A switch strategy for the synthesis of C4-ethylamine indole and C7-aminoindoline via controllable carbon elimination.

Controllable ß-carbon elimination to extrude norbornene remains a long-standing challenge in palladium and norbornene chemistry. Herein, this manuscript describes a switchable synthesis of biologically active C4-ethylaminoindole and C7-aminoindoline scaffolds by controlling ß-carbon elimination, utilizing aziridine as a C-H ethylamination reagent through a C-N bond cleavage reaction. Furthermore, the protecting groups of the product can be easily removed, offering an unusual method for the synthesis of dopamine receptor agonists.

Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction.

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required for skeletal indole editing. In contrast, we herein show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) and proved robust on scale, while tolerating a variety of valuable functional groups.

Direct Synthesis of C4-Acyl Indoles via C-H Acylation.

The direct synthesis of C4-acyl indoles deprived of C2 and C3 substituents has proven to be challenging, with scarce efficient synthetic routes being reported. Herein, we disclose a highly site-selective palladium-catalyzed C-H acylation for the construction of C4-acyl indoles via a Catellani-Lautens cyclization strategy. In addition, we systematically studied the ortho C-H acylation mechanism of iodoaniline through density functional theory (DFT) calculations and combined experimental results to elucidate the principle of high chemoselectivity brought by triazine benzoate as an acylation reagent.

Optimization of Using Multiple Machine Learning Approaches in Atrial Fibrillation Detection Based on a Large-Scale Data Set of 12-Lead Electrocardiograms: Cross-Sectional Study.

BACKGROUND: Atrial fibrillation (AF) represents a hazardous cardiac arrhythmia that significantly elevates the risk of stroke and heart failure. Despite its severity, its diagnosis largely relies on the proficiency of health care professionals. At present, the real-time identification of paroxysmal AF is hindered by the lack of automated techniques. Consequently, a highly effective machine learning algorithm specifically designed for AF detection could offer substantial clinical benefits. We hypothesized that machine learning algorithms have the potential to identify and extract features of AF with a high degree of accuracy, given the intricate and distinctive patterns present in electrocardiogram (ECG) recordings of AF. OBJECTIVE: This study aims to develop a clinically valuable machine learning algorithm that can accurately detect AF and compare different leads' performances of AF detection. METHODS: We used 12-lead ECG recordings sourced from the 2020 PhysioNet Challenge data sets. The Welch method was used to extract power spectral features of the 12-lead ECGs within a frequency range of 0.083 to 24.92 Hz. Subsequently, various machine learning techniques were evaluated and optimized to classify sinus rhythm (SR) and AF based on these power spectral features. Furthermore, we compared the effects of different frequency subbands and different lead selections on machine learning performances. RESULTS: The light gradient boosting machine (LightGBM) was found to be the most effective in classifying AF and SR, achieving an average F1-score of 0.988 across all ECG leads. Among the frequency subbands, the 0.083 to 4.92 Hz range yielded the highest F1-score of 0.985. In interlead comparisons, aVR had the highest performance (F1=0.993), with minimal differences observed between leads. CONCLUSIONS: In conclusion, this study successfully used machine learning methodologies, particularly the LightGBM model, to differentiate SR and AF based on power spectral features derived from 12-lead ECGs. The performance marked by an average F1-score of 0.988 and minimal interlead variation underscores the potential of machine learning algorithms to bolster real-time AF detection. This advancement could significantly improve patient care in intensive care units as well as facilitate remote monitoring through wearable devices, ultimately enhancing clinical outcomes.

Home-Based Intelligent Exercise System for Seniors' Healthcare: The Example of Golf Croquet.

In 2020, the world experienced the threat of the COVID-19 epidemic, and seniors and chronic disease patients generally reduced their exercise and social activities to avoid increasing the risk of infection, which could lead to increased loneliness and even many diseases. Combining golf croquet games with a mobile application (App) and AIoT companion robots, this research constructs a home-based intelligent exercise system, uses the technology acceptance model (TAM), deduces users' intention to use this system based on perceived usefulness and perceived ease of use, and adds the needs of love and belonging, esteem, cognitive, aesthetic, and self-actualization in Maslow's hierarchy of needs theory (HNT) to conduct an analysis of system needs. This study collected empirical data, totaling 320 participants including seniors and their caregivers, from elderly care centers in northern Taiwan using a cross-sectional survey and purposive sampling. Based on regression and variance analysis, the results show that participants have a high level of acceptance of this system, believing that it is easy to learn and operate and can increase interaction with others, improve self-confirmation, satisfy the thirst for knowledge, increase the feeling of happiness, and fulfill self-actualization needs. In the future, by collecting and recording the process of seniors using the App, so as to find out their health problems as soon as possible, expand their daily life through this exercise, and achieve the goal of happy living and better healthcare.

