Identification of FTY720 and COH29 as novel topoisomerase I catalytic inhibitors by experimental and computational studies.

The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.

Saponins as therapeutic candidates for atherosclerosis.

Drug development for atherosclerosis, the underlying pathological state of ischemic cardiovascular diseases, has posed a longstanding challenge. Saponins, classified as steroid or triterpenoid glycosides, have shown promising therapeutic potential in the treatment of atherosclerosis. Through an exhaustive examination of scientific literature spanning from May 2013 to May 2023, we identified 82 references evaluating 37 types of saponins in terms of their prospective impacts on atherosclerosis. These studies suggest that saponins have the potential to ameliorate atherosclerosis by regulating lipid metabolism, inhibiting inflammation, suppressing apoptosis, reducing oxidative stress, and modulating smooth muscle cell proliferation and migration, as well as regulating gut microbiota, autophagy, endothelial senescence, and angiogenesis. Notably, ginsenosides exhibit significant potential and manifest essential pharmacological attributes, including lipid-lowering, anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects. This review provides a comprehensive examination of the pharmacological attributes of saponins in atherosclerosis, with particular emphasis on their role in the regulation of lipid metabolism regulation and anti-inflammatory effects. Thus, saponins may warrant further investigation as a potential therapy for atherosclerosis. However, due to various reasons such as low oral bioavailability, the clinical application of saponins in the treatment of atherosclerosis still needs further exploration.

Rationally Constructed De Novo Fluorescent Nanosensor for Nitric Oxide Detection and Imaging in Living Cells and Inflammatory Mice Models.

For the early diagnosis and effective evaluation of treatment effects of inflammation, a de novo bioanalytical method is urgently needed to monitor the metabolite nitric oxide (NO) associated with inflammatory diseases. However, developing a reliable detection method with excellent water solubility, biocompatibility, long retention time, and blood circulation is still challenging. In this work, we reported for the first time a de novo host-guest self-assembled nanosensor CTA for the quantitative detection and visualization of NO levels in inflammatory models. CTA mainly consists of two parts: (i) an adamantyl-labeled guest small-molecule RN-adH containing a classical response moiety o-phenylenediamine for a chemical-specific response toward NO and fluorophore rhodamine B with excellent optical properties as an internal reference for self-calibration and (ii) a remarkable water-soluble and biocompatible supramolecular ß-cyclodextrin polymer (Poly-ß-CD) host. In the presence of NO, the o-phenylenediamine unit was reacted with NO at a low pH value of ∼7.0, accompanied by changes in the intensity of the two emission peaks corrected for each other and the change in fluorescence color of the CTA solution from fuchsia to pink. Furthermore, CTA was an effective tool for NO detection with a fast response time (∼60 s), high selectivity, and sensitivity (LOD: 22.3 nM). Impressively, the CTA nanosensor has successfully achieved the targeted imaging of NO in living inflammatory RAW 264.7 cells and mice models with satisfactory results, which can provide a powerful molecular tool for the visualization and assessment of the occurrence and development of NO-related inflammatory diseases in complex biosystems.

Clinical value of noninvasive lens advanced glycation end product detection in early screening and severity evaluation of patients with diabetic kidney disease.

BACKGROUND: Advanced glycation end products (AGEs) deposited in the lens are correlated with those in the kidneys, indicating a possible value in evaluating diabetic kidney disease (DKD). This study explored the value of noninvasively measuring lens AGEs to diagnose and evaluate the severity of diabetic nephropathy in patients with type 2 diabetes mellitus (T2DM). METHODOLOGY: A total of 134 T2DM patients admitted to the Fifth People's Hospital of Shanghai from March 2020 to May 2021 were selected randomly. Patients were divided into low-, medium-and high-risk groups according to the risk assessment criteria for DKD progression and into DKD and non-DKD (non-DKD) groups according to the Guidelines for the Prevention and Treatment of Diabetic Nephropathy in China. The concentrations of noninvasive AGEs in the lens in all the groups were retrospectively analyzed. RESULTS: The concentration of noninvasive lens AGEs in the high-risk patients, according to the 2012 guidelines of the Global Organization for Improving the Prognosis of Kidney Diseases, was significantly higher than that in the remaining groups. Regression analysis suggested the value of lens AGEs in diagnosing DKD and evaluating DKD severity. Cox regression analysis indicated that the noninvasive lens AGE concentration was positive correlated with the course of disease. CONCLUSION: The receiver operating characteristic (ROC) curve suggested that using noninvasive lens AGE measurements has clinical value in the diagnosis of DKD (area under the curve 62.4%,95% confidence interval (CI) 52.4%-73.9%, p = 0.014) and in assessing the severity of DKD (area under the curve 83.2%, 95% CI 74.1%-92.3%, P < 0.001). Noninvasive lens AGE testing helps screen T2DM patients for DKD and evaluate the severity of DKD.

