Electrophile-Arene Affinity: An Energy Scale for Evaluating the Thermodynamics of Electrophilic Dearomatization Reactions.

Rational design and development of organic reactions are lofty goals in synthetic chemistry. Quantitative description of the properties of molecules and reactions by physical organic parameters plays an important role in this regard. In this Article, we report an energy scale, namely, electrophile-arene affinity (EAA), for evaluating the thermodynamics of electrophilic dearomatization reactions, a class of important transformations that can rapidly build up molecular complexity and structural diversity by converting planar aromatic compounds into three-dimensional cyclic molecules. The acquisition of EAA data can be readily achieved by theoretically calculating the enthalpy changes (ΔH) of the hypothetical reactions of various (cationic) electrophiles with aromatic systems (taking the 1-methylnaphthalen-2-olate ion as an example in this study). Linear correlations are found between the calculated ΔH values and established physical organic parameters such as the percentage of buried volume %VBur (steric effect), Hammett's σ or Brown's σ+ (electronic effect), and Mayr's E (reaction kinetics). Careful analysis of the ΔH values leads to the rational design of a dearomative alkynylation reaction using alkynyl hypervalent iodonium reagents as the electrophiles.

125I seed implantation for lymph node metastasis from radioactive iodine-refractory differentiated thyroid carcinoma: a study on short-term efficacy and dosimetry.

Objective: To investigate the feasibility and evaluate the safety and effectiveness of Computed Tomography (CT) guided125I radioactive particle implantation for treating lymph node metastases in radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). To verify the accuracy of the computerized three-dimensional treatment planning system (TPS) in treating lymph node metastasis using125I particle implantation at the dosimetric level. Methods: A retrospective analysis was conducted on 42 patients with RAIR-DTC and lymph node metastases who were admitted to the General Hospital of the Northern Theater Command between December 2016 and January 2019. During this analysis, physicians utilized preoperative CT images to design an intraoperative plan using TPS. The dosimetric parameters of the postoperative plan were then compared to the preoperative plan. Additionally, this study examined the changes in tumor size and tumor-related marker Thyroglobulin (Tg) values in patients at 2, 6, and 12 months after the operation. Results: The number of125I radioactive particles implanted in 42 patients was 226, with an average of 14.5 (range 2.0-30.0) particles implanted per lesion. The local remission rates were 97.62% (41/42), 88.10% (37/42), and 85.71% (36/42) at 2, 6, and 12 months postoperatively, respectively. The volume of the lesions was (4.44 ± 1.57) cm3, (4.20 ± 1.70) cm3, and (4.23 ± 1.77) cm3at 2, 6, and 12 months after treatment, respectively, which significantly decreased from the preoperative baseline level of (6.87 ± 1.67) cm3(t-values: 9.466, 9.923, 7.566, all P<0.05). The Tg levels were 15.95 (5.45, 73.93) µg/L, 8.90 (2.20, 39.21) µg/L, and 6.00 (1.93, 14.18) µg/L at 2, 6, and 12 months after treatment, respectively, which were significantly lower than the preoperative baseline levels of 53.50 (20.94, 222.92) µg/L (Z values: -5.258, -5.009, -4.987, all P < 0.001). Postoperatively, Delivered to 90% of the GTV(D90) was slightly lower than the prescribed dose in 95.23% (40/42) of patients, but the difference was not statistically significant [(12,378.8 ± 3,182.0), (12,497.8 ± 1,686.4) cGy; t=0.251, P>0.05], and postoperative dose parameters delivered to 100% of the gross tumor volume (GTV)(D100) (6,881.5 ± 1,381.8) cGy, the volume percentages of GTV receiving 150% of the prescribed dose(V150) (58.5 ± 18.40)%) were lower than the preoperative plan D100 (8,085.8 ± 2,330.0) cGy, V150 (66.5 ± 17.70)%; t-value=8.913 and 3.032, both P<0.05; the remaining indicators were not significantly different from the preoperative plan (the differences in the number of implanted particles, Planning Target Volume(PTV), the volume percentages of GTV receiving 100% of the prescribed dose(V100), Homogeneity Index(HI)were not statistically significant (t/Z = -0.593, -1.604, 1.493, -0.663, all P>0.05). Conclusion: Referring to the TPS preoperative plan, the125I particle implantation therapy for RAIR-DTC lymph node metastasis can achieve the expected dose distribution, ensuring precise short-term local tumor control efficacy.