Template Synthesis to Solve the Unreachable Ortho C-H Functionalization Reaction of Aryl Iodide.

This report describes the use of a simple Pd/NBE catalytic system to achieve ortho C-H oxylation and phosphonylation and other functionalizations of aryl iodide through templated conversion reactions. Dimethylamine is introduced in the ortho-site of aryl iodide through C-H amination, and aryl dimethylamine is quickly converted to methyl quaternary ammonium salt precipitation. Methyl quaternary ammonium salt avoids Hofmann elimination in subsequent functionalization. This method solves various ortho functionalization reactions of aryl iodide that have not been achieved for a long time in the field of Pd/NBE chemistry indirectly.

Corneal optical density: Structural basis, measurements, influencing factors, and roles in refractive surgery.

The cornea is the main refractive medium of the human eye, and its clarity is critical to visual acuity. Corneal optical density (COD) is an important index to describe corneal transparency. Intact corneal epithelial and endothelial cells, regular arrangement of collagen fibers in the stroma, and normal substance metabolism are all integral for the cornea to maintain its transparency. In the last two decades, the Pentacam Scheimpflug imaging system has emerged as a breakthrough for the measurement of COD (also called corneal densitometry). It has been found that a wide variety of factors such as age, refractive status, and corneal diseases can affect COD. Different corneal refractive surgery methods also change COD in different corneal regions and layers and affect visual acuity following the surgery. Thus, COD has gradually become a significant indicator to evaluate corneal health, one on which the attention of clinicians has been increasingly focused.

Synthesis of C-Aryl Glycosides by C-H Functionalization.

In recent years, the synthesis of C-aryl glycosides hrough C-H functionalization has attracted extensive attention of organic synthesis chemists due to its steps and atomic economy. In this concept, we systematically summarizes the synthesis of C-aryl glycosides with diverse regioselectivity and diastereoselectivity from the perspective of C-H arylation of glycosides and C-H glycosylation of arenes. It can be found that a series of recently developed C-H glycosylation reactions have higher site-selectivity and diastereomeric selectivity than Friedel-Crafts glycosylation reaction. The reaction conditions are milder, which can be compatible with acid-sensitive protective groups, such as acetals or ketals, and the deprotection is more convenient. It can be seen that there are few reports on remote C-H glycosylation of aromatic hydrocarbons, which is a new field and needs further research. In addition, C-H glycosylation has a lot of shortcomings, which need to be further explored: a) the precise regulation of stereoselectivity in the reaction process also needs further optimization; b) the research on the reaction mechanism is almost limited to DFT calculation, and there is no exact experimental evidence. For key parts, such as the specific reaction mechanism between cyclo-metal intermediates and glycosyl donors in ortho-CAr -H glycosylation is still unclear; c) due to the fact that aryl glycoside compounds contain bare hydroxyl groups in practical applications, it is an urgent problem to realize the compatibility of glycoside substrates containing naked hydroxyl groups or to remove the protective groups on hydroxyl groups by a mild and efficient method after the reaction; d) In this rapidly developing field, we need to study a greener, more economical and more practical C-H glycosylation of arenes in the future, which will be conducive to the synthesis of C-aryl glycosides with more biological application significance.

Computed tomography texture analysis combined with preoperative clinical factors serve as a predictor of early efficacy of transcatheter arterial chemoembolization in hepatocellular carcinoma.