Jia-Wei-Kai-Xin-San Treatment Alleviated Mild Cognitive Impairment through Anti-Inflammatory and Antiapoptotic Mechanisms in SAMP8 Mice.

Background: Alleviating mild cognitive impairment (MCI) is crucial to delay the progression of Alzheimer's disease (AD). Jia-Wei-Kai-Xin-San (JWKXS) is applied for treating AD with MCI. However, the mechanism of JWKXS in the treatment of MCI is unclear. Thus, this study aimed to investigate the effect and mechanism of JWKXS in SAMP8 mice models of MCI. Methods: MCI models were established to examine learning and memory ability and explore the pathomechanisms in brain of SAMP8 mice at 4, 6, and 8 months. The mice were treated for 8 weeks and the effects of JWKXS on MCI were characterized through Morris water maze and HE/Nissl's/immunohistochemical staining. Its mechanism was predicted by the combination of UPLC-Q-TOF/MS and system pharmacology analysis, further verified with SAMP8 mice, BV2 microglial cells, and PC12 cells. Results: It was found that 4-month-old SAMP8 mice exhibited MCI. Two months of JWKXS treatment improved the learning and memory ability, alleviated the hippocampal tissue and neuron damage. Through network pharmacology, four key signaling pathways were found to be involved in treatment of MCI by JWKXS, including TLR4/NF-κB pathway, NLRP3 inflammasome activation, and intrinsic and extrinsic apoptosis. In vitro and in vivo experiments demonstrated that JWKXS attenuated neuroinflammation by inhibiting microglia activation, suppressing TLR4/NF-κB and NLRP3 inflammasome pathways, and blocking the extrinsic and intrinsic apoptotic pathways leading to neuronal apoptosis suppression in the hippocampus. Conclusion: JWKXS treatment improved the learning and memory ability and conferred neuroprotective effects against MCI by inducing anti-inflammation and antiapoptosis. Limitations. The small sample size and short duration of the intervention limit in-depth investigation of the mechanisms. Future Prospects. This provides a direction for further clarification of the anti-AD mechanism, and provides certain data support for the formulation to move toward clinical practice.

Therapeutic Candidates for Alzheimer's Disease: Saponins.

Drug development for Alzheimer's disease, the leading cause of dementia, has been a long-standing challenge. Saponins, which are steroid or triterpenoid glycosides with various pharmacological activities, have displayed therapeutic potential in treating Alzheimer's disease. In a comprehensive review of the literature from May 2007 to May 2023, we identified 63 references involving 40 different types of saponins that have been studied for their effects on Alzheimer's disease. These studies suggest that saponins have the potential to ameliorate Alzheimer's disease by reducing amyloid beta peptide deposition, inhibiting tau phosphorylation, modulating oxidative stress, reducing inflammation, and antiapoptosis. Most intriguingly, ginsenoside Rg1 and pseudoginsenoside-F11 possess these important pharmacological properties and show the best promise for the treatment of Alzheimer's disease. This review provides a summary and classification of common saponins that have been studied for their therapeutic potential in Alzheimer's disease, showcasing their underlying mechanisms. This highlights the promising potential of saponins for the treatment of Alzheimer's disease.

Observing the Agostic Hydrogen in Pd(II)-Catalyzed Aromatic C-H Activation.

Direct C-H activation and functionalization offer a convenient protocol for pharmaceutical and material syntheses. Although versatile mechanisms have been proposed to depict transition-metal-catalyzed C-H activation, to date, the shared key agostic hydrogen intermediate in several major mechanisms has not been observed yet, which apparently puzzles the mechanism-based catalyst design. This work reports the direct observations of this intermediate in Pd(II)/Sc(III)-catalyzed C-H activation of acetanilides, and its stability and reactivity in C-H activation are investigated. Remarkably, this intermediate is only observed in electron-rich acetanilides, and the meta-substituent with increased σm constant generally accelerates C-H activation, a characteristic of the base-assisted C-H activation mechanism. This study has unveiled the masks of this intermediate with an understanding of its first-hand physicochemical properties, shedding new light on mechanism-based catalyst design.

