Optimal Strategies for Autologous Fat Grafting in Breast Augmentation and Reconstruction: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Currently, cell-assisted lipotransfer (CAL) and platelet-rich plasma (PRP) -assisted lipotransfer have been used to overcome the low survival rate of conventional lipotransfer. However, there is still insufficient evidence to determine which technique is the best strategy for autologous fat grafting in breast cosmetic and reconstructive surgery. OBJECTIVE: The present study aimed to compare the efficacy of traditional fat transplantation, CAL, and PRP-assisted lipotransfer. METHODS: A systematic search was conducted in several databases including PUBMED, Web of Science, Cochrane, ClinicalTrials.gov, and EMBASE from January 21, 2024, to identify studies that met the inclusion criteria. Twelve studies were included after a rigorous selection process based on predefined criteria. Statistical analyses were conducted using R Ver. 4.0.5 with the netmeta and dmetar packages, employing a frequentist approach with a random-effects model. A network meta-analysis was performed to compare different fat graft procedures regarding fat survival rate and complication events. The review protocol was prospectively registered in PROSPERO (CRD42024501780). RESULTS: The results indicate that CAL and PRP-assisted lipotransfer are better than traditional fat grafts in terms of fat survival rate. And there is no significant difference in the incidence of postoperative complications between the CAL group, PRP group, and traditional group. CONCLUSION: Based on the results of network meta-analysis, it appears that both CAL and PRP-assisted lipotransfer have a higher fat survival rate for autologous fat grafting in breast augmentation and reconstruction. However, the transplantation strategy still needs to be analyzed based on actual conditions in clinical applications.

The association between physical activity intensity and frailty risk among older adults across different age groups and genders: Evidence from four waves of the China Health and Retirement Longitudinal Survey.

"Exercise is the best medicine" is well known, but the optimal dose of physical activity (PA) for males and females across different age groups is still unknown. This study, using data from the four waves of CHARLS, aimed to determine the optimal PA dose that reduces frailty risks among older adults across various age groups and both sexes. We created a frailty index score using 63 health-related variables and used 0.21 as the frailty cut point. Binary logistic regression was used to compare the effect of vigorous, moderate, and light intensity PA under IPAQ criteria on frailty risk. The study found that regardless of whether males or females, the optimal effect of vigorous-intensity PA in reducing the risk of frailty is consistently observed throughout the entire old age career. Moreover, the age groups at which moderate-intensity PA reduces the risk of frailty were from age 70 for males and from age 80 for females. And light-intensity PA had no effect on reducing the risk of frailty. Moderate and vigorous intensity of PA in older adults should be promoted, but guidelines and recommendations must account for optimal associations with PA dose across genders and age groups.

The causal relationship between physical activity, sedentary behavior and brain cortical structure: a Mendelian randomization study.

Physical activity and sedentary behavior, both distinct lifestyle behaviors associated with brain health, have an unclear potential relationship with brain cortical structure. This study aimed to determine the causal link between physical activity, sedentary behavior, and brain cortical structure (cortical surface area and thickness) through Mendelian randomization analysis. The inverse-variance weighted method was primarily utilized, accompanied by sensitivity analyses, to confirm the results' robustness and accuracy. Analysis revealed nominally significant findings, indicating a potential positive influence of physical activity on cortical thickness in the bankssts (ß = 0.002 mm, P = 0.043) and the fusiform (ß = 0.002 mm, P = 0.018), and a potential negative association of sedentary behavior with cortical surface area in the caudal middle frontal (ß = -34.181 mm2, P = 0.038) and the pars opercularis (ß = -33.069 mm2, P = 0.002), alongside a nominally positive correlation with the cortical surface area of the inferior parietal (ß = 58.332 mm2, P = 0.035). Additionally, a nominally significant negative correlation was observed between sedentary behavior and cortical thickness in the paracentral (ß = -0.014 mm, P = 0.042). These findings offer insights into how lifestyle behaviors may influence brain cortical structures, advancing our understanding of their interaction with brain health.

Association of depressive symptom severity and suicidal ideation with health-related quality of life among stroke survivors, NHANES 2005-2018.

