Reaction of 1,3,5-Triazinanes with Phosphoryl Diazomethanes: Access to 5-Phosphoryl-1,2,3,4-tetrahydropyrimidines.

Conversion of 1,3,5-triazinanes into 5-phosporyl-1,2,3,4-tetrahydropyrimidines is achieved efficiently through the microwave-assisted reaction with phosphoryl diazomethanes. Both trialkyl and triaryl 1,3,5-triazinanes were converted by diazomethyldiarylphosphine oxides, dialkyl diazomethylphosphonates, and alkyl diazomethyl(aryl)phosphinates and functionalized simultaneously in good to excellent yields. The reaction is a sequence of 1,3,5-triazinane fragmentation, tandem nucleophilic addition of the generated formaldimines and phosphoryl diazomethanes, and final N,N-acetalization.

Recent Advances in π-Stacking Interaction-Controlled Asymmetric Synthesis.

The π-stacking interaction is one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry. It plays an important role in stabilizing some structures and transition states in certain reactions via both intramolecular and intermolecular interactions, facilitating different selectivities, such as chemo-, regio-, and stereoselectivities. This minireview focuses on the recent examples of the π-stacking interaction-controlled asymmetric synthesis, including auxiliary-induced asymmetric synthesis, kinetic resolution, asymmetric synthesis of helicenes and heterohelicenes, and multilayer 3D chiral molecules.

Predictive and Prognostic Potentials of Lymphocyte-C-Reactive Protein Ratio Upon Hospitalization in Adult Patients with Acute Pancreatitis.

Purpose: In this study, our objective was to investigate the potential utility of lymphocyte-C-reactive protein ratio (LCR) as a predictor of disease progression and a screening tool for intensive care unit (ICU) admission in adult patients with acute pancreatitis (AP). Methods: We included a total of 217 adult patients with AP who were admitted to the First Affiliated Hospital of Harbin Medical University between July 2019 and June 2022. These patients were categorized into three groups: mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP), based on the presence and duration of organ dysfunction. Various demographic and clinical data were collected and compared among different disease severity groups. Results: Height, diabetes, lymphocyte count (LYMPH), lymphocyte percentage (LYM%), platelet count (PLT), D-Dimer, albumin (ALB), blood urea nitrogen (BUN), serum creatinine (SCr), glucose (GLU), calcium ion (Ca2+), C-reactive protein (CRP), procalcitonin (PCT), hospitalization duration, ICU admission, need for BP, LCR, sequential organ failure assessment (SOFA) score, bedside index for severity in AP (BISAP) score, and modified Marshall score showed significant differences across different disease severity groups upon hospitalization. Notably, there were significant differences in LCR between the MAP group and the MSAP and SAP combined group, and the MAP and MSAP combined group and the SAP group, and adult AP patients with ICU admission and those without ICU admission upon hospitalization. Conclusion: In summary, LCR upon hospitalization can be utilized as a simple and reliable predictor of disease progression and a screening tool for ICU admission in adult patients with AP.

Dynamic lymphocyte-CRP ratio as a predictor: a single-centre retrospective study on disease severity and progression in adult COVID-19 patients.

OBJECTIVE: To assess the efficacy of dynamic changes in lymphocyte-C-reactive protein ratio (LCR) on differentiating disease severity and predicting disease progression in adult patients with Coronavirus disease 2019 (COVID-19). METHODS: This single-centre retrospective study enrolled adult COVID-19 patients categorized into moderate, severe and critical groups according to the Diagnosis and Treatment of New Coronavirus Pneumonia (ninth edition). Demographic and clinical data were collected. LCR and sequential organ failure assessment (SOFA) score were calculated. Lymphocyte count and C-reactive protein (CRP) levels were monitored on up to four occasions. Disease severity was determined concurrently with each LCR measurement. RESULTS: This study included 145 patients assigned to moderate (n = 105), severe (n = 33) and critical groups (n = 7). On admission, significant differences were observed among different disease severity groups including age, comorbidities, neutrophil proportion, lymphocyte count and proportion, D-Dimer, albumin, total bilirubin, direct bilirubin, indirect bilirubin, CRP and SOFA score. Dynamic changes in LCR showed significant differences across different disease severity groups at different times, which were significantly inversely correlated with disease severity of COVID-19, with correlation coefficients of -0.564, -0.548, -0.550 and -0.429 at four different times. CONCLUSION: Dynamic changes in LCR can effectively differentiate disease severity and predict disease progression in adult COVID-19 patients.