Efficacy and Safety of Adding Ketamine to Lidocaine in Intravenous Regional Anesthesia: A Meta-analysis of Randomized Controlled Trials.

PURPOSE: To systematically evaluate the efficacy and safety of adding ketamine (K) to lidocaine (L) for intravenous regional anesthesia (IVRA). DESIGN: A systematic review and meta-analysis. METHODS: A comprehensive search of the Cochrane library, Embase, PubMed, Web of Science, and ProQuest databases, and the Google Scholar search engine was conducted from inception to March 2023. All retrieved articles were imported into Endnote X20 software and independently screened by two researchers according to predetermined inclusion and exclusion criteria. The data were analyzed using Revman 5.4 software and the assessed outcomes included the time of sensory and motor block onset, time of sensory and motor block recovery, fentanyl consumption, time of tourniquet pain onset, intraoperative and postoperative visual analog scale scores, and complications. FINDINGS: A total of 532 patients from 11 randomized controlled trials were included in the meta-analysis. The results showed that the time of sensory (P < .00001) and motor block onset (P < .00001) were shorter in the L + K group than in the L-only group. The time of sensory (P = .01) and motor block recovery (P = .006) and time of tourniquet pain onset (P < .00001) were longer in the L + K group than in the L-only group. There was a significant reduction in fentanyl consumption (P = .0002) in the L + K group compared to the L-only group. Moreover, the visual analog scale scores in the L + K group were significantly lower than the L-only group 10 minutes (P = .04), 20 minutes (P = .0004), 30 minutes (P < .00001), and 40 minutes (P < .0001) after tourniquet inflation, and 5 minutes (P < .00001), 15 minutes (P = .04), 30 minutes (P = .008), 1 hour (P = .002), 2 hours (P < .00001), and 4 hours (P < .00001) after tourniquet deflation. There was no evidence that the use of K as an adjuvant in IVRA increased adverse effects. CONCLUSIONS: The addition of K to L in IVRA shortened the onset time, prolonged the block time, and reduced intraoperative and postoperative pain without increasing complications.

Pd Nanoclusters-Sensitized MIL-125/TiO2 Nanochannel Arrays for Sensitive and Humidity-Resistant Formaldehyde Detection at Room Temperature.

Among the various hazardous substances, formaldehyde (HCHO), produced worldwide from wood furniture, dyeing auxiliaries, or as a preservative in consumer products, is harmful to human health. In this study, a sensitive room-temperature HCHO sensor, MTiNCs/Pd, has been developed by integrating Pd nanoclusters (PdNCs) into mesoporous MIL-125(Ti)-decorated TiO2 nanochannel arrays (TiNCs). Thanks to the enrichment effect of the mesoporous structure of MIL-125 and the large surface area offered by TiNCs, the resulting gas sensor accesses significantly enhanced HCHO adsorption capacity. The sufficient energetic active defects formed on PdNCs further allow an electron-extracting effect, thus effectively separating the photogenerated electrons and holes at the interface. The resulting HCHO sensor exhibits a short response/recovery time (37 s/12 s) and excellent sensitivity with a low limit of detection (4.51 ppb) under ultraviolet (UV) irradiation. More importantly, the cyclic redox reactions of Pdδ+ in PdNCs facilitated the regeneration of O2-(ads), thus ensuring a stable and excellent gas sensing performance even under a high-humidity environment. As a proof-of-principle of this design, a wearable gas sensing band is developed for the real-time and on-site detection of HCHO in cigarette smoke, with the potential as an independent device for environmental monitoring and other smart sensing systems.

Effect of supraglottic jet oxygenation and ventilation on hypoxemia in patients undergoing endoscopic surgery with sedation: A meta-analysis of randomized controlled trials.