Stroke, a critical health issue in the US, not only has physical repercussions but also potentially affects the health-related quality of life (HRQoL) through neuropsychiatric outcomes like depressive symptoms and suicidal thoughts. This study utilized a nationally representative sample of 1302 US stroke survivors (age ≥ 20) from the US National Health and Nutrition Examination Survey (2005-2018) to assessed relationships between QoL via the CDC HRQOL-4 and evaluated depressive symptoms and suicidal ideation using the Patient Health Questionnaire-9 (PHQ-9). Participants (mean age: 64.4; 56.0 % female) showed that 40.7 % had at least mild depressive symptoms, and 18.8 % exhibited major depressive symptoms. Suicidal ideation was reported by 8.1 %. After sociodemographic and health condition adjustments, mild and major depressive symptoms, along with suicidal ideation, were associated with poorer general health status and more physically and mentally unhealthy days and activity limitation days. A dose-response relationship between PHQ-9 scores and HRQoL outcomes was evident (All P for trend <0.001). Stroke survivors with suicidal ideation also experienced more physically and mentally unhealthy days and activity limitation days. Depressive symptoms and suicidal ideation are associated with reduced HRQoL among US stroke survivors, underscoring the importance of thorough neuropsychiatric evaluations and interventions to bolster stroke survivors' well-being.

Bioinspired engineering ADSC nanovesicles thermosensitive hydrogel enhance autophagy of dermal papilla cells for androgenetic alopecia treatment.

Androgenic alopecia (AGA) is a highly prevalent form of non-scarring alopecia but lacks effective treatments. Stem cell exosomes have similar repair effects to stem cells, suffer from the drawbacks of high cost and low yield yet. Cell-derived nanovesicles acquired through mechanical extrusion exhibit favorable biomimetic properties similar to exosomes, enabling them to efficiently encapsulate substantial quantities of therapeutic proteins. In this study, we observed that JAM-A, an adhesion protein, resulted in a significantly increased the adhesion and resilience of dermal papilla cells to form snap structures against damage caused by dihydrotestosterone and macrophages, thereby facilitating the process of hair regrowth in cases of AGA. Consequently, adipose-derived stem cells were modified to overexpress JAM-A to produce engineered JAM-A overexpressing nanovesicles (JAM-AOE@NV). The incorporation of JAM-AOE@NV into a thermosensitive hydrogel matrix (JAM-AOE@NV Gel) to effectively addresses the limitations associated with the short half-life of JAM-AOE@NV, and resulted in the achievement of a sustained-release profile for JAM-AOE@NV. The physicochemical characteristics of the JAM-AOE@NV Gel were analyzed and assessed for its efficacy in promoting hair regrowth in vivo and vitro. The JAM-AOE@NV Gel, thus, presents a novel therapeutic approach and theoretical framework for promoting the treatment of low cell adhesion diseases similar to AGA.

M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.

Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.

TransVQA: Transferable Vector Quantization Alignment for Unsupervised Domain Adaptation.

Unsupervised Domain adaptation (UDA) aims to transfer knowledge from the labeled source domain to the unlabeled target domain. Most existing domain adaptation methods are based on convolutional neural networks (CNNs) to learn cross-domain invariant features. Inspired by the success of transformer architectures and their superiority to CNNs, we propose to combine the transformer with UDA to improve their generalization properties. In this paper, we present a novel model named Trans ferable V ector Q uantization A lignment for Unsupervised Domain Adaptation (TransVQA), which integrates the Transferable transformer-based feature extractor (Trans), vector quantization domain alignment (VQA), and mutual information weighted maximization confusion matrix (MIMC) of intra-class discrimination into a unified domain adaptation framework. First, TransVQA uses the transformer to extract more accurate features in different domains for classification. Second, TransVQA, based on the vector quantization alignment module, uses a two-step alignment method to align the extracted cross-domain features and solve the domain shift problem. The two-step alignment includes global alignment via vector quantization and intra-class local alignment via pseudo-labels. Third, for intra-class feature discrimination problem caused by the fuzzy alignment of different domains, we use the MIMC module to constrain the target domain output and increase the accuracy of pseudo-labels. The experiments on several datasets of domain adaptation show that TransVQA can achieve excellent performance and outperform existing state-of-the-art methods.

Safety and efficacy of melatonin supplementation as an add-on treatment for infantile epileptic spasms syndrome: A randomized, placebo-controlled, double-blind trial.