Gut Microbiota Dysbiosis and Inflammation Dysfunction in Late-Life Depression: An Observational Cross-Sectional Analysis.

Purpose: There are some challenges to diagnosis in the context of similar diagnostic criteria for late-life depression (LLD) and adult depression due to cognitive impairment and other clinical manifestations. The association between gut microbiota and inflammation remains unclear in LLD. We analyzed gut microbiota characteristics and serum inflammatory cytokines in individuals with LLD to explore the combined role of these two factors in potential biomarkers of LLD. Methods: This was an observational cross-sectional study. Fecal samples and peripheral blood from 29 patients and 33 sex- and age-matched healthy controls (HCs) were collected to detect gut microbiota and 12 inflammatory factors. We analyzed differences in diversity and composition of gut microbiota and evaluated relations among gut microbiota, inflammatory factors, and neuropsychological scales. We extracted potential biomarkers using receiver-operating characteristic curve analysis to predict LLD utilizing the combination of the microbiota and inflammatory cytokines. Results: Elevated systemic inflammatory cytokine levels and gut microbiota dysbiosis were found in LLD patients. Relative abundance of Verrucomicrobia at the phylum level and Megamonas, Citrobacter, and Akkermansia at the genus level among LLD patients was lower than HCs. Abundance of Coprococcus, Lachnobacterium, Oscillospira, and Sutterella was higher in LLD patients. Notably, IL6, IFNγ, Verrucomicrobia, and Akkermansia levels were correlated with depression severity. Our study identified IL6, Akkermansia, and Sutterella as predictors of LLD, and their combination achieved an area under the curve of 0.962 in distinguishing LLD patients from HCs. Conclusion: This research offers evidence of changes within gut microbiota and systemic inflammation in LLD. These findings possibly help elucidate functions of gut microbiota and systemic inflammation in LLD development and offer fresh ideas on biomarkers for clinical practise in the context of LLD.

π-Stacking-Controlled Dearomatic Sulfur-Shifted Ene Reaction of Ketenes and Polycyclic Arylthiiranes: Access to Areno[d]-ε-thiolactones.

Electrophilic ring-expansion of polycyclic arylthiiranes and ketenes generated from alkoxy/aryloxyacetyl chlorides in the presence of triethylamine (TEA) is developed and provides a new strategy for the synthesis of areno[d]-ε-thiolactones, areno[d]thiepinones, directly without catalysts or additives. This strategy features atom- and step-economic one-pot characteristic via a tandem sequence of in situ ketene generation, π-stacking-controlled dearomatic sulfur-shifted ene, and aromatization. The current reaction is a novel strategy of electrophilic ring expansions of three-membered saturated heterocycles.

Hollow Ni3S4@Co3S4 with core-satellite nanostructure derived from metal-organic framework (MOF)-on-MOF hybrids as an electrode material for supercapacitors.

Metal-organic frameworks (MOFs) have found wide applications in the field of supercapacitors due to their highly controllable porous structure, big specific surface area, and abundant chemical functional groups. MOF-on-MOF hybrids not only enhance the composition of MOFs (such as ligands and/or metal centers) but also provide greater structural diversity. By utilizing MOFs as precursors for preparing sulfides, the unique characteristics and inherent structure of MOFs are preserved but their conductivity and capacitance are enhanced. This study successfully synthesized hollow-structured Ni3S4@Co3S4 derived from an Ni-MOF@ZIF-67 hybrid structure, where the Ni-MOF serves as the core and ZIF-67 as the satellite. The Ni3S4@Co3S4 electrode demonstrated a specific capacity as high as 747.3 C g-1 at 1 A g-1, and it could still maintain 77% of its initial capacity at 10 A g-1. Furthermore, the assembled Ni3S4@Co3S4//AC hybrid supercapacitor (HSC) device achieved a maximum energy density of 30.8 W h kg-1 when the power density was 750 W kg-1. The device exhibited remarkable cycling durability, retaining 85.4% of its initial capacitance after 5000 cycles. Therefore, the derived functional materials based on MOF-on-MOF provide a more scalable and promising approach for the preparation of efficient electrode materials.