BACKGROUND: Nasal cannulas and face masks are common oxygenation tools used in conventional oxygen therapy for patients undergoing endoscopic surgery with sedation. However, as a novel supraglottic ventilation technique, the application of supraglottic jet oxygenation and ventilation (SJOV) in endoscopic surgery has not been well established. METHOD: We searched six electronic databases from inception to January 16, 2024, to assess the oxygenation/ventilation efficacy and side effects of the of SJOV in endoscopic surgery. The primary outcome was the incidence of hypoxemia. The secondary outcomes were the incidence of respiratory depression and adverse effects (nasal bleeding, sore throat, and dry mouth). RESULTS: Nine trials involving 2017 patients were included. The results demonstrated that the incidence of hypoxemia was lower in the SJOV group compared with the conventional oxygen therapy (COT) group [9 trails; 2017 patients; risk ratio (RR) = 0.18; 95% confidence interval (CI), (0.11-0.28)]. Subgroup analyses showed that SJOV reduced the incidence of hypoxemia in the high-risk group but had no effect on the low-risk group. The incidence of respiratory depression is lower in SJOV than in COT, but has increased side effects such as dry mouth. There was no statistically significant difference in nose bleeding or sore throat between the two groups. CONCLUSION: Compared with the COT, the SJOV decreased the incidence of hypoxemia in high-risk patients during endoscopic surgery with sedation. There was an increased risk of dry mouth, but not of nose bleeding or sore throat, during endoscopic surgery under sedation.

Multi-modal fusion and feature enhancement U-Net coupling with stem cell niches proximity estimation for voxel-wise GBM recurrence prediction.

Objective.We aim to develop a Multi-modal Fusion and Feature Enhancement U-Net (MFFE U-Net) coupling with stem cell niche proximity estimation to improve voxel-wise Glioblastoma (GBM) recurrence prediction.Approach.57 patients with pre- and post-surgery magnetic resonance (MR) scans were retrospectively solicited from 4 databases. Post-surgery MR scans included two months before the clinical diagnosis of recurrence and the day of the radiologicaly confirmed recurrence. The recurrences were manually annotated on the T1ce. The high-risk recurrence region was first determined. Then, a sparse multi-modal feature fusion U-Net was developed. The 50 patients from 3 databases were divided into 70% training, 10% validation, and 20% testing. 7 patients from the 4th institution were used as external testing with transfer learning. Model performance was evaluated by recall, precision, F1-score, and Hausdorff Distance at the 95% percentile (HD95). The proposed MFFE U-Net was compared to the support vector machine (SVM) model and two state-of-the-art neural networks. An ablation study was performed.Main results.The MFFE U-Net achieved a precision of 0.79 ± 0.08, a recall of 0.85 ± 0.11, and an F1-score of 0.82 ± 0.09. Statistically significant improvement was observed when comparing MFFE U-Net with proximity estimation couple SVM (SVMPE), mU-Net, and Deeplabv3. The HD95 was 2.75 ± 0.44 mm and 3.91 ± 0.83 mm for the 10 patients used in the model construction and 7 patients used for external testing, respectively. The ablation test showed that all five MR sequences contributed to the performance of the final model, with T1ce contributing the most. Convergence analysis, time efficiency analysis, and visualization of the intermediate results further discovered the characteristics of the proposed method.Significance. We present an advanced MFFE learning framework, MFFE U-Net, for effective voxel-wise GBM recurrence prediction. MFFE U-Net performs significantly better than the state-of-the-art networks and can potentially guide early RT intervention of the disease recurrence.

Boosting the Formation of Brønsted Acids on Flame-made WOx/ZrO2 for Glucose Conversion.