This was a prospective, randomized, double-blind, single-center placebo-controlled trial to assess the efficacy and safety of melatonin as an add-on treatment for infantile epileptic spasms syndrome (IESS). Participants aged 3 months to 2 years with a primary diagnosis of IESS were recruited and assigned to two groups in a 1:1 ratio. Both treatment groups received a combination of adrenocorticotrophic hormone (ACTH) and magnesium sulfate (MgSO4 ) for 2 weeks, and the treatment group also received melatonin (3 mg) between 20:00 and 21:00 daily, 0.5-1 h before bedtime. The study's primary endpoint was the average reduction rate in spasm frequency assessed by seizure diaries. Secondary endpoints included assessment of the response rate, EEG hypsarrhythmia (Kramer score), and psychomotor development (Denver Developmental Screening Test, DDST). Sleep quality was assessed by using the Brief Infant Sleep Questionnaire (BISQ), the Infant Sleep Assessment Scale (ISAS), and actigraphy. Safety parameters were also evaluated. Statistical analyses were conducted on intention-to-treat and per-protocol populations. The trial is registered at Clinicaltrials.gov (ChiCTR2000036208). Out of 119 screened patients, 70 were randomized and 66 completed treatments. In the intention-to-treat population, there were no significant differences in the average percentage reduction of spasm frequency (median [interquartile range, IQR: Q3-Q1], 100% [46.7%] vs. 66.7% [55.3%], p = .288), the 3-day response rate (51.4% vs. 37.1%, p = .229), the 28-day response rate (42.9% vs. 28.6%, p = .212), EEG Kramer scores (2 [3.5] vs. 2 [3], p = .853), or DDST comprehensive months (5 [2.5] vs. 6 [6], p = .239) between the melatonin (n = 35) and placebo (n = 35) groups. However, caregivers reported improved sleep quality after melatonin treatment, with 85.7% reporting regular sleep compared to 42.9% with placebo (42.9%, p < .001). The melatonin group had lower ISAS scores in 4-11-month-old patients compared to the placebo (mean ± SD, 29.3 ± 4.4 vs. 35.2 ± 5.9, p < .001). Moreover, the median (IQR) value of sleep-onset latency was shortened by 6.0 (24.5) min after melatonin treatment, while that in the placebo group was extended by 3.0 (22.0) min (p = .030). The serum melatonin (6:00 h) level (pg/mL) of the children in the melatonin group after treatment was significantly higher than in the placebo group (median [IQR], 84.8 [142] vs. 17.5 [37.6], p < .001). No adverse effects related to melatonin were observed in the study, and there were no significant differences in adverse effects between the melatonin and placebo groups. Although not statistically significant, the results of this randomized clinical trial proved that melatonin supplementation, as an add-on treatment, can improve spasm control rate in the treatment of IESS. For IESS children treated with ACTH, the addition of melatonin was found to improve sleep quality, shorten sleep onset latency, and increase blood melatonin levels. Moreover, it was observed to be a safe treatment option.

Biosynthesis of barley wax ß-diketones: a type-III polyketide synthase condensing two fatty acyl units.

The surface coatings of cereal plants are dominated by waxy ß-diketones crucial for drought resistance and, therefore, grain yield. Here, barley (Hordeum vulgare) wax analyses reveal ß-diketone and associated 2-alkanol ester profiles suggesting a common C16 3-ketoacid precursor. Isotope analysis further shows that the major (C31) diketone is synthesized from two plastidial C16 acyl units. Previous studies identified a gene cluster encoding enzymes responsible for ß-diketone formation in barley, but left their biochemical functions unknown. Various assays now characterize one of these enzymes as a thioesterase producing long-chain (mainly C16) 3-ketoacids, and another one as a polyketide synthase (PKS) condensing the 3-ketoacids with long-chain (mainly C16) acyl-CoAs into ß-diketones. The two enzymes are localized to the plastids and Endoplasmic Reticulum (ER), respectively, implying substrate transfer between these two sub-cellular compartments. Overall, our findings define a two-step pathway involving an unprecedented PKS reaction leading directly to the ß-diketone products.

Extracellular vesicles from 3D cultured dermal papilla cells improve wound healing via Krüppel-like factor 4/vascular endothelial growth factor A -driven angiogenesis.