Tf2O/2-Chloropyridine-Triggered Synthesis of Benzo[b]thiophene 1,1-Dioxides from Sulfonium α-Acyl Sulfonylmethylides.

Triflic anhydride and 2-chloropyridine-comediated tandem activation, intramolecular aromatic electrophilic addition, and 1,2-sulfonyl shift via spirocyclic intermediates of sulfonium α-acyl sulfonylmethylides realize the efficient synthesis of 2-alkyl/arylthiobenzo[b]thiophene 1,1-dioxides. The deactivated sulfonyl group determines the site-selectivity of the electrophilic addition via the ipso-attack, while the following S-migration controls the regioselectivity. Some of 2-methylthiobenzo[b]thiophene 1,1-dioxides show fluorescence properties in the solid state and in their solutions.

Agomelatine prevented depression in the chronic restraint stress model through enhanced catalase activity and halted oxidative stress.

BACKGROUND: Agomelatine (AGO) is an antidepressant with unique pharmacological effects; however, its underlying mechanisms remain unknown. In this study, we examined agomelatine's effects on catalase activity, oxidative stress, and inflammation. METHODS: Chronic restraint stress (CRS) model mice were established over 4 weeks, and AGO 50 mg/kg was administered to different groups alongside a deferasirox (DFX) 10 mg/kg gavage treatment. Behavioral tests were performed to assess the effect of AGO on the remission of depression-like behaviors. Meanwhile, the expression of CAT, the oxidative stress signaling pathway and inflammatory protein markers were assessed using ELISA, qRT-PCR, Western blot, and immunohistochemistry. RESULTS: Four weeks of AGO treatment significantly improved depression-like behavior in mice through the activation of catalase in the hippocampus and serum of the model mice, increased superoxide dismutase expression, reduced malondialdehyde expression, and reduced oxidative stress damage. Deferasirox was found to offset this therapeutic effect partially. In addition, the inflammatory pathway (including nuclear factor-κB and nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha) was not significantly altered. CONCLUSIONS: AGO can exert antidepressant effects by altering oxidative stress by modulating catalase activity.

Integrative Multiomics Profiling Unveils the Protective Function of Ulinastatin against Dextran Sulfate Sodium-Induced Colitis.

Ulcerative colitis is an inflammatory bowel disease with multiple pathogeneses. Here, we aimed to study the therapeutic role of ulinastatin (UTI), an anti-inflammatory bioagent, and its associated mechanisms in treating colitis. Dextran sulfate sodium was administrated to induce colitis in mice, and a subgroup of colitis mice was treated with UTI. The gut barrier defect and inflammatory manifestations of colitis were determined via histological and molecular experiments. In addition, transcriptomics, metagenomics, and metabolomics were employed to explore the possible mechanisms underlying the effects of UTI. We found that UTI significantly alleviated the inflammatory manifestations and intestinal barrier damage in the mice with colitis. Transcriptome sequencing revealed a correlation between the UTI treatment and JAK-STAT signaling pathway. UTI up-regulated the expression of SOCS1, which subsequently inhibited the phosphorylation of JAK2 and STAT3, thus limiting the action of inflammatory mediators. In addition, 16S rRNA sequencing illustrated that UTI maintained a more stable intestinal flora, protecting the gut from dysbiosis in colitis. Moreover, metabolomics analysis demonstrated that UTI indeed facilitated the production of some bile acids and short-chain fatty acids, which supported intestinal homeostasis. Our data provide evidence that UTI is effective in treating colitis and support the potential use of UTI treatment for patients with ulcerative colitis.

