, gender, BMI, physical activity (PA), and smoking status. A subsequent sensitivity analysis provided additional confirmation of the stability and reliability of the results. For females, the inflection points for the nonlinear relationships between log2-CMI and FEV1, as well as log2-CMI and FVC, were identified at 2.33 and 2.11, respectively. While in males, a consistent negative association was observed. CONCLUSIONS: Our findings suggest that higher CMI is associated with lower FEV1 and FVC. CMI may serve as a complementary consideration to the assessment and management of pulmonary function in clinical practice.

Spontaneous formation of multilayer refractory carbide coatings in a molten salt media.

Refractory materials hold great promise to develop functional multilayer coating for extreme environments and temperature applications but require high temperature and complex synthesis to overcome their strong atomic bonding and form a multilayer structure. Here, a spontaneous reaction producing sophisticated multilayer refractory carbide coatings on carbon fiber (CF) is reported. This approach utilizes a relatively low-temperature (950 °C) molten-salt process for forming refractory carbides. The reaction of titanium (Ti), chromium (Cr), and CF yields a complex, high-quality multilayer carbide coating composed of 1) Cr carbide (Cr3C2), 2) Ti carbide, and 3) Cr3C2 layers. The layered sequence arises from a difference in metal dissolutions, reactions, and diffusion rates in the salt media. The multilayer-coated CFs act as a permeable oxidation barrier with no crystalline degradation of the CFs after extreme temperature (1,200 °C) and environment (oxyacetylene flame) exposure. The synthesis of high-quality multilayer refractory coating in a fast, efficient, easy, and clean manner may answer the need for industrial applications that develop cheap and reliable extreme environment protection barriers.

A2AR-mediated lymphangiogenesis via VEGFR2 signaling prevents salt-sensitive hypertension.

AIMS: Excess dietary sodium intake and retention lead to hypertension. Impaired dermal lymphangiogenesis and lymphatic dysfunction-mediated sodium and fluid imbalance are pathological mechanisms. The adenosine A2A receptor (A2AR) is expressed in lymphatic endothelial cells (LECs), while the roles and mechanisms of LEC-A2AR in skin lymphangiogenesis during salt-induced hypertension are not clear. METHODS AND RESULTS: The expression of LEC-A2AR correlated with lymphatic vessel density in both high-salt diet (HSD)-induced hypertensive mice and hypertensive patients. Lymphatic endothelial cell-specific A2AR knockout mice fed HSD exhibited 17 ± 2% increase in blood pressure and 17 ± 3% increase in Na+ content associated with decreased lymphatic density (-19 ± 2%) compared with HSD-WT mice. A2AR activation by agonist CGS21680 increased lymphatic capillary density and decreased blood pressure in HSD-WT mice. Furthermore, this A2AR agonist activated MSK1 directly to promote VEGFR2 activation and endocytosis independently of VEGF as assessed by phosphoprotein profiling and immunoprecipitation assays in LECs. VEGFR2 kinase activity inhibitor fruquintinib or VEGFR2 knockout in LECs but not VEGF-neutralizing antibody bevacizumab suppressed A2AR activation-mediated decrease in blood pressure. Immunostaining revealed phosphorylated VEGFR2 and MSK1 expression in the LECs were positively correlated with skin lymphatic vessel density and A2AR level in hypertensive patients. CONCLUSION: The study highlights a novel A2AR-mediated VEGF-independent activation of VEGFR2 signaling in dermal lymphangiogenesis and sodium balance, which might be a potential therapeutic target in salt-sensitive hypertension.

Intravenous immunoglobulin for treatment of hospitalized COVID-19 patients: an evidence mapping and meta-analysis.

BACKGROUND: The clinical efficacy and safety of intravenous immunoglobulin (IVIg) treatment for COVID-19 remain controversial. This study aimed to map the current status and gaps of available evidence, and conduct a meta-analysis to further investigate the benefit of IVIg in COVID-19 patients. METHODS: Electronic databases were searched for systematic reviews/meta-analyses (SR/MAs), primary studies with control groups, reporting on the use of IVIg in patients with COVID-19. A random-effects meta-analysis with subgroup analyses regarding study design and patient disease severity was performed. Our outcomes of interest determined by the evidence mapping, were mortality, length of hospitalization (days), length of intensive care unit (ICU) stay (days), number of patients requiring mechanical ventilation, and adverse events. RESULTS: We included 34 studies (12 SR/MAs, 8 prospective and 14 retrospective studies). A total of 5571 hospitalized patients were involved in 22 primary studies. Random-effects meta-analyses of very low to moderate evidence showed that there was little or no difference between IVIg and standard care or placebo in reducing mortality (relative risk [RR] 0.91; 95% CI 0.78-1.06; risk difference [RD] 3.3% fewer), length of hospital (mean difference [MD] 0.37; 95% CI - 2.56, 3.31) and ICU (MD 0.36; 95% CI - 0.81, 1.53) stays, mechanical ventilation use (RR 0.92; 95% CI 0.68-1.24; RD 2.8% fewer), and adverse events (RR 0.98; 95% CI 0.84-1.14; RD 0.5% fewer) of patients with COVID-19. Sensitivity analysis using a fixed-effects model indicated that IVIg may reduce mortality (RR 0.76; 95% CI 0.60-0.97), and increase length of hospital stay (MD 0.68; 95% CI 0.09-1.28). CONCLUSION: Very low to moderate certainty of evidence indicated IVIg may not improve the clinical outcomes of hospitalized patients with COVID-19. Given the discrepancy between the random- and fixed-effects model results, further large-scale and well-designed RCTs are warranted.