Background: Non-healing wounds are an intractable problem of major clinical relevance. Evidence has shown that dermal papilla cells (DPCs) may regulate the wound-healing process by secreting extracellular vesicles (EVs). However, low isolation efficiency and restricted cell viability hinder the applications of DPC-EVs in wound healing. In this study, we aimed to develop novel 3D-DPC spheroids (tdDPCs) based on self-feeder 3D culture and to evaluate the roles of tdDPC-EVs in stimulating angiogenesis and skin wound healing. Methods: To address the current limitations of DPC-EVs, we previously developed a self-feeder 3D culture method to construct tdDPCs. DPCs and tdDPCs were identified using immunofluorescence staining and flow cytometry. Subsequently, we extracted EVs from the cells and compared the effects of DPC-EVs and tdDPC-EVs on human umbilical vein endothelial cells (HUVECs) in vitro using immunofluorescence staining, a scratch-wound assay and a Transwell assay. We simultaneously established a murine model of full-thickness skin injury and evaluated the effects of DPC-EVs and tdDPC-EVs on wound-healing efficiency in vivo using laser Doppler, as well as hematoxylin and eosin, Masson, CD31 and α-SMA staining. To elucidate the underlying mechanism, we conducted RNA sequencing (RNA-seq) of tdDPC-EV- and phosphate-buffered saline-treated HUVECs. To validate the RNA-seq data, we constructed knockdown and overexpression vectors of Krüppel-like factor 4 (KLF4). Western blotting, a scratch-wound assay, a Transwell assay and a tubule-formation test were performed to detect the protein expression, cell migration and lumen-formation ability of KLF4 and vascular endothelial growth factor A (VEGFA) in HUVECs incubated with tdDPC-EVs after KLF4 knockdown or overexpression. Dual-luciferase reporter gene assays were conducted to verify the activation effect of KLF4 on VEGFA. Results: We successfully cultured tdDPCs and extracted EVs from DPCs and tdDPCs. The tdDPC-EVs significantly promoted the proliferation, lumen formation and migration of HUVECs. Unlike DPC-EVs, tdDPC-EVs exhibited significant advantages in terms of promoting angiogenesis, accelerating wound healing and enhancing wound-healing efficiency both in vitro and in vivo. Bioinformatics analysis and further functional experiments verified that the tdDPC-EV-regulated KLF4/VEGFA axis is pivotal in accelerating wound healing. Conclusions: 3D cultivation can be utilized as an innovative optimization strategy to effectively develop DPC-derived EVs for the treatment of skin wounds. tdDPC-EVs significantly enhance wound healing via KLF4/VEGFA-driven angiogenesis.

A potential immunotherapy target for breast cancer: parenchymal and immune-stromal expression of the NLRP3 inflammasome pathway.

BACKGROUND: The NOD-, LRR- and pyrin domain­containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. It has been known to play an important role in the carcinogenesis and prognosis of breast cancer patients. While the clinical evidence of the relationship between NLRP3 inflammasome activation and long-term survival is still limited, the possible roles of parenchymal or immune-stromal cells of breast cancer tissues in contributing to such carcinogenesis and progression still need to be clarified. This study is an analysis of patients receiving breast cancer surgery in a previous clinical trial. METHODS: Immunohistochemistry (IHC) was used to detect the expression levels of NLRP3 inflammasome pathway-related proteins, including NLRP3, caspase-1, apoptosis-associated speck-like protein (ASC), IL-1ß, and IL-18, in parenchymal and immune-stromal cells of breast cancer tissues compared to those of adjacent normal tissues, respectively. The relationship between NLRP3 inflammasome expression and clinicopathological characteristics, as well as 5-year survivals were analyzed using the Chi-square test, Kaplan-Meier survival curves, and Cox regression analysis. RESULTS: In the parenchymal cells, ASC and IL-18 protein levels were significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (P<0.05). In the immune-stromal cells, all the five NLRP3 inflammasome pathway-related proteins were significantly elevated in breast cancer tissues compared with adjacent normal tissues (P < 0.05). Carcinoma cell embolus was found to significantly correlate with high NLRP3 expression in parenchymal cells of the tumor (x2=4.592, P=0.032), while the expression of caspase-1 was negatively correlated with tumor progression. Histological grades were found to have a positive correlation with IL-18 expression in immune-stromal cells of the tumor (x2=14.808, P=0.001). Kaplan-Meier survival analysis revealed that high IL-18 expression in the immune-stromal cells and the positive carcinoma cell embolus were both associated with poor survival (P < 0.05). The multivariable Cox proportional hazards regression model implied that the high IL-18 expression and positive carcinoma cell embolus were both independent risk factors for unfavorable prognosis. CONCLUSIONS: The activation of NLRP3 inflammasome pathways in immune-stromal and tumor parenchymal cells in the innate immune system was not isotropic and the main functions are somewhat different in breast cancer patients. Caspase-1 in parenchymal cells of the tumor was negatively correlated with tumor progression, and upregulation of IL-18 in immune-stromal cells of breast cancer tissues is a promising prognostic biomarker and a potential immunotherapy target. TRIAL REGISTRATION: This clinical trial has been registered at the Chictr.org.cn registry system on 21/08/2018 (ChiCTR1800017910).

