Dual Nickel/Photoredox-Catalyzed Arylsulfonylation of Allenes.

The nickel/photoredox dual catalysis system is an efficient conversion platform for the difunctionalization of unsaturated hydrocarbons. Herein, we disclose the first dual nickel/photoredox-catalyzed intramolecular 1,2-arylsulfonylation of allenes, which can accurately construct a C(sp2)-C(sp2) bond and a C(sp3)-S bond. The reaction exhibits excellent chemoselectivity and regioselectivity, allowing modular conformations of a diverse series of 3-sulfonylmethylbenzofuran derivatives. Control experiments showed that the bipyridine ligand is crucial for the formation of a stable σ-alkyl nickel intermediate, providing the possibility for sulfonyl radical insertion. Meanwhile, the electrophilic sulfonyl radical facilitates further oxidative addition of the σ-alkyl nickel intermediate and inhibits addition with allenes. In addition, control experiments, cyclic voltammetry tests, Stern-Volmer experiments, and density functional theory calculations afford evidence for the Ni(0)/Ni(I)/Ni(II)/Ni(III) pathway in this 1,2-arylsulfonylation.

Metal-catalyzed Markovnikov-type selective hydrofunctionalization of terminal alkynes.

Metal-catalyzed highly Markovnikov-type selective hydrofunctionalization of terminal alkynes provides a straightforward and atom-economical route to access 1,1-disubstituted alkenes, which have a wide range of applications in organic synthesis. However, the highly Markovnikov-type selective transformations are challenging due to the electronic and steric effects during the addition process. With the development of metal-catalyzed organic synthesis, different metal catalysts have been developed to solve this challenge, especially for platinum group metal catalysts. In this perspective, we review homogeneous metal-catalyzed Markovnikov-type selective hydrofunctionalization of terminal alkynes according to the classified element types as well as reaction mechanisms. Future avenues for investigation are also presented to help expand this exciting field.

Inhibition of GSDMD-dependent pyroptosis decreased methamphetamine self-administration in rats.

It is widely believed that the activation of the central dopamine (DA) system is crucial to the rewarding effects of methamphetamine (METH) and to the behavioral outcomes of METH use disorder. It was reported that METH exposure induced gasdermin D (GSDMD)-dependent pyroptosis in rats. The membrane pore formation caused by METH-induced pyroptosis may also contribute to the overflow of DA into the extracellular space and subsequently increase the DA levels in the brain. The present study firstly investigated whether the membrane pore information induced by GSDMD-dependent pyroptosis was associated with the increased DA levels in the ventral tegmental area (VAT) and nucleus accumbens (NAc) of rats self-administering METH and SY-SH5Y cells treated by METH. Subsequently, the effect of pore formation blockade or genetic inhibition of GSDMD on the reinforcing and motivational effect of METH was determined in rats, using the animal model of METH self-administration (SA). METH exposure significantly increased the activity of NLRP1/Cas-1/GSDMD pathway and the presence of pyroptosis, accompanied by the significantly increased DA levels in VTA and NAc. Moreover, intraperitoneal injections of disulfiram (DSF) or microinjection of rAAV-shGSDMD into VTA/NAc significantly reduced the reinforcing and motivational effect of METH, accompanied by the decreased level of DA in VTA and NAc. The results provided novel evidence that METH-induced pyroptosis could increase DA release in VTA and NAc via the NLRP1/Cas-1/GSDMD pathway. Additionally, membrane pores or GSDMD blockade could significantly reduce the reinforcing and motivational effect of METH. In conclusion, blocking GSDMD and membrane pore formation could be a promising potential target for the development of agents to treat METH use disorder.

Recent advancements in metal-catalyst-free multicomponent radical sulfonylation of alkynes.