Chromium Catalyzed Asymmetric Reformatsky Reaction.

This study describes an unprecedented chromium-catalyzed asymmetric Reformatsky reaction, enabling the synthesis of chiral ß-hydroxy carbonyl compounds from α-chlorinated or α-brominated esters and amides. By employing a chiral chromium/diarylamine bis(oxazoline) catalyst, we achieved relatively broad functional group tolerance. Distinct from known reports, the protocol operates under both classical and photoredox conditions, facilitated by the in situ formation of a nucleophilic chiral chromium intermediate through a radical-polar crossover mechanism. Preliminary mechanistic insights, supported by DFT calculations, identify the nucleophilic aldehyde addition as the key stereo-determining step. This approach not only overcomes the limitations of existing Reformatsky reactions but also provides a versatile strategy for accessing complex chiral molecules.

Systematic and benchmarking studies of pipelines for mammal WGBS data in the novel NGS platform.

BACKGROUND: Whole genome bisulfite sequencing (WGBS), possesses the aptitude to dissect methylation status at the nucleotide-level resolution of 5-methylcytosine (5-mC) on a genome-wide scale. It is a powerful technique for epigenome in various cell types, and tissues. As a recently established next-generation sequencing (NGS) platform, GenoLab M is a promising alternative platform. However, its comprehensive evaluation for WGBS has not been reported. We sequenced two bisulfite-converted mammal DNA in this research using our GenoLab M and NovaSeq 6000, respectively. Then, we systematically compared those data via four widely used WGBS tools (BSMAP, Bismark, BatMeth2, BS-Seeker2) and a new bisulfite-seq tool (BSBolt). We interrogated their computational time, genome depth and coverage, and evaluated their percentage of methylated Cs. RESULT: Here, benchmarking a combination of pre- and post-processing methods, we found that trimming improved the performance of mapping efficiency in eight datasets. The data from two platforms uncovered ~ 80% of CpG sites genome-wide in the human cell line. Those data sequenced by GenoLab M achieved a far lower proportion of duplicates (~ 5.5%). Among pipelines, BSMAP provided an intriguing representation of 5-mC distribution at CpG sites with 5-mC levels > ~ 78% in datasets from human cell lines, especially in the GenoLab M. BSMAP performed more advantages in running time, uniquely mapped reads percentages, genomic coverage, and quantitative accuracy. Finally, compared with the previous methylation pattern of human cell line and mouse tissue, we confirmed that the data from GenoLab M performed similar consistency and accuracy in methylation levels of CpG sites with that from NovaSeq 6000. CONCLUSION: Together we confirmed that GenoLab M was a qualified NGS platform for WGBS with high performance. Our results showed that BSMAP was the suitable pipeline that allowed for WGBS studies on the GenoLab M platform.

Cu(I)-Catalyzed Chemo- and Enantioselective Desymmetrizing C-O Bond Coupling of Acyl Radicals.

Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemo- and stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C-O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters. Partnered by one- or two-step follow-up transformations, this reaction provides a convenient and practical strategy for the rapid preparation of chiral C3 building blocks from readily available alcohols, particularly the industrially relevant glycerol. Mechanistic studies supported the proposed C-O bond coupling of acyl radicals.

Development of meso-Five-Membered Heterocycle BODIPY-Based AIE Fluorescent Probes for Dual-Organelle Viscosity Imaging.