PI4KIIIß-Mediated Phosphoinositides Metabolism Regulates Function of the VTA Dopaminergic Neurons and Depression-Like Behavior.

Phosphoinositides, including phosphatidylinositol-4,5-bisphosphate (PIP2), play a crucial role in controlling key cellular functions such as membrane and vesicle trafficking, ion channel, and transporter activity. Phosphatidylinositol 4-kinases (PI4K) are essential enzymes in regulating the turnover of phosphoinositides. However, the functional role of PI4Ks and mediated phosphoinositide metabolism in the central nervous system has not been fully revealed. In this study, we demonstrated that PI4KIIIß, one of the four members of PI4Ks, is an important regulator of VTA dopaminergic neuronal activity and related depression-like behavior of mice by controlling phosphoinositide turnover. Our findings provide new insights into possible mechanisms and potential drug targets for neuropsychiatric diseases, including depression. Both sexes were studied in basic behavior tests, but only male mice could be used in the social defeat depression model.

Eu3+-Modified Covalent Organic Frameworks for the Detection of a Vinyl Chloride Monomer Exposure Biomarker.

The vinyl chloride monomer (VCM), a common raw material in the plastics industry, is one of the environmental pollutants to which humans are mostly exposed. Thiodiglycolic acid (TDGA) in human urine is a specific biomarker of its exposure. TDGA plays an important role in understanding the relationships between exposure to the VCM and the identification of subgroups that are at increased risk for disease diagnosis. Therefore, its detection is of great significance. Here, we designed and established a ratiometric fluorescent sensor for TDGA by using Eu3+ as a bridge connecting the covalent organic framework (COF) and the energy donor molecule 2,6-dipicolinic acid (DPA) and named it DPA/Eu@PY-DHPB-COF-COOH. The sensor not only possesses the advantages of a ratiometric fluorescent sensor that can provide built-in self-calibration to correct a variety of target-independent factors but also presents high selectivity and high sensitivity. Currently, there are only a few reports on the detection of TDGA, and to the extent of our knowledge, this report is the first work on the detection of TDGA based on a COF system; so, it has an important reference value and lays a solid foundation for designing advanced sensors of TDGA.

MARK2 phosphorylates KIF13A at a 14-3-3 binding site to polarize vesicular transport of transferrin receptor within dendrites.

Neurons regulate the microtubule-based transport of certain vesicles selectively into axons or dendrites to ensure proper polarization of function. The mechanism of this polarized vesicle transport is still not fully elucidated, though it is known to involve kinesins, which drive anterograde transport on microtubules. Here we explore how the kinesin-3 family member KIF13A is regulated such that vesicles containing transferrin receptor (TfR) travel only to dendrites. In experiments involving live-cell imaging, knockout of KIF13A, BioID assay, we found that the kinase MARK2 phosphorylates KIF13A at a 14-3-3 binding motif, strengthening interaction of KIF13A with 14-3-3 such that it dissociates from TfR-containing vesicles, which therefore cannot enter axons. Overexpression of KIF13A or knockout of MARK2 leads to axonal transport of TfR-containing vesicles. These results suggest a novel kinesin-based mechanism for polarized transport of vesicles to dendrites. Significance: Our findings suggest that at least one type of vesicles, those containing transferrin receptor, travel exclusively to dendrites and are excluded from axons because the kinase MARK2 phosphorylates the kinesin KIF13A to promote its separation from vesicles at the proximal axon, preventing vesicle transport into axons, such that they travel only to dendrites. Future studies should explore how this mechanism of polarized vesicle transport supports neuronal function.

A triple-synergistic small-molecule sulfur cathode promises energetic Cu-S electrochemistry.