Vinyl sulfones are crucial building blocks in synthetic chemistry and core structural units of pharmaceutically active molecules, thus extensive investigations have been conducted on the construction of these skeletons. In contrast to the classical synthetic approaches, the radical sulfonylation of alkynes for producing vinyl sulfones has garnered considerable interest because of its mild conditions and high efficiency. Radical sulfonation of alkynes typically begins with the sulfonyl radical attacking the alkynes, followed by further functionalization. Moreover, the association of metal-catalyst-free systems with multicomponent reactions (MCRs) offers an environmentally friendly pathway for efficiently constructing complex scaffolds from readily available partners. However, there is no comprehensive review summarizing the advancements in metal-catalyst-free multicomponent radical sulfonylation of alkynes. Hence, we provide a categorical overview based on the objects of sulfonylation of alkynes (hydrosulfonylation, carbosulfonylation, aminosulfonylation, oxysulfonylation, sulfosulfonylation, selenosulfonylation, and iodosulfonylation), along with interpretations of the reaction mechanisms.

Four-Component Radical 1,2-Selenosulfonylation of Allenes.

Selenosulfones, as pivotal pharmaceutical molecule frameworks, have become a research hotspot in modern organic synthesis due to their vital need for efficient preparation. Herein, we have developed an iron-catalyzed four-component controllable radical tandem reaction of allenes involving cycloketone oxime esters, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), and diphenyl diselenides for the synthesis of complex selenosulfones. This is the first case of achieving the 1,2-selenosulfonylation of allenes via a radical process, wherein precise control of radical rates and polarity matching enhance high regioselective conversion. The reaction conditions are ecofriendly and mild with step-efficiency by forming two new C-S bonds and one C-Se bond in one pot. Moreover, the 1,2-selenosulfonylation of allenes can be achieved by replacing cycloketone oxime esters with aryldiazonium tetrafluoroborates in this system.

Copper-Catalyzed Radical Relay 1,3-Carbocarbonylation across Two Distinct C═C Bonds.

The radical relay provides an effective paradigm for intermolecular assembly to achieve functionalization across remote chemical bonds. Herein, we report the first radical relay 1,3-carbocarbonylation of α-carbonyl alkyl bromides across two separate C═C bonds. The reaction is highly chemo- and regioselective, with two C(sp3)-C(sp3) bonds and one C═O bond formed in a single orchestrated operation. In addition, the synthesis method under mild conditions and using inexpensive copper as the catalyst allows facile access to structurally diverse 1,3-carbocarbonylation products. The plausible mechanism is investigated through a series of control experiments, including radical trapping, radical clock experiments, critical intermediate trapping, and 18O labeling experiment.

Docosahexaenoic and Eicosapentaenoic Acids Promote the Accumulation of Browning-Related Myokines via Calcium Signaling in Insulin-Resistant Mice.

BACKGROUND: Myokines have a prominent effect on improving insulin resistance (IR) by inducing browning of white adipose tissue (WAT). Although docosahexaenoic acids (DHA) and eicosapentaenoic acids (EPA) play roles in improving IR and stimulating browning, whether they mediate myokines directly remains unknown. OBJECTIVE: This study aims to investigate the effects of DHA and EPA on browning-related myokines under IR and clarify the mechanism via Ca2+ signaling. METHODS: The expression and secretion levels of myokines in IR mice and IR myotubes were detected after DHA/EPA treatment. The crosstalk between myotubes and adipocytes was evaluated through a method in which IR adipocytes were treated with the culture medium supernatant of myotubes treated with DHA/EPA. The expression of browning markers in the WAT of IR mice and adipocytes was determined. A calcium chelator was used to determine whether DHA and EPA regulate myokine production through a calcium ion-dependent pathway. RESULTS: In vivo experiments: 3:1 and 1:3 DHA/EPA promoted the mRNA levels of Irisin, IL-6, IL-15, and FGF21 in skeletal muscle, stimulated WAT browning, reduced lipid accumulation; 3:1 DHA/EPA upregulated the serum concentration of Irisin; 1:3 DHA/EPA upregulated the serum concentrations of Irisin, IL-6, and FGF21. In vitro experiments: the levels of Irisin and IL-6 in C2C12 myotubes and their medium supernatant were significantly elevated in the 3:1 and 1:3 groups and the upregulation of browning markers and reduction in fat accumulation were observed in adipocytes treated with the medium supernatant of C2C12 myotubes in the 3:1 and 1:3 groups. However, the above phenomena disappeared when Ca2+ signaling was inhibited. CONCLUSIONS: Treatment with DHA and EPA at composition ratios of 3:1 and 1:3 induces browning of WAT in IR mice, which is likely related to the promotion of the accumulation of myokines, especially Irisin and IL-6, via Ca2+ signaling.