Pd(II)/Lewis Acid Catalyzed Intramolecular Annulation of Indolecarboxamides with Dioxygen through Dual C-H Activation.

Transition-metal ion catalyzed intramolecular dual C-H activation to construct polycyclic heteroarene skeletons is merited for its step and atom-economic advantages in organic synthesis. However, in most cases, stoichiometric oxidants, elevated temperature, and other harsh conditions were commonly faced for this reaction, which apparently block the synthetic applications. Herein, we report a Pd(II)/LA (LA: Lewis acid) catalyzed intramolecular dual C-H activation to construct indoloquinolinone derivatives under mild conditions with dioxygen as the sole oxidant. It was found that adding LA such as Sc3+ to Pd(OAc)2 sharply improved its catalytic efficiency, whereas Pd(OAc)2 alone was very sluggish. The activity improvement was attributed to the linkage of the Sc3+ cation to the Pd(II) species through a diacetate bridge that significantly enhanced the electrophilic properties of Pd(II) for dual C-H activation.

Palladium(II)/Lewis Acid-Catalyzed Olefination of Arylacetamides with Dioxygen.

The present work introduces Pd(II)/LA-catalyzed (LA: Lewis acid) olefination of arylacetamides with dioxygen as the oxidant source. This protocol tolerates with different functional groups on the substrates, and the catalytic efficiency is highly Lewis acidity-dependent on added LA, that is, a stronger LA provided a better promotional effect. The 1H NMR studies of the semireaction between the arylacetamide and the Pd(II)/Sc(III) catalyst in HOAc-d4 disclosed the formation of a palladacycle intermediate, and the C-H activation step was reversible, which led to the formation of the deuterated arylacetamide substrate and the palladacycle intermediate. Further semireaction between the palladacycle intermediate and the olefin disclosed that it was a clean and much faster reaction than the C-H activation step, thus revealing multiple mechanistic information for Pd(II)-catalyzed C-H activation.

Pd(II)/Lewis acid catalyzed regioselective olefination of indole with dioxygen.

Transition metal ion catalyzed indole olefination through C-H activation is a convenient protocol to synthesize versatile bioactive vinylindole compounds; however, in most cases, stoichiometric amounts of oxidants were necessary to accomplish the catalytic cycle. The present study describes a Pd(II)/LA (LA: Lewis acid) catalyzed indole olefination with dioxygen as the sole oxidant. The olefination reaction with electron-rich olefins proceeded smoothly through the pyrrolyl N-carboxamide group directed remote C-H activation at the C3 position of the indole with the Pd(II)/LA catalyst, whereas Pd(II) alone was a very sluggish catalyst under identical conditions. For the electron-deficient olefins, the directing N-carboxamide group was not essential for olefination with this Pd(II)/LA catalyst, demonstrating a different olefination pathway from that of electron-rich olefins. Remarkably, 1H NMR kinetics disclosed that olefination proceeded much faster with electron-rich olefins than with electron-deficient ones.

Serum Trimethylamine N-oxide and the Diversity of the Intestinal Microbial Flora in Type 2 Diabetes Complicated by Diabetic Kidney Disease.

BACKGROUND: Trimethylamine N-oxide (TMAO) serves as a metabolite of intestinal bacteria as well as a urotoxin influencing the prognosis of chronic kidney disease (CKD), which has become a research hotspot in the field of kidney disease. This study preliminarily explored the alternations of the microbial flora and serum TMAO in patients with type 2 diabetes mellitus (T2DM) complicated with diabetic kidney disease (DKD). METHODS: Seventeen T2DM patients at the Affiliated Hospital of Zunyi Medical University between September 2018 and February 2019 were included. Among these patients, 8 patients had T2DM complicated with DKD. Eight healthy volunteers constituted the control group. Fresh stool was collected for Illumina sequencing. Based on the sequencing outcomes, the flora diversity and species differences were analyzed. Serum TMAO, cystatin C, urinary albumin/urine creatinine ratios (ACRs), and routine biochemical outcomes were also compared. RESULTS: The DKD group exhibited a significantly higher TMAO level than the remaining groups. The high-TMAO group had a significantly increased ACR level compared with the low-TMAO group. TMAO positively correlated with the ACR. Compared with the control group, the DKD group exhibited a decreased flora diversity. At the genus level, both the T2DM group and the DKD group showed decreased numbers of Alloprevotella and Megasphaera compared with the control group. The difference in Megasphaera between the DKD group and the control group was significant. CONCLUSIONS: The alternation of the intestinal microbial flora may participate in the development of DKD, and TMAO and chronic inflammation might be important factors for DKD development.