WOx/ZrO2 with a higher concentration of Brønsted acid sites (BAS) and a bigger ratio of Brønsted to Lewis acid sites (B/L) than achievable by conventional impregnation (IM) were synthesized using flame spray pyrolysis (FSP). The rapid quenching and short residence time inherent to FSP prevent the accumulation of W atoms on the ZrO2 support and thus provide an excellent surface dispersion of WOx species. As a result, FSP-made WOx/ZrO2 (FSP-WOx/ZrO2) has a much higher surface concentration of three-dimensional Zr-WOx clusters than corresponding materials prepared by conventional impregnation (IM-WOx/ZrO2). The coordination of W-OH to the unsaturated Zr4+ sites in these clusters results in a remarkable decrease of the concentration of Lewis acid sites (LAS) on the surface of ZrO2 and promotes the formation of bridging W-O(H)-Zr hydroxyl groups acting as BAS. FSP-WOx/ZrO2 possesses ~80% of BAS and a B/L ratio of around 4, while IM-WOx/ZrO2 exhibits ~50% BAS and a B/L ratio of around 1. These catalysts were evaluated in the dehydration of glucose to HMF. The catalytic study demonstrated that B/L ratio plays a crucial role in glucose conversion. The best catalyst, FSP-WOx/ZrO2 with a W/Zr ratio of 1/10 affords nearly 100% glucose conversion and an HMF selectivity of 56-69%.

High efficiency and stability of perovskite solar cells prepared by alkali metal interfacial modification.

Perovskite solar cells (PSCs) have attracted much attention at home and abroad due to their excellent photoelectric properties. Defects in the electron transport layer (ETL) and ETL/perovskite interface greatly affect the power conversion efficiency (PCE) and stability of PSCs. In the paper, the surface of tin dioxide (SnO2) ETL was modified by an alkali metal salt (NaBr, KBr, and RbBr) solution to optimize electron transport and passivate SnO2/perovskite. The results show that the photovoltaic performance of the PSCs is significantly improved after interfacial modification, especially the KBr-modified PSC has the highest PCE, which is 7.8% higher than that of the unmodified device, and the open-circuit voltage, short-circuit current density and fill factor are all greatly improved. This improvement is attributed to the fact that interfacial modification reduces the trap density of the SnO2 films, increases the mobility of the SnO2 films film, effectively passivates defects, and significantly inhibits the recombination at the SnO2/perovskite interface. This method aims to use simple and low-cost inorganic materials for effective interface modification.

Navel orange peel essential oil inhibits the growth and progression of triple negative breast cancer.

BACKGROUND: Triple Negative Breast Cancer (TNBC) is a particular type of breast cancer with the highest mortality rate. Essential oils are concerned more and more as potential anti-cancer drugs. METHODS: TNBC cells were treated with different concentrations of navel orange peel essential oil (NOPEO), and then a variety of  experiments were performed to investigate the changes in the growth and progression of TNBC cells. MTT assay was performed to detect the proliferation of TNBC cells. The changes of cell cycle and apoptosis were analyzed by FACS. In order to explored the migration of TNBC cells, scratch wound assay was carried out. Western blotting and qPCR were used to examine the expression of proteins and mRNA of related genes. Furthermore, RNA-seq was used to analyze the altered genes and explored the possible signal pathway. RESULTS: NOPEO demonstrated dose- and time-dependent suppression of TNBC cell growth. TNBC cells showed an increased percentage of G2/M-phase cells and the protein levels of CyclinB1 and CyclinD1 were decreased after NOPEO treatment. The apoptotic cells were increased in the NOPEO treated TNBC cells. The migration mobility was significantly inhibited by NOPEO. In total, 1376 genes were found to be up-regulated and 1335 genes were down-regulated after NOPEO treatment. According to KEGG and GO pathways, the differentially expressed genes were related to MAPK, Jak/stat and FoxQ signaling pathways. CONCLUSION: This investigation explored the bio-activity and molecular mechanisms of NOPEO against TNBC cells. These results indicated that NOPEO could suppress TNBC growth and migration perhaps via the MAPK and Jak/stat signaling pathways, which may provide theoretical reference for anticancer drug development. NOPEO may be a potential natural product for the chemotherapeutic of TNBC.

Efficient production of guanosine in Escherichia coli by combinatorial metabolic engineering.