Economic burden of advanced lung cancer patients treated by gefitinib alone and combined with chemotherapy in two regions of China.

AIM: To assess the economic burden of different chemotherapies for lung cancer patients and influencing factors in China. MATERIALS AND METHODS: The economic burden of lung cancer, including direct, indirect and intangible costs was measured within three months after diagnosis and treatment. Direct cost included the cost of hospitalization, outpatient visits, out-of-pocket drug purchases, costs of transportation, accommodation and meal expenses while seeking treatments in hospitals. Cost information was attained from questionnaire and patients' medical record. Indirect cost was measured by the patients' and their caregivers' productive days lost due to outpatient visits and hospitalization for lung cancer treatment. Intangible cost was obtained through the willingness-to-pay method from a questionnaire completed by the patient. RESULTS: Among the total cost of CNY71,401.92, direct cost, indirect cost and intangible cost constituted 89.02%, 4.29%, and 6.69% respectively. Educational level, occupation, family income, lung cancer classification, and the city of residence significantly influenced the total cost. LIMITATIONS: Limitations in our study included: First, our follow-up period of three months was relatively short compared to the whole survival period of lung cancer patients. Second, the sample size of the chemotherapy combined with targeted therapy group was not large enough, and the cost data obtained would need confirmation in future studies. Third, participants came from only two localities, which may somewhat limit the representativeness of the study results for the whole of China. CONCLUSIONS: The economic burden of lung cancer treatment mainly came from the cost of the drugs. Patients taking chemotherapy had significantly higher cost compared to patients using targeted therapy. The cost was generally higher for those with higher educational level, those with higher family income, and those living in an economically more developed city. Patients with NSCLC had higher cost compared to patients with SCLC.

In China, lung cancer is the leading cause of cancer-related deaths and imparts a heavy economic burden. Most lung cancer patients are treated with chemotherapeutic and/of targeted agents because they are usually diagnosed at an advanced stage (IIIB or IV). The use of targeted therapy has achieved high response rates, longer overall survival, and longer progression-free survival compared with conventional chemotherapies. Adverse reactions with targeted therapeutic agents are usually mild compared with conventional chemotherapy. However, targeted drugs for lung cancer are usually more expensive than conventional chemotherapeutic drugs. It should be noted that the adverse effects and toxicities caused by chemotherapeutic drugs are generally more serious compared to targeted drugs; therefore, a number of measures are needed to prevent or relieve these reactions clinically. This can increase the financial burden of lung cancer treatment. Does these two treatments have a different cost? Our results showed that educational level, occupation, family income, classification of lung cancer, and the city of residence significantly influenced the total cost. Patients taking chemotherapy had significantly higher cost compared to patients using targeted therapy. This result suggests that targeted therapy for lung cancer is a better choice than chemotherapy.

Photoinduced Copper-Catalyzed Aminoalkylation of Amino-Pendant Olefins.

The combination of photo and copper catalysts has emerged as a novel paradigm in organic catalysis, which provides access to the acceleration of chemical synthesis. Herein, we describe an aminoalkylation of amino-dependent olefins with maleimides through a cooperative photo/copper catalytic system. In this report, the strategy allows the generation of a broad complex of functionalized nitrogenous molecules including oxazolidinones, 2-pyrrolidones, imidazolidinones, thiazolidinones, pyridines, and piperidines in the absence of an external photosensitizer and base. The approach is achieved through a photoinduced Cu(I)/Cu(II)/Cu(III) complex species of nitrogen nucleophiles, intermolecular radical addition, and hydrogen atom transfer (HAT) processes. The plausible mechanism is investigated by a series of control experiments and theoretical tests, including radical scavenging experiments, deuterium labeling experiments, ultraviolet-visible absorption, and cyclic voltammetry (CV) tests.