Metal-sulfur batteries have received great attention for electrochemical energy storage due to high theoretical capacity and low cost, but their further development is impeded by low sulfur utilization, poor electrochemical kinetics, and serious shuttle effect of the sulfur cathode. To avoid these problems, herein, a triple-synergistic small-molecule sulfur cathode is designed by employing N, S co-doped hierarchical porous bamboo charcoal as a sulfur host in an aqueous Cu-S battery. Expect the enhanced conductivity and chemisorption induced by N, S synergistic co-doping, the intrinsic synergy of macro-/meso-/microporous triple structure also ensures space-confined small-molecule sulfur as high utilization reactant and effectively alleviates the volume expansion during conversion reaction. Under a further joint synergy between hierarchical structure and heteroatom doping, the resulting sulfur cathode endows the Cu-S battery with outstanding electrochemical performance. Cycled at 5 A g-1, it can deliver a high reversible capacity of 2,509.8 mAh g-1 with a good capacity retention of 97.9% after 800 cycles. In addition, a flexible hybrid pouch cell built by a small-molecule sulfur cathode, Zn anode, and gel electrolytes can firmly deliver high average operating voltage of about 1.3 V with a reversible capacity of over 2,500 mAh g-1 under various destructive conditions, suggesting that the triple-synergistic small-molecule sulfur cathode promises energetic metal-sulfur batteries.

Development and validation of a nomogram based on preoperative variables for predicting recurrence-free survival in stage IA lung adenocarcinoma.

BACKGROUND: This study aimed to establish a nomogram for predicting risk of recurrence and provide a model for decision-making between lobectomy and sublobar resection in patients with stage IA lung adenocarcinoma. METHODS: Patients diagnosed with stage IA lung adenocarcinoma (LUAD) between December 2010 and October 2018 from Cancer Hospital Chinese Academy of Medical Sciences were included. Patients were randomly assigned to training and validation cohorts, accounting for 70% and 30% of the total cases, respectively. We collected laboratory variables before surgery. Univariate and multivariate analyses were performed in the training cohort to identify variables significantly associated with recurrence-free survival (RFS) which were subsequently used to construct a nomogram. Validation was conducted in both cohorts. A receiver operating characteristic curve was used to determine the optional cutoff values of the scores calculated from the nomogram. Patients were then divided into low- and high-risk groups. Survival was performed to determine if the nomogram could guide the operation method. RESULTS: A total of 543 patients were included in this study. Gender, albumin level, carcinoembryonic antigen level and cytokeratin-19-fragment level were included in the nomogram. In both cohorts, the nomogram stratified the patients into high- and low-risk groups in terms of RFS. In particular, there was a significant difference in RFS between lobectomy and sublobar resection in the high-risk group. CONCLUSIONS: Gender, albumin level, carcinoembryonic antigen level and cytokeratin-19-fragment level are valuable markers in predicting recurrence and can guide surgical practice in patients with stage IA LUAD.

Theoretical mechanistic insights into the electrophilic addition of hydrogen halides to alkynes.

The electrophilic addition of hydrogen halides to alkynes, also called polar hydrohalogenation of alkynes, is one of the most classical and important organic reactions. Mechanistic and stereoselective insights into the hydrohalogenation of various structurally different distinct alkynes, including both alkyl and aryl substituted acetylenes, in acetic acid were investigated theoretically via density functional theory (DFT) calculations. The results indicate that π-complexes between hydrogen halides and alkynes are first formed, and then all alkynes can undergo a competitive bimolecular intimate ion-pair syn-addition process and a pentamolecular concerted anti-addition process through the cyclic proton transfer mechanism for proton transfer in the absence of tetraalkylammonium halides or a termolecular electrophilic addition (AdE3) process in the presence of tetraalkylammonium halides. All aliphatic alkynes undergo slightly to obviously predominant anti-addition in hydrohalogenations both in the absence and presence of tetraalkylammonium halides. Aromatic 1-arylalk-1-ynes favour syn-additions through bimolecular intimate ion-pair processes with asynchronous concerted characteristics in the absence of tetraalkylammonium halides, while most of them generally prefer anti-addition in the presence of tetraalkylammonium halides. The stereoselectivity is significantly affected by both the electronic and steric effects of 1-arylalk-1-ynes and halides in the reaction mixture. Strongly electron-rich and bulky 1-arylalk-1-ynes generally favour syn-addition in the presence of tetraalkylammonium halides, especially arylethynes in hydrochlorination. Anti-Markovnikov hydrohalogenations of 1-arylalk-1-ynes also prefer anti-addition both in the absence and presence of tetraalkylammonium halides even in small amounts due to high activation energies. The current investigation provides deep insights into the mechanism and stereoselectivity in polar hydrohalogenations of alkynes.