COMBINATION OF VITRECTOMY AND INTENTIONAL MACULAR DETACHMENT IS ASSOCIATED WITH A FASTER EDEMATOUS REGRESSION THAN VITRECTOMY ALONE IN THE TREATMENT OF REFRACTORY DIABETIC MACULAR EDEMA.

PURPOSE: To compare clinical outcomes in eyes with refractory diabetic macular edema managed by vitrectomy combined with and without intentional macular detachment (IMD). METHODS: This is a retrospective cohort study. Forty-one eyes with diabetic macular edema that were previously poorly responsive to at least 5 monthly anti-vascular endothelial growth factor and at least twice switch therapy previously were included in this study. All eyes underwent pars plana vitrectomy with internal limiting membrane peeling, 21 of which were combined with an IMD procedure (assigned to an IMD group) and 20 of which did not have IMD performed (nMD group). Macular morphologic and visual acuity changes were analyzed from baseline through the endpoint (24 weeks) postprocedure, and were compared between groups. RESULTS: All patients completed at least six months of follow-up, with a mean of 29.7 weeks (24-56 weeks). The mean central retinal thickness reduction was greater in the IMD group than that in the nMD group at 1 week (P = 0.001), 2 weeks (P = 0.008), and 4 weeks (P = 0.004), but there was no statistically significant difference at 12 weeks (P = 0.051) or 24 weeks (P = 0.056). There were no significant differences in the mean changes of best-corrected visual acuity from baseline to the 24 weeks endpoint in either group (P = 0.83). CONCLUSION: Vitrectomy can release macular edema in the eyes with refractory diabetic macular edema. Combined with IMD technical, patients seemed to achieve a faster central retinal thickness decrease but neither the final morphologic outcome nor the visual acuity was affected.

Subthreshold micropulse laser photocoagulation versus half-dose photodynamic therapy for acute central serous chorioretinopathy.

PURPOSE: To compare the efficacy and safety of subthreshold micropulse (STMP) laser photocoagulation and half-dose photodynamic therapy (PDT) in the treatment of acute central serous chorioretinopathy (CSC). METHODS: A total of 39 acute CSC patients were included. 18 patients were treated with STMP laser and 21 patients were treated with half-dose PDT. The main outcome measures were best-corrected visual acuity (BCVA) according to Early Treatment Diabetic Retinopathy Study (ETDRS) chart, the proportion of eyes with complete resolution of subretinal fluid, the number of treatments, and the retinal sensitivity by microperimetry during the 12-month study period. RESULTS: The mean number of treatments during the 12-month period was 1.6 in STMP group and 1.3 in half-dose PDT group, respectively (P = 0.174). The proportion of eyes with complete resolution of subretinal fluid was 83.3% in STMP group compared with 90.5% in half-dose PDT group at 12-month (P = 0.647). The mean BCVA at 12-month after treatment was 75.28 ± 12.58 for STMP group and 76.62 ± 11.57 for half-dose PDT group, respectively (P = 0.731). No statistically significant difference was found in the mean retinal sensitivity between the two groups during the 12 months follow-up (P = 0.701 at 3 months; P = 0.725 at 6 months; P = 0.695 at 12 months). CONCLUSIONS: Subthreshold micropulse Laser Photocoagulation is as effective as half-dose PDT for acute CSC, while minimizing the damage effect on retinal.

Binding of Duck Tembusu Virus Nonstructural Protein 2A to Duck STING Disrupts Induction of Its Signal Transduction Cascade To Inhibit Beta Interferon Induction.