Characterization of the follicular fluid microbiota based on culturomics and sequencing analysis.

Introduction. The human oocyte microenvironment is follicular fluid, which is important for follicle growth, ovulation and maturation of the oocyte. The micro-organisms present in follicular fluid could be a predictor of in vitro fertilization outcomes.Hypothesis/Gap Statement. Women with follicular fluid colonized with micro-organisms can be asymptomatic, but the presence of some genera in the follicular fluid correlates with in vitro fertilization.Aim. To confirm the existence of micro-organisms in follicular fluid, and to profile the micro-organisms present in follicular fluid sampled from women undergoing in vitro fertilization with different outcomes.Methodology. Women undergoing in vitro fertilization (n=163) were divided into different subgroups according to their in vitro fertilization outcomes. Their follicular fluid samples were collected, and among them, 157 samples were analysed by 16S rDNA sequencing, and 19 samples were analysed using culturomics.Results. The culturomics results suggested that the 19 follicular fluid samples were not sterile. The isolation rates for Streptococcus, Finegoldia and Peptoniphilus were >50 % in the 19 samples. Linear discriminant analysis effect size analysis showed differential bacteria abundance according to the pregnancy rate, the rate of normal fertilization, the rate of high-quality embryos and the rate of available oocytes. The sequencing results showed that micro-organisms could be detected in all 157 samples. Pseudomonas, Lactobacillus, Comamonas, Streptococcus and Acinetobacter were detected in all of the samples, but with a wide range of relative abundance. Pseudomonas, Lactobacillus, Ralstonia and Vibrio constituted a notable fraction of the microbiota.Conclusions. Follicular fluid is not sterile. Micro-organisms in follicular fluid could be a predictor of in vitro fertilization outcomes.

Recent advances in radical-mediated intermolecular (4 + 2) cycloaddition.

(4 + 2) Cycloaddition plays an important role in the synthesis of versatile carbocyclic/heterocyclic compounds with its high atom- and step-economy. Additionally, with mild conditions and indispensable functional group compatibility, the radical reaction has been recognized as a useful tool in organic chemistry. Given the enormous impact of radical-mediated (4 + 2) cycloaddition processes and their promising applications, we summarize and highlight the recent works in this attractive area. On the basis of the types of radicals that initiate different (4 + 2) cycloaddition processes, we classify them into processes involving alkenyl cations or alkenyl radicals, aryl radicals, acyl radicals, alkyl radicals, and heteroatom radicals, and this review places special emphasis on the reaction design and mechanisms, which will stimulate future developments in radical-mediated intermolecular (4 + 2) cycloaddition.

Applications of sulfonyl hydrazides in radical cyclization of alkenes.

Radical cyclization is regarded as a powerful and promising strategy for the assembly of diverse important cyclic structures because of its high atom- and step-economy. As excellent radical acceptors, alkenes offer two potential directions, pushing the research domain of radical cyclization. In this context, as a radical precursor, sulfonyl hydrazide plays an important role in accomplishing radical cyclization of alkenes in a facile and efficient way. This review focuses on the applications of sulfonyl hydrazides in radical cyclization of alkenes, which generally has two radical conversion modes, sulfonyl radicals and sulfoxide radicals. In particular, the section of sulfonyl radicals consists of eight parts containing aromatic rings, alkenes, alkynes, cyanides, aldehydes, carboxylic acids, amides, and small ring compounds, according to the objects of cyclization after addition with alkenes. Within each category, representative instances are presented and discussed in terms of their general mechanistic perspectives when needed.

Photoredox and Copper Dual-Catalyzed Cyclization of Alkyne-tethered α-Bromocarbonyls.