AIM: To investigate a pre-therapeutic radiomics nomogram to accurately predict hepatocellular carcinoma (HCC) lesion responses to transcatheter arterial chemoembolization (TACE). METHODS: This retrospective study from January 2012 to 2022 included 92 TACE-treated patients who underwent liver contrast-enhanced CT scan 7 days before treatment, having complete clinical information. We extracted quantitative texture parameters and clinical factors for the largest tumors on the baseline arterial and portal venous phase CT images. An adaptive least absolute shrinkage and selection operator (LASSO)-penalized logistic regression identified independent predictors of tumor activity after TACE. RESULTS: We fitted an adaptive LASSO regression model to narrow down the texture features and clinical risk factors of the tumor activity status. The selected texture features were used to construct radiomic scores (RadScore), which demonstrated superior performance in predicting tumor activity on both the training (area under the curve (AUC): 0.881, 95% CI: 0.799-0.963) and testing sets (AUC: 0.88, 95% CI: 0.726-1). A logistic regression-based nomogram was developed using RadScore and four selected clinical features. In the testing set, nomogram total points were significant predictors (P = 0.034), and the training set showed no departure from perfect fit (P = 0.833). Internal validation of the nomogram was obtained for the training (AUC: 0.91, 95% CI: 0.837-0.984) and testing (AUC: 0.889, 95% CI: 0.746-1) sets. CONCLUSION: We propose a nomogram to predict the early response of HCC lesions to TACE treatment with high accuracy, which may serve as an additional criterion in multidisciplinary decision-making treatment.

The hTERT-p50 homodimer inhibits PLEKHA7 expression to promote gastric cancer invasion and metastasis.

Although accumulating evidence has highlighted the molecular mechanisms by which hTERT promotes tumour cell invasion and metastasis, the molecular mechanisms of the properties enabling hTERT to contribute to invasion and metastasis have not been clearly illustrated. Here, we report that hTERT promotes gastric cancer invasion and metastasis by recruiting p50 to synergistically inhibit PLEKHA7 expression. We observed that the expression of PLEKHA7 in gastric cancer was significantly negatively associated with the TNM stage and lymphatic metastasis and that decreased PLEKHA7 expression dramatically increased invasion and metastasis in gastric cancer cells. Further mechanistic research showed that hTERT directly regulates PLEKHA7 expression by binding p50 and recruiting the hTERT/p50 complex to the PLEKHA7 promoter. Increased hTERT dramatically decreased PLEKHA7 expression and promoted invasion and metastasis in gastric cancer cells. The hTERT-mediated invasion/metastasis properties at least partially depended on PLEKHA7. Our work uncovers a novel molecular mechanism underlying invasion/metastasis in gastric cancer orchestrated by hTERT and p50.

Synthesis of C4-Aminated Carbazoles and Their Derivatives via Pd/NBE Chemistry.

Carbazole, as one of the most important organic frameworks, has been used in optoelectronic materials and biochemistry. However, the synthesis of C4-substituted carbazole has always been an unsolved problem. This report describes the one-step synthesis of C4-aminated carbazoles and their derivatives through the series reaction of C-H amination and arylation. The substrate scope is wide. C4-Amino carbazoles substituted by C2, C6, C7, and C8 methyl groups, especially carbazole derivatives of fused rings, pyridine, and dibenzofuran, can be synthesized.

Effects of Rehabilitation Training Combined with Acupuncture on Upper Limb Function of Stroke Patients Based on Kinect / 医用生物力学

Objective To investigate the effect of rehabilitation training combined with acupuncture ( RTA) on upper limb function of stroke patients by Kinect. Methods Stroke patients with upper limb dysfunction werrandomly divided into control group (rehabilitation training) and treatment group ( RTA), with 15 cases in each group. The modified Barthel Index ( MBI), Fugl Meyer assessment ( FMA), and Wolf motor function test (WMFT) were compared between two groups before and after treatment. The changes in motor time ( MT), motor unit number (MUN), index of curvature (IC), elbow flexion angle (EFA), shoulder flexion angle (SFA),and shoulder adduction angle ( SAA) during three actions, namely, placing forearm on the table, extending elbow and drinking water, were evaluated by Kinect and then compared between two groups before and after treatment. Results After 6 weeks of intervention, the scores of MBI, FMA, WMFT and elbow extension in treatment group were higher than those in control group (P<0. 05). The scores of MBI, FMA, WMFT and three actions after treatment were higher than those before treatment (P<0. 05). For three actions, the improvement of MT, MUN, IC, EFA, SFA, and SAA in treatment group were better than those in control group ( P< 0. 05). Compared with pre-treatment, for the action of forearm placement on the table and elbow extension, both treatment group and control group showed an increase in EFA (P<0. 05), and a decrease in MT, MUN, IC, SFA and SA (P<0. 05). For the action of drinking water, both treatment group and control group showed an increase in EFA and SAA (P< 0. 05), and a decrease in MT, MUN, IC and SAA ( P< 0. 05). Conclusions RTA can improve the upper limb function of stroke patients. Kinect can accurately reflect the changes in upper limb function of stroke patients, and it is suitable for clinical work.