BACKGROUND: Guanosine is a purine nucleoside that is widely used as a raw material for food additives and pharmaceutical products. Microbial fermentation is the main production method of guanosine. However, the guanosine-producing strains possess multiple metabolic pathway interactions and complex regulatory mechanisms. The lack of strains with efficiently producing-guanosine greatly limited industrial application. RESULTS: We attempted to efficiently produce guanosine in Escherichia coli using systematic metabolic engineering. First, we overexpressed the purine synthesis pathway from Bacillus subtilis and the prs gene, and deleted three genes involved in guanosine catabolism to increase guanosine accumulation. Subsequently, we attenuated purA expression and eliminated feedback and transcription dual inhibition. Then, we modified the metabolic flux of the glycolysis and Entner-Doudoroff (ED) pathways and performed redox cofactors rebalancing. Finally, transporter engineering and enhancing the guanosine synthesis pathway further increased the guanosine titre to 134.9 mg/L. After 72 h of the fed-batch fermentation in shake-flask, the guanosine titre achieved 289.8 mg/L. CONCLUSIONS: Our results reveal that the guanosine synthesis pathway was successfully optimized by combinatorial metabolic engineering, which could be applicable to the efficient synthesis of other nucleoside products.

Conversion obstacle from Mg-protoporphyrin IX to protochlorophyllide might be responsible for chlorophyll-deficient phenotype of the Huangjinya's albino offspring.

The albino tea cultivar is one of the most important germplasms for key gene mining and high-quality tea producing. In order to elucidate the chlorophyll-deficient mechanism of albino cultivar 'Huangjinya' and its offspring, color difference, photosynthetic pigments and the relevant genes' expression of the tender shoots were comprehensively investigated in this study. Among the tested 16 offspring, 5 exhibited albino phenotype in spring and autumn, 3 showed albino phenotype in spring but normal green in autumn, while the rests were all normal green. The shoot of albino offspring had significantly higher lightness and/or yellowness than that of green ones, and possessed dramatically lower photosynthetic pigments and chlorophyll precursor protochlorophyllide (Pchlide), as well as higher chlorophyll a/chlorophyll b but lower chlorophylls/carotenoids in comparison with green ones. Among the tested genes involved in chlorophyll and carotenoid metabolism pathways, expression of the magnesium protoporphyrin IX monomethyl ester cyclase (CRD), 3,8-divinyl chlorophyllide 8-vinyl reductase (DVR), 5-aminolevulinate dehydratase 1 (HEMB1), 1-deoxy-D-xylulose 5-phosphate synthase 1 (DXS1) and 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (ISPH) was remarkably down-regulated in shoots of the albino offspring. Color difference indices of the offspring were significantly correlated with the levels of photosynthetic pigments and Pchlide, and low level of chlorophylls in shoot of albino offspring was mainly due to conversion obstacle from magnesium protoporphyrin Ⅸ (Mg-Proto IX) to Pchlide which might be attributed to down-regulatory expression of CRD and DVR.

Plasmodium vivax serological exposure markers: PvMSP1-42-induced humoral and memory B-cell response generates long-lived antibodies.

Plasmodium vivax serological exposure markers (SEMs) have emerged as promising tools for the actionable surveillance and implementation of targeted interventions to accelerate malaria elimination. To determine the dynamic profiles of SEMs in current and past P. vivax infections, we screened and selected 11 P. vivax proteins from 210 putative proteins using protein arrays, with a set of serum samples obtained from patients with acute P. vivax and documented past P. vivax infections. Then we used a murine protein immune model to initially investigate the humoral and memory B cell response involved in the generation of long-lived antibodies. We show that of the 11 proteins, especially C-terminal 42-kDa region of P. vivax merozoite surface protein 1 (PvMSP1-42) induced longer-lasting long-lived antibodies, as these antibodies were detected in individuals infected with P. vivax in the 1960-1970s who were not re-infected until 2012. In addition, we provide a potential mechanism for the maintenance of long-lived antibodies after the induction of PvMSP1-42. The results indicate that PvMSP1-42 induces more CD73+CD80+ memory B cells (MBCs) compared to P. vivax GPI-anchored micronemal antigen (PvGAMA), allowing IgG anti-PvMSP1-42 antibodies to be maintained for a long time.