Accessing para-Alkylphenols via Iridium-Catalyzed Site-Specific Deoxygenation of Alcohols.

An iridium-catalyzed and phenol-directed deoxygenation of benzylic alcohols comes as an alternative access to 4-alkylphenols, featuring low catalyst loading (S/C up to 20,000, TOF up to 12,400 h-1), high functionality compatibility, and excellent site-selectivity. The applications in late-stage modification of steroids and gram-scale total synthesis of a Gastrodia elata extract are highlighted. Mechanistically, the intermediacy of quinone methide controls the site-selectivity, and the formation of iridium hydride serves as the rate-limiting step.

Tailoring short-chain sulfur molecules to drive redox dynamics for sulfur-based aqueous battery.

Solid-solid reactions stand out in rechargeable sulfur-based batteries due to the robust redox couples and high sulfur utilization in theory. However, conventional solid-solid reactions in sulfur cathode always present slow reaction kinetics and huge redox polarization due to the low electronic conductivity of sulfur and the generation of various electrochemical inert intermediates. In view of this, it is crucial to improve the electrochemical activity of sulfur cathode and tailor the redox direction. Guided by thermodynamics analysis, short-chain sulfur molecules (S2-4) are successfully synthesized by space-limited domain principle. Unlike conventional cyclic S8 molecules with complex routes in solid-solid reaction, short-chain sulfur molecules not only shorten the length of the redox chain but also inhibit the formation of irreversible intermediates, which brings excellent redox dynamics and reversibility. As a result, the Cu-S battery built by short-chain sulfur molecules can deliver a high reversible capacity of 3,133 mAh g-1. To put this into practice, quasi-solid-state aqueous flexible battery based on short-chain sulfur molecules is also designed and evaluated, showing superior mechanical flexibility and electrochemical property. It indicates that the introduction of short-chain sulfur molecules in rechargeable battery can promote the development and application of high-performance sulfur-based aqueous energy storage systems.

Aryne and CO2-based formal [2 + 2 + 2] annulation to access tetrahydroisoquinoline-fused benzoxazinones.

Tetrahydroisoquinoline and its fused polyheterocycles are prevalent structural motifs found in numerous natural products. In this study, we report a highly efficient and convergent synthetic approach for the construction of tetrahydroisoquinoline-fused polyheterocycles through a three-component formal [2 + 2 + 2] annulation process by combining 3,4-dihydroisoquinolines, CO2, and benzynes. Notably, electron-rich 3,4-dihydroisoquinolines and electron-deficient benzynes exhibit greater reactivity in this annulation. Moreover, this method benefits from the convergent synthesis and the utilization of carbon dioxide, providing a valuable strategy for the facile synthesis of tetrahydroisoquinoline-fused polyheterocycles, with potential applications in the discovery and development of novel organic molecules.

A review of current evidence for mild behavioral impairment as an early potential novel marker of Alzheimer's disease.

Mild behavioral impairment (MBI) is a neurobehavioral syndrome that occurs in the absence of cognitive impairment later in life (≥50 years of age). MBI is widespread in the pre-dementia stage and is closely associated with the progression of cognitive impairment, reflecting the neurobehavioral axis of pre-dementia risk states and complementing the traditional neurocognitive axis. Despite being the most common type of dementia, Alzheimer's disease (AD) does not yet have an effective treatment; therefore, early recognition and intervention are crucial. The Mild Behavioral Impairment Checklist is an effective tool for identifying MBI cases and helps identify people at risk of developing dementia. However, because the concept of MBI is still quite new, the overall understanding of it is relatively insufficient, especially in AD. Therefore, this review examines the current evidence from cognitive function, neuroimaging, and neuropathology that suggests the potential use of MBI as a risk indicator in preclinical AD.