Water reduces iron toxicity.

An 86-year-old man presented to the emergency room with vomiting and melena. The patient was hemodynamically stable and remained alert and orientated. According to his family, ingestion of a pack of disposable hand warmers, which he mistook for black sesame powder, occurred 17 h prior to admission. Before ingestion, he mixed the powder with warm water. Physical examination revealed no thermal injury of the oral mucosa with no abdominal pain or tenderness. An abdominal plain film showed multiple scattered radiopaque material with zonal distribution over the right abdomen. An intravenous 500-mg deferoxamine challenge test showed no vin rosé urine discoloration. Serial serum iron levels remained within the normal range. The patient remained clinically stable with no medical complications. He was discharged 3 days after admission. The hand warmers consisted of iron powder (50% w/w), sodium chloride, activated charcoal, and nontoxic vermiculite: a potential risk for intestinal thermal injury. In this case, the water added beforehand rapidly terminated the iron oxidation reaction. This explained the lack of thermal injury. Ferric oxide is poorly absorbed by the digestive tract and explained the absence of iron intoxication. Therefore, clinicians should clarify the method of ingestion. If a hand warmer has been premixed with water, less mucosa injury can be expected with a lower risk of iron intoxication. This report also provided evidence that abdominal plain films can be used to confirm the ingestion of iron and monitor its elimination.

Ortho C-H Hydroxyalkylation or Methylation of Aryl Iodides by Ethers and TMSI via a Catellani Strategy.

In this paper, in the presence of trimethylsilyl iodide, the direct ortho-C-H hydroxyalkylation/methylation of aryl iodines was effectively realized via palladium/norbornene cooperative catalysis when low-cost tetrahydrofuran and 1,2-dimethoxyethane were used as alkyl sources. Heck, Suzuki, and Sonogashira coupling and hydrogenation were all compatible with the reaction as termination steps. In addition, neuromuscular agents and cardiovascular agents were synthesized in one step by this method, showing their potential application value.

Visible light-promoted intermolecular cyclization/aromatization of chalcones and 2-mercaptobenzimidazoles via an EDA complex and a mechanism study.

Visible-light-promoted cyclization and aromatization of chalcones with 2-mercaptobenzimidazoles have been successfully developed to obtain diverse imidazo[2,1-b]thiazoles, and C-S and C-N bonds were constructed in one step. The reaction uses oxygen in the air as an oxidant, and the method does not need an external photocatalyst or a transition metal catalyst. The strategy features mild conditions, a simple system, readily accessible feedstocks, and a friendly environment. UV absorption spectroscopy and control experiments have shown that the reaction mechanism involves the formation of an electron-donor-acceptor (EDA) complex from thiolate anions and chalcones. In order to verify the mechanism, we studied the structure and HOMO/LUMO of the EDA complex by density functional theory (DFT) calculations. The results show that the π-π stacking between chalcones and 2-mercaptobenzimidazoles will cause a red shift of the UV absorption wavelength in the presence of Cs2CO3, and also provide a theoretical basis for the electron transfer of EDA complexes.

Ruthenium-Catalyzed Stereo- and Site-Selective ortho- and meta-C-H Glycosylation and Mechanistic Studies.

C-aryl glycosides are popular basic skeletons in biochemistry and pharmaceutical chemistry. Herein, ruthenium-catalyzed highly stereo- and site-selective ortho- and meta-CAr -H glycosylation is described. A series of C-aryl pyranosides and furanosides were synthesized by this method. The strategy showed good substrate scope, and various N-heterocyclic directing groups were compatible with the reaction system. A mechanistic study suggested that the key pathway of ortho-CAr -H glycosylation might involve oxidative addition/reduction elimination, whereas aryl meta-C-H glycosylation was mediated by σ-activation. Density functional theory calculations also showed that the high stereoselectivity of meta-CAr -H glycosylation was due to steric hindrance.

Role of clinical data and multidetector computed tomography findings in acute superior mesenteric artery embolism.