Synthesis of 4-Alkylated 1,4-Dihydropyridines: Fe(II)-Mediated Oxidative Cascade Cyclization Reaction of Cyclic Ethers with Enaminones.

Syntheses of highly functionalized 4-alkylated 1,4-dihydropyridines (1,4-DHPs) from cyclic ethers and enaminones via iron(II)-mediated oxidative free radical cascade C(sp3)-H bond functionalization/C(sp3)-O bond cleavage/cyclization reaction have been first developed. This novel synthetic strategy offers an alternative method for the construction of 1,4-DHPs by using esters as the C4 sources, as well as expands the application of ethers in heterocycle synthesis.

Fe-mediated oxidative cascade [1 + 2 + 3]-cyclization/esterification reaction: synthesis of 4-alkylated 1,4-dihydropyridines.

An Fe-mediated four-component reaction of enaminones, anhydrides and tetrahydrofuran through a cascade [1 + 2 + 3]-cyclization/esterification process is presented. This protocol provides a new and effective method to construct 4-alkylated 1,4-dihydropyridines with an ester fragment. Cyclic ether is employed as the C4 source of 1,4-dihydropyridines for the first time.

Tumor-derived proliferative CTCs and CTC clusters predict aggressiveness and early recurrence in hepatocellular carcinoma patients.

BACKGROUND: Circulating tumor cells (CTCs), an indispensable liquid biopsy classifier, can provide extra information for the diagnosis and prognosis of hepatocellular carcinoma (HCC). METHODS: We systematically analyzed the peripheral blood of preoperative HCC patients (n = 270) for CTC number, Ki67 index reflecting the proliferative CTC percentage (PCP), and CTC clusters correlated with the characteristics of malignant HCC tumors. RESULTS: Driver gene mutations were found with high levels of consistency between CTCs and primary tumors (n = 73). CTC number and PCP were associated with tumor size, microvascular invasion (MVI), presence or absence of multiple tumors, and thrombosis significantly. CTC number and PCP robustly separated patients with and without relapse, with a sensitivity of 88.89%/81.48% and a specificity of 72.73%/94.81% in the training set (n = 104) and corresponding values of 80.00%/86.67% and 78.38%/89.19% in the validation set (n = 52), showing a better performance than that associated with the alpha-fetoprotein (AFP) level. CTC number, PCP, CTC clusters, and MVI were independent significant risk factors for HCC recurrence (P = 0.0375, P < 0.0001, P = 0.0017, and P = 0.0157). A nomogram model based on these risk factors showed a considerable prediction ability for HCC recurrence (area under the curve = 0.947). PCP (training: log-rank P < 0.0001; hazard ratio [HR] 30.13, 95% confidence interval [CI] = 11.12-81.62; validation: log-rank P < 0.0001; HR 25.73, 95% CI = 5.28-106.60) and CTC clusters (training: log-rank P < 0.0001; HR 17.34, 95% CI = 7.46-40.30; validation: log-rank P < 0.0001; HR 9.92, 95% CI = 2.55-38.58) were more significantly correlated with worse recurrence-free survival than CTC number (training: log-rank P < 0.0001; HR 14.93, 95% CI = 4.48-49.78; validation: log-rank P = 0.0007; HR 9.03, 95% CI = 2.53-32.24). CONCLUSION: PCP and CTC clusters may predict HCC recurrence and improve the performance of the serum biomarker AFP.

Comparison of the effects of remimazolam tosylate and propofol on postoperative delirium among older adults undergoing major non-cardiac surgery: protocol for a randomised controlled trial.