Duck Tembusu virus (DTMUV), which is similar to other mosquito-borne flaviviruses that replicate well in most mammalian cells, is an emerging pathogenic flavivirus that has caused epidemics in egg-laying and breeding waterfowl. Immune organ defects and neurological dysfunction are the main clinical symptoms of DTMUV infection. Preinfection with DTMUV makes the virus impervious to later interferon (IFN) treatment, revealing that DTMUV has evolved some strategies to defend against host IFN-dependent antiviral responses. Immune inhibition was further confirmed by screening for DTMUV-encoded proteins, which suggested that NS2A significantly inhibited IFN-ß and IFN-stimulated response element (ISRE) promoter activity in a dose-dependent manner and facilitated reinfection with duck plague virus (DPV). DTMUV NS2A was able to inhibit duck retinoic acid-inducible gene-I (RIG-I)-, and melanoma differentiation-associated gene 5 (MDA5)-, mitochondrial-localized adaptor molecules (MAVS)-, stimulator of interferon genes (STING)-, and TANK-binding kinase 1 (TBK1)-induced IFN-ß transcription, but not duck TBK1- and interferon regulatory factor 7 (IRF7)-mediated effective phases of IFN response. Furthermore, we found that NS2A competed with duTBK1 in binding to duck STING (duSTING), impaired duSTING-duSTING binding, and reduced duTBK1 phosphorylation, leading to the subsequent inhibition of IFN production. Importantly, we first identified that the W164A, Y167A, and S361A mutations in duSTING significantly impaired the NS2A-duSTING interaction, which is important for NS2A-induced IFN-ß inhibition. Hence, our data demonstrated that DTMUV NS2A disrupts duSTING-dependent antiviral cellular defenses by binding with duSTING, which provides a novel mechanism by which DTMUV subverts host innate immune responses. The potential interaction sites between NS2A and duSTING may be the targets of future novel antiviral therapies and vaccine development.IMPORTANCE Flavivirus infections are transmitted through mosquitos or ticks and lead to significant morbidity and mortality worldwide with a spectrum of manifestations. Infection with an emerging flavivirus, DTMUV, manifests with clinical symptoms that include lesions of the immune organs and neurological dysfunction, leading to heavy egg drop and causing serious harm to the duck industry in China, Thailand, Malaysia, and other Southeast Asian countries. Mosquito cells, bird cells, and mammalian cell lines are all susceptible to DTMUV infection. An in vivo study revealed that BALB/c mice and Kunming mice were susceptible to DTMUV after intracerebral inoculation. Moreover, there are no reports about DTMUV-related human disease, but antibodies against DTMUV and viral RNA were detected in serum samples of duck industry workers. This information implies that DTMUV has expanded its host range and may pose a threat to mammalian health. However, the pathogenesis of DTMUV is largely unclear. Our results show that NS2A strongly blocks the STING-induced signal transduction cascade by binding with STING, which subsequently blocks STING-STING binding and TBK1 phosphorylation. More importantly, the W164, Y167, or S361 residues in duSTING were identified as important interaction sites between STING and NS2A that are vital for NS2A-induced IFN production and effective phases of IFN response. Uncovering the mechanism by which DTMUV NS2A inhibits IFN in the cells of its natural hosts, ducks, will help us understand the role of NS2A in DTMUV pathogenicity.

Decarboxylative Addition of Propiolic Acids with Indoles to Synthesize Bis(indolyl)methane Derivatives with a Pd(II)/LA Catalyst.

Exploring new protocols for efficient organic synthesis is crucial for pharmaceutical developments. The present work introduces a Pd(II)/LA-catalyzed (LA: Lewis acid) decarboxylative addition reaction for the synthesis of bis(indolyl)methane derivatives. The presence of Lewis acid such as Sc(OTf)3 triggered Pd(II)-catalyzed decarboxylative addition of propiolic acids with indoles to offer the bis(indolyl)methane derivatives in moderate to good yields, whereas neither Pd(II) nor Lewis acid alone was active for this synthesis. The catalytic efficiency of Pd(OAc)2 was highly dependent on the Lewis acidity of the added Lewis acid, that is, a stronger Lewis acid provided a higher yield of the bis(indolyl)methane derivatives. Meanwhile, this Pd(II)/LA-catalyzed decarboxylative addition reaction showed good tolerance toward versatile electron-rich or -deficient substituents on the indole skeleton and on the benzyl ring of propiolic acids. The studies on the in situ 1H NMR kinetics of this Pd(II)/Sc(III) catalysis disclosed the formation of a transient vinyl-Pd(II)/Sc(III) intermediate generated by the pyrrole addition to the alkynyl-Pd(II)/Sc(III) species after decarboxylation, which was scarcely observed before.