The synergistic systems of photoredox and copper catalyst have already appeared as a novel formation of green synthetic chemistry, which open new avenues for chemical synthesis applications. We describe a novel strategy for the cyclization of alkyne-tethered α-bromocarbonyls initiated by the cleavage of C(sp3 )-Br bond via the collaboration of photoredox and copper catalyst. The present protocol exhibits mildness using economical copper catalyst and visible-light at room temperature. The gram-scale and sunlight irradiation experiments proceeded smoothly to show the practicality of the methodology. It is notable that the newly generated oxygen in the product originates from H2 O.

Chemodivergent Tandem Radical Cyclization of Alkene-Substituted Quinazolinones: Rapid Access to Mono- and Di-Alkylated Ring-Fused Quinazolinones.

Chemodivergent tandem radical cyclization offers exciting possibilities for the synthesis of structurally diverse cyclic compounds. Herein, we revealed a chemodivergent tandem cyclization of alkene-substituted quinazolinones under metal- and base-free conditions, this transformation is initiated by alkyl radicals produced from oxidant-induced α-C(sp3 )-H functionalization of alkyl nitriles or esters. The reaction resulted in the selective synthesis of a series of mono- and di-alkylated ring-fused quinazolinones by modulating the loading of oxidant, reaction temperature, and reaction time. Mechanistic investigations show that the mono-alkylated ring-fused quinazolinones is constructed by the key process of 1,2-hydrogen shift, whereas the di-alkylated ring-fused quinazolinones is mainly achieved through crucial steps of resonance and proton transfer. This protocol is the first example of remote second alkylation on the aromatic ring via α-C(sp3 )-H functionalization and difunctionalization achieved by association of two unsaturated bonds in radical cyclization.

Radical bicyclization of 1,6-enynes with sulfonyl hydrazides by the use of TBAI/TBHP in the aqueous phase.

A novel 5-exo-dig/6-endo-trig bicyclization of 1,6-enynes with sulfonyl hydrazides in the aqueous phase using the cheap and available tetrabutylammonium iodide (TBAI)-tert-butyl hydroperoxide (TBHP) combined system is reported. The resulting reaction of diverse nitrogen- and oxygen-polyheterocycles displays high chemical selectivity, high step-economy, and a moderate substrate scope. Moreover, iodosulfonylation can be realized by modulating the structure of the 1,6-enynes.

MFCNet: A multi-modal fusion and calibration networks for 3D pancreas tumor segmentation on PET-CT images.

In clinical diagnosis, positron emission tomography and computed tomography (PET-CT) images containing complementary information are fused. Tumor segmentation based on multi-modal PET-CT images is an important part of clinical diagnosis and treatment. However, the existing current PET-CT tumor segmentation methods mainly focus on positron emission tomography (PET) and computed tomography (CT) feature fusion, which weakens the specificity of the modality. In addition, the information interaction between different modal images is usually completed by simple addition or concatenation operations, but this has the disadvantage of introducing irrelevant information during the multi-modal semantic feature fusion, so effective features cannot be highlighted. To overcome this problem, this paper propose a novel Multi-modal Fusion and Calibration Networks (MFCNet) for tumor segmentation based on three-dimensional PET-CT images. First, a Multi-modal Fusion Down-sampling Block (MFDB) with a residual structure is developed. The proposed MFDB can fuse complementary features of multi-modal images while retaining the unique features of different modal images. Second, a Multi-modal Mutual Calibration Block (MMCB) based on the inception structure is designed. The MMCB can guide the network to focus on a tumor region by combining different branch decoding features using the attention mechanism and extracting multi-scale pathological features using a convolution kernel of different sizes. The proposed MFCNet is verified on both the public dataset (Head and Neck cancer) and the in-house dataset (pancreas cancer). The experimental results indicate that on the public and in-house datasets, the average Dice values of the proposed multi-modal segmentation network are 74.14% and 76.20%, while the average Hausdorff distances are 6.41 and 6.84, respectively. In addition, the experimental results show that the proposed MFCNet outperforms the state-of-the-art methods on the two datasets.