Fluorescent rotors with aggregation-induced emission (AIE) and organelle-targeting properties have attracted great attention for sensing subcellular viscosity changes, which could help understand the relationships of abnormal fluctuations with many associated diseases. Despite the numerous efforts spent, it remains rare and urgent to explore the dual-organelle targeting probes and their structural relationships with viscosity-responsive and AIE properties. Therefore, in this work, we reported four meso-five-membered heterocycle-substituted BODIPY-based fluorescent probes, explored their viscosity-responsive and AIE properties, and further investigated their subcellular localization and viscosity-sensing applications in living cells. Interestingly, the meso-thiazole probe 1 showed both good viscosity-responsive and AIE (in pure water) properties and could successfully target both mitochondria and lysosomes, further imaging cellular viscosity changes by treating lipopolysaccharide and nystatin, attributing to the free rotation and potential dual-organelle targeting ability of the meso-thiazole group. The meso-benzothiophene probe 3 with a saturated sulfur only showed good viscosity-responsive properties in living cells with the aggregation-caused quenching effect and no subcellular localization. The meso-imidazole probe 2 showed the AIE phenomenon without an obvious viscosity-responsive property with a C═N bond, while the meso-benzopyrrole probe 4 displayed fluorescence quenching in polar solvents. Therefore, for the first time, we investigated the structure-property relationships of four meso-five-membered heterocycle-substituted BODIPY-based fluorescent rotors with viscosity-responsive and AIE properties, and among these, 1 with a C═N bond and a saturated sulfur on the meso-thiazole, potentially contributing to their corresponding AIE and viscosity-responsive properties, served as a sensitive AIE fluorescent rotor for imaging dual-organelle viscosity in both mitochondria and lysosomes.

Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia.

Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1-26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0-5.4) in nonresponders (P = 0.002). Grade 2-3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4+ CD127+ PD-1+ T cells might serve as a predictor of treatment response.ClinicalTrials.gov identifier NCT04541277.

A method describing the microdissection of trabecular meshwork tissue from Brown Norway rat eyes.

Glaucoma is often associated with elevated intraocular pressure (IOP), generally due to obstruction of aqueous humor outflow within the trabecular meshwork (TM). Despite many decades of research, the molecular cause of this obstruction remains elusive. To study IOP regulation, several in vitro models, such as perfusion of anterior segments or mechanical stretching of TM cells, have identified several IOP-responsive genes and proteins. While these studies have proved informative, they do not fully recapitulate the in vivo environment where IOP is subject to additional factors, such as circadian rhythms. Thus, rodent animal models are now commonly used to study IOP-responsive genes in vivo. Several single-cell RNAseq studies have been performed where angle tissue, containing cornea, iris, ciliary body tissue in addition to TM, is dissected. However, it is advantageous to physically separate TM from other tissues because the ratio of TM cells is relatively low compared to the other cell types. In this report, we describe a new technique for rat TM microdissection. Evaluating tissue post-dissection by histology and immunostaining clearly shows successful removal of the TM. In addition, TaqMan PCR primers targeting biomarkers of trabecular meshwork (Myoc, Mgp, Chi3l1) or ciliary body (Myh11, Des) genes showed little contamination of TM tissue by the ciliary body. Finally, pitfalls encountered during TM microdissection are discussed to enable others to successfully perform this microsurgical technique in the rat eye.

Transjugular liver biopsy: enlarge the indications for liver biopsy with reliable diagnostic quality.

BACKGROUND: Complications and diagnostic efficiency for liver biopsy are main concerns for clinicians. This study aimed to assess the safety and efficacy of transjugular liver biopsy (TJLB) compared with percutaneous liver biopsy (PLB) when patients had equal level of liver function and number of passes, using propensity score matching (PSM). METHODS: The clinical and pathological data of patients who received TJLB or PLB between January 2012 and October 2022 were collected. Matching factors included age, gender, cirrhosis, portal hypertension, liver function, creatinine, number of passes, hemodialysis, history of anti-coagulation and anti-platelet, and comorbidities. Coagulation indexes were not considered as matching factors due to different indications of the two techniques. RESULTS: 2711 PLBs and 30 TJLBs were evaluated. By PSM, 75 patients (50 PLBs, 25 TJLBs) were matched. The complication rates for TJLB and PLB were 4.0% (1/25) and 10.0% (5/50) (P > 0.05). Two PLBs had hepatic hemorrhage, one of which required only close monitoring (Grade 1) and the other needed hemostasis and rehydration therapy (Grade 2). The other 3 cases presented with mild abdominal pain (Grade 1). And only one TJLB presented with mild pain. The median number of complete portal tracts were 6.0 and 10.0 for TJLBs and PLBs (P < 0.05). Moreover, the median length of sample for TJLBs and PLBs were 10.0 and 16.5 mm (P < 0.05). The diagnostic efficiency of hepatopathy of unknown etiology of TJLB versus PLB groups before and after matching were 96.4% vs. 94.1% and 95.7% vs. 93.2%, respectively (P > 0.05). CONCLUSION: TJLB is an effective invasive diagnostic procedure that expands indications for liver biopsy with reliable diagnostic quality.