BACKGROUND: Superior mesenteric artery embolism (SMAE) has acute onset and fast progression, which seriously threatens the life of patients. Multidetector computed tomography (MDCT) is one of the most important diagnostic methods for SMAE, which plays an important role in the diagnosis and prognosis of SMAE. AIM: To evaluate the value of combined clinical data and MDCT findings in the diagnosis of acute SMAE and predict the risk factors for SMAE-related death. METHODS: Data from 53 SMAE patients who received abdominal MDCT multi-phase enhancement and superior mesenteric artery digital subtraction angiography examinations were collected. Univariate cox regression and multivariate cox model were used to analyze the correlation between death risk and clinical and computed tomography features in SMAE patients. RESULTS: Univariate Cox regression model showed that intestinal wall thinning, intestinal wall pneumatosis, blood lactate > 2.1 mmol/L and blood pH < 7.35 increased the risk of death in patients with SMAE. After adjusting for age, sex, embolic involvement length and embolic distribution region, multivariate Cox regression model I showed that blood lactate > 2.1 mmol/L (HR = 5.26, 95%CI: 1.04-26.69, P = 0.045) and intestinal wall thinning (HR = 9.40, 95%CI: 1.05-83.46, P = 0.044) were significantly increases the risk of death in patients with SMAE. CONCLUSION: For patients with SAME, increased blood lactate and intestinal wall thinning are the risk factors for death; hence, close monitoring may reduce the mortality rate. Clinical observation combined with MDCT signs can significantly improve SMAE diagnosis.

Role of lncSLCO1C1 in gastric cancer progression and resistance to oxaliplatin therapy.

BACKGROUND: Gastric carcinoma (GC) is one of the most deadly diseases due to tumour metastasis and resistance to therapy. Understanding the molecular mechanism of tumour progression and drug resistance will improve therapeutic efficacy and develop novel intervention strategies. METHODS: Differentially expressed long non-coding RNAs (lncRNAs) in clinical specimens were identified by LncRNA microarrays and validated in different clinical cohorts by quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridisation and bioinformatics analysis. Biological functions of lncRNA were investigated by using cell proliferation assays, migration assays, xenograft tumour models and bioinformatics analysis. Effects of lncSLCO1C1 on GC cell survival were assessed by comet assays and immunofluorescence assays. Underlying molecular mechanisms were further explored by using a number of technologies including RNA pull-down, mass spectrometry analysis, RNA immunoprecipitation, co-immunoprecipitation, miRNA sequencing, luciferase reporter assays and molecular modelling. RESULTS: LncSLCO1C1 was highly upregulated in GC tissue samples and associated with GC patients' poor overall survival. Overexpression of lncSLCO1C1 promoted proliferation and migration, whereas decreased lncSLCO1C1 expression produced the opposite effects. lncSLCO1C1 also mediated tumour resistance to chemotherapy with oxaliplatin by reducing DNA damage and increasing cell proliferation. Despite sequence overlapping between lncSLCO1C1 and PDE3A, alternations of PDE3A expression had no effect on the GC cell progression, indicating that lncSLCO1C1, not PDE3A, related with the progression of GC cells. Mechanistically, lncSLCO1C1 serves as a scaffold for the structure-specific recognition protein 1 (SSRP1)/H2A/H2B complex and regulates the function of SSRP1 in reducing DNA damage. Meanwhile, lncSLCO1C1 functions as a sponge to adsorb miR-204-5p and miR-211-5p that target SSRP1 mRNA, and thus increases SSRP1 expression. Patients with high expressions of both lncSLCO1C1 and SSRP1 have poor overall survival, highlighting the role of lncSLCO1C1 in GC progression. CONCLUSIONS: LncSLCO1C1 promotes GC progression by enhancing cell growth and preventing DNA damage via interacting and scaffolding the SSRP1/H2A/H2b complex and absorbing both miR-211-5p and miR-204-5p to increase SSRP1 expression.

Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer.

Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed and synthesized to access a previously unexplored chemical space. The assessment of biochemical affinity and cellular potency, along with computational, structural, and biophysical characterization, was applied to influence the design and optimization of novel STING agonists, resulting in the discovery of MK-1454 as a molecule with appropriate properties for clinical development. When administered intratumorally to immune-competent mice-bearing syngeneic tumors, MK-1454 exhibited robust tumor cytokine upregulation and effective antitumor activity. Tumor shrinkage in mouse models that are intrinsically resistant to single-agent therapy was further enhanced when treating the animals with MK-1454 in combination with a fully murinized antimouse PD-1 antibody, mDX400. These data support the development of STING agonists in combination with pembrolizumab (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 therapy.