Palladium(II)/Lewis Acid-Catalyzed Oxidative Olefination/Annulation of N-Methoxybenzamides: Identifying the Active Intermediates through NMR Characterizations.

Although Pd(II)-catalyzed C-H activation in arenes has been widely successful in organic synthesis with many palladacycle compounds isolated as the intermediates in ligand-directed C-H activation, direct identification of the reaction intermediates such as the π-complex prior to the C-H activation is still not successful because of their instability. In the present study, we introduce a Pd(II)/LA (LA: Lewis acid)-catalyzed oxidative olefination/annulation reaction between N-methoxybenzamides and acrylates with oxygen as the oxidant source, in which two intermediates, including an unsymmetrical η6-complex and a palladacycle species without the proton releasing to the environment, were identified through NMR characterizations. The in situ formation of the heterobimetallic Pd(II)/LA species such as Pd(II)/Sc(III) may have enhanced the electrophilic properties of the Pd2+ cation, thus improving the stability of the π-complex, herein, an unsymmetrical η6-complex, and improving its catalytic efficiency. The observed insensitive electronic effect preferred the concerted metalation-deprotonation (CMD) mechanism for this C-H activation, and the detected palladacycle intermediate without the proton releasing to the environment offered an experimental clue to support the proposed CMD mechanism.

Heterogeneity in the dynamic change of cognitive function among older Chinese people: A growth mixture model.

OBJECTIVES: Our aim is to distinguish different trajectories of cognitive change in Chinese geriatric population and identify risk factors for cognitive decline in each subpopulation. METHODS: We obtained data from five waves (2002, 2005, 2008, 2011, 2014) of the Chinese Longitudinal Health Longevity Survey, using the Chinese Mini-Mental State Examination (C-MMSE) as a proxy for cognitive function. We applied growth mixture modeling (GMM) to identify heterogeneous subpopulations and potential risk factors. RESULTS: Our sample included 3859 older adults, 1387 (48.7%) male and 1974 (51.2%) female with age range of 62 to 108 (average of 74.5) at initial survey. Using GMM and best fit statistics, we identified two distinct subgroups in respect to their longitudinal cognitive function: (a) cognitively stable (87.8%) group with 0.49 C-MMSE points decline per 3 years, and (b) cognitively declining (12.2%) group with 6.03 C-MMSE points decline per 3 years. Of note, cognitive activities were protective, and hearing and visual impairments were risk factors in both groups. Diabetes, hypertension, stroke and cardiovascular disease were associated with cognitive decline in the cognitively declining group. Physical activities, and intake of fresh vegetables, fruits, and fish products were protective in the cognitively stable group. CONCLUSIONS: Using GMM, we identified heterogeneity in trajectories of cognitive change in older Chinese people. Moreover, we found risk factors specific to each subgroup, which should be considered in future studies.

Lewis Acid Promoted Aerobic Oxidative Coupling of Thiols with Phosphonates by Simple Nickel(II) Catalyst: Substrate Scope and Mechanistic Studies.

Exploring new catalysts for efficient organic synthesis is among the most attractive topics in chemistry. Here, using Ni(OAc)2/LA as catalyst (LA: Lewis acid), a novel catalyst strategy was developed for oxidative coupling of thiols and phosphonates to phosphorothioates with oxygen oxidant. The present study discloses that when Ni(OAc)2 alone was employed as the catalyst, the reaction proceeded very sluggishly with low yield, whereas adding non-redox-active metal ions such as Y3+ to Ni(OAc)2 dramatically promoted its catalytic efficiency. The promotional effect is highly Lewis acidity dependent on the added Lewis acid, and generally, a stronger Lewis acid provided a better promotional effect. The stopped-flow kinetics confirmed that adding Y(OTf)3 can obviously accelerate the activation of thiols by Ni(II) and next accelerate its reaction with phosphonate to generate the phosphorothioate product. ESI-MS characterizations of the catalyst disclosed the formation of the heterobimetallic Ni(II)/Y(III) species in the catalyst solution. Additionally, this Ni(II)/LA catalyst can be applied in the synthesis of a series of phosphorothioate compounds including several commercial bioactive compounds. This catalyst strategy has clearly supported that Lewis acid can significantly improve the catalytic efficiency of these traditional metal ions in organic synthesis, thus opening up new opportunities in their catalyst design.