INTRODUCTION: Postoperative delirium (POD) is a common cognitive disturbance in elderly individuals that is characterised by acute and fluctuating impairments in attention and awareness. Remimazolam tosylate is a novel, ultrashort-acting benzodiazepine, and there is limited evidence of its correlation with the incidence of early POD. The aim of this study is to evaluate the incidence of POD after anaesthesia induction and maintenance with remimazolam tosylate or propofol in elderly patients undergoing major non-cardiac surgery. METHODS AND ANALYSIS: This is a single-centre, randomised controlled trial. 636 elderly patients undergoing major non-cardiac surgery will be enrolled and randomised at a 1:1 ratio to receive total intravenous anaesthesia with either remimazolam tosylate or propofol. The primary outcome is the incidence of POD within 5 days after surgery. Delirium will be assessed twice daily by the 3 min Diagnostic Interview for the Confusion Assessment Method or the Confusion Assessment Method for the intensive care unit (ICU) for ICU patients. Secondary outcomes are the onset and duration of delirium, cognitive function at discharge and within 1-year postoperatively, postoperative analgesia within 5 days, chronic pain at 3 months, quality of recovery and postoperative inflammatory biomarker levels. ETHICS AND DISSEMINATION: The study was approved by the institutional ethics committee of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (approval No. 22/520-3722). Written informed consent will be obtained from each patient before enrolment. The results of this trial will be presented at scientific conferences and in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: ChiCTR2300067368.

Immunomodulatory role of estrogen in ischemic stroke: neuroinflammation and effect of sex.

Although estrogen is predominantly related to the maintenance of reproductive functioning in females, it mediates various physiological effects in nearly all tissues, especially the central nervous system. Clinical trials have revealed that estrogen, especially 17ß-estradiol, can attenuate cerebral damage caused by an ischemic stroke. One mechanism underlying this effect of 17ß-estradiol is by modulating the responses of immune cells, indicating its utility as a novel therapeutic strategy for ischemic stroke. The present review summarizes the effect of sex on ischemic stroke progression, the role of estrogen as an immunomodulator in immune reactions, and the potential clinical value of estrogen replacement therapy. The data presented here will help better understand the immunomodulatory function of estrogen and may provide a basis for its novel therapeutic use in ischemic stroke.

Aminoguanidine-Catalyzed Reductive Cyclization of o-Phenylenediamines with CO2 in the Presence of Triethoxysilane.

An inexpensive and efficient aminoguanidine-catalyzed reductive cyclization of o-phenylenediamines with CO2 in the presence of triethoxysilane is described. Various functionalized benzimidazoles, benzoxazole, and benzothiazole were synthesized in high yields. Mechanistic studies indicate that formic acid as a cocatalyst promotes the cyclization reaction.

Allantoin induces pruritus by activating MrgprD in chronic kidney disease.

Chronic kidney disease (CKD) is a disease with decreased, irreversible renal function. Pruritus is the most common skin symptom in patients with CKD, especially in end-stage renal disease. The underlying molecular and neural mechanism of CKD-associated pruritus (CKD-aP) remains obscure. Our data show that the level of allantoin increases in the serum of CKD-aP and CKD model mice. Allantoin could induce scratching behavior in mice and active DRG neurons. The calcium influx and action potential reduced significantly in DRG neurons of MrgprD KO or TRPV1 KO mice. U73122, an antagonist of phospholipase C, could also block calcium influx in DRG neurons induced by allantoin. Thus, our results concluded that allantoin plays an important role in CKD-aP, mediated by MrgprD and TrpV1, in CKD patients.

Copper-Catalyzed Oxidative [1+2+1+2] Cascade Cyclization of N,N-Dimethyl Enaminones with Benzylamines: A Facile Access to Functionalized 1,4-Dihydropyridines.

Using benzylamines as the C4 source of 1,4-dihydropyridines (1,4-DHPs), a Cu-catalyzed oxidative [1+2+1+2] cascade cyclization for the synthesis of 1,4-DHPs was firstly developed. A broad range of easily available N,N-dimethyl enaminones and benzylamines are employed smoothly to provide a diverse range of 1,4-DHPs with high efficiency. This method is performed by a one-pot cascade C(sp3 )-H bond functionalization/C(sp3 )-N cleavage/cyclization strategy to form simultaneously two C(sp3 )-C(sp2 ) bonds, two C(sp2 )-N bonds, and a 1,4-DHP ring.