Metal- and Base-Free Radical Cascade Cyclization/Hydrolysis of CN-Containing 1,6-Enynes with Ethers to Access Polyheterocycles.

A convenient and straightforward approach for the radical cascade cyclization/hydrolysis of CN-containing 1,6-enynes with simple ethers under metal- and base-free conditions is described. This strategy provides a variety of valuable ethers-substituted polyheterocycles via the construction of three C-C bonds, one C=O bond, and two new six-membered rings within a single procedure. The resulting products can smoothly undergo follow-up conversions to various useful scaffolds. The methodology shows excellent functional group tolerance, high step- and atom- economy, and mild reaction conditions, which can be further scaled up to gram quantity in a satisfactory yield.

A multidomain fusion model of radiomics and deep learning to discriminate between PDAC and AIP based on 18F-FDG PET/CT images.

PURPOSE: To explore a multidomain fusion model of radiomics and deep learning features based on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images to distinguish pancreatic ductal adenocarcinoma (PDAC) and autoimmune pancreatitis (AIP), which could effectively improve the accuracy of diseases diagnosis. MATERIALS AND METHODS: This retrospective study included 48 patients with AIP (mean age, 65 ± 12.0 years; range, 37-90 years) and 64 patients with PDAC patients (mean age, 66 ± 11.3 years; range, 32-88 years). Three different methods were discussed to identify PDAC and AIP based on 18F-FDG PET/CT images, including the radiomics model (RAD_model), the deep learning model (DL_model), and the multidomain fusion model (MF_model). We also compared the classification results of PET/CT, PET, and CT images in these three models. In addition, we explored the attributes of deep learning abstract features by analyzing the correlation between radiomics and deep learning features. Five-fold cross-validation was used to calculate receiver operating characteristic (ROC), area under the roc curve (AUC), accuracy (Acc), sensitivity (Sen), and specificity (Spe) to quantitatively evaluate the performance of different classification models. RESULTS: The experimental results showed that the multidomain fusion model had the best comprehensive performance compared with radiomics and deep learning models, and the AUC, accuracy, sensitivity, specificity were 96.4% (95% CI 95.4-97.3%), 90.1% (95% CI 88.7-91.5%), 87.5% (95% CI 84.3-90.6%), and 93.0% (95% CI 90.3-95.6%), respectively. And our study proved that the multimodal features of PET/CT were superior to using either PET or CT features alone. First-order features of radiomics provided valuable complementary information for the deep learning model. CONCLUSION: The preliminary results of this paper demonstrated that our proposed multidomain fusion model fully exploits the value of radiomics and deep learning features based on 18F-FDG PET/CT images, which provided competitive accuracy for the discrimination of PDAC and AIP.

Fe-Catalyzed Selective Formal Insertion of Diazo Compounds into C(sp)-C(sp3) Bonds of Propargyl Alcohols: Access to Alkyne-Substituted All-Carbon Quaternary Centers.

The construction of all-carbon quaternary centers, especially those containing an alkyne-substituted framework, represents an important challenge in organic synthesis. Here we present a novel Fe-catalyzed selective formal insertion of diazo compounds into C(sp)-C(sp3) bonds of propargyl alcohols under mild conditions that enables the streamlined construction of alkyne-substituted all-carbon quaternary centers. This unique strategy starts with in situ generation of an ester group in the presence of carboxylic acids, followed by insertion of metal-carbene into C(sp)-C(sp3) bonds, which may open up a new reaction mode for exploring metal-carbene insertion into acyclic C-C bonds.

The polychloromethylation/acyloxylation of 1,6-enynes with chloroalkanes and diacyl peroxides through dual-role designs.

The novel polychloromethylation/acyloxylation of 1,6-enynes with chloroalkanes and diacyl peroxides through dual-role designs has been developed to prepare 2-pyrrolidinone derivatives with polychloromethyl units with the use of an inexpensive copper salt under mild conditions. This strategy includes two dual-role designs, not only improving atomic utilization but also allowing a cleaner process. The wide substrate scope and simple reaction conditions demonstrate the practicability of this protocol.