Lung Adenocarcinoma has a Higher Risk of Lymph Node Metastasis than Squamous Cell Carcinoma: A Propensity Score-Matched Analysis.

BACKGROUND: Controversy still exists in which subtype of non-small-cell lung cancer [squamous cell carcinoma (SCC) or adenocarcinoma] is more likely to have lymph node (LN) metastasis. The aim of this study is to compare the pattern of LN metastasis in two cohorts of matched patients surgically treated for SCC or adenocarcinoma. METHODS: A retrospective analysis of patients undergoing lobectomy or segmentectomy with systematic lymphadenectomy without preoperative treatment for lung SCC or adenocarcinoma was conducted in this study. Data for analysis consisted of age, gender, tumor size, lobe-specific tumor location, tumor location (peripheral or central), and pathologic findings. We conducted the propensity score-matched (PSM) analysis to eliminate potential bias effects of possible confounding factors. RESULTS: From January 2015 to December 2016 in our department, we finally included a total of 387 patients (including 63 patients with SCC and 324 patients with adenocarcinoma) for analysis. For the unmatched cohort, there was no sufficient evidence of significantly different number of positive LNs (P = 0.90) and rate of LN metastasis (P = 0.23) between SCC patients and adenocarcinoma patients. However, potential confounding factors, for example gender, tumor size, tumor location, tumor differentiation, and total number of dissected LNs, were significantly different between patients with SCC and those with adenocarcinoma. In the analysis of matched cohort after PSM analysis, those above confounding factors were comparable between the two groups. However, patients with adenocarcinoma had significantly more mean positive LNs (2.2 and 0.7; P = 0.008) and a higher rate of LN metastasis (53% and 29%; P = 0.016) than those with SCC. CONCLUSIONS: Lung adenocarcinoma had a higher risk of LN metastasis than SCC, suggesting that different therapeutic modalities may be indicated for the two different subtypes of lung cancer.

FACEDOWN POSITIONING AFTER VITRECTOMY WILL NOT FACILITATE MACULAR HOLE CLOSURE BASED ON SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY IMAGING IN GAS-FILLED EYES: A Prospective, Randomized Comparative Interventional Study.

PURPOSE: To compare clinical outcomes in eyes with macular hole (MH) managed by either facedown (FD) or no-FD (nFD) postoperative positioning protocols. METHODS: This is a prospective randomized cohort study. Eighty eyes of 80 consecutive patients with MH who had undergone vitrectomy surgery with internal limiting membrane peeling and gas tamponade were included in this study. Forty eyes of 40 patients who were kept in FD position for 3 days after surgery were assigned to the FD group, 40 eyes of 40 patients with nFD positioning were assigned to the nFD group. Macular hole was examined with swept-source optical coherence tomography images at 1 day, 2 days, 3 days, 2 weeks, 1 month, and 3 months after surgery. The MH closure rate and change of best-corrected visual acuity were compared. RESULTS: At postoperative Day 1, MH was closed in 24 of 32 eyes (with clear optical coherence tomography images) (75%) in the FD group and 23 of 30 eyes (with clear optical coherence tomography images) (77%) in the nFD group (P = 0.97). At postoperative Day 2, MH closure was confirmed in 32 of 36 eyes (88.9%) in the FD group and in 31 of 33 eyes (94%) in the nFD group (P = 0.84), and the results were unchanged at Day 3. At 2 weeks after surgery, clear optical coherence tomography images were acquired from all eyes in both groups, and MH closure was confirmed in 36 of 40 eyes (90%) in the FD group and in 37 of 40 (92.5%) eyes in the nFD group (P = 0.91). Macular hole closure was not achieved in eyes that were kept open by Day 3 after surgery, and none of the eyes with confirmed MH closure by Day 3 had a reopening of the MH by 3 months. The distribution of macular configuration at 3 months was not significantly different between the two groups (P = 0.96). There was no difference in terms of the improvement in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letters gain) between the 2 groups at 1 month (P = 0.22) and 3 months (P = 0.45). CONCLUSION: The nFD protocol neither delayed the MH closure nor decreased the final closure rate after vitrectomy surgery. Therefore, postoperative prone position seems to be unnecessary for all MH repair procedures.