Endometrial microbial dysbiosis and metabolic alteration promote the development of endometrial cancer.

OBJECTIVE: Emerging evidence suggests that the endometrial microbiome plays important roles in the development of endometrial cancer (EC). Here, we evaluate stage-specific roles of microbial dysbiosis and metabolic disorders in patients with EC, patients with endometrial hyperplasia (EH), and patients afflicted with benign uterine conditions (CK). METHODS: This prospective cohort study included 33 women with EC, 15 women with endometrial EH, and 15 women with benign uterine conditions (CK) from November 2022 to September 2023. Different typical endometrial samples were imaged with a scanning electron microscope and a transmission electron microscope. The endometrial microbiome was assessed by sequencing the V3-V4 region of the 16S rRNA gene and the ITS1 to fill the gap in relation to the study of the uterine fungal microbiome. Moreover, liquid chromatography-mass spectrometry-based metabolomics was used to identify and quantify metabolic changes among these groups. RESULTS: The endometrial microbiome revealed that there is a structural microbiome shift and an increase in the α-diversity in the EC and EH cases, distinguishable from the benign cases, especially the fungal community structure. The fungal microbiome from patients with EC and EH was altered relative to controls and dominated by Penicillium sp. By contrast, Sarocladium was more abundant in controls. Significant differences were observed in the composition and content of compounds between benign cases and EC, especially estradiol-like metabolism-related substances. Altered microbiota was correlated with the concentrations of interleukin-6 (IL-6), IL-11, transforming growth factor-beta, and ß-glucuronidase activity especially the relative abundance increase of Penicillium sp. CONCLUSIONS: This study suggested that the endometrial microbiome is complicit in modulating the development of EC such as estrogen activity and a pro-inflammatory response. Our work provides a new insight into the endometrial microbiome from a perspective of stages, which opens up new avenues for EC prognosis and therapy.

Human amnion mesenchymal stem cells promote endometrial repair via paracrine, preferentially than transdifferentiation.

BACKGROUND: Intrauterine adhesion (IUA) is one of the most severe causes of infertility in women of childbearing age with injured endometrium secondary to uterine performance. Stem cell therapy is effective in treating damaged endometrium. The current reports mainly focus on the therapeutic effects of stem cells through paracrine or transdifferentiation, respectively. This study investigates whether paracrine or transdifferentiation occurs preferentially in treating IUA. METHODS: Human amniotic mesenchymal stem cells (hAMSCs) and transformed human endometrial stromal cells (THESCs) induced by transforming growth factor beta (TGF-ß1) were co-cultured in vitro. The mRNA and protein expression levels of Fibronectin (FN), Collagen I, Cytokeratin19 (CK19), E-cadherin (E-cad) and Vimentin were detected by Quantitative real-time polymerase chain reaction (qPCR), Western blotting (WB) and Immunohistochemical staining (IHC). The Sprague-Dawley (SD) rats were used to establish the IUA model. hAMSCs, hAMSCs-conditional medium (hAMSCs-CM), and GFP-labeled hAMSCs were injected into intrauterine, respectively. The fibrotic area of the endometrium was evaluated by Masson staining. The number of endometrium glands was detected by hematoxylin and eosin (H&E). GFP-labeled hAMSCs were traced by immunofluorescence (IF). hAMSCs, combined with PPCNg (hAMSCs/PPCNg), were injected into the vagina, which was compared with intrauterine injection. RESULTS: qPCR and WB revealed that FN and Collagen I levels in IUA-THESCs decreased significantly after co-culturing with hAMSCs. Moreover, CK19, E-cad, and Vimentin expressions in hAMSCs showed no significant difference after co-culture for 2 days. 6 days after co-culture, CK19, E-cad and Vimentin expressions in hAMSCs were significantly changed. Histological assays showed increased endometrial glands and a remarkable decrease in the fibrotic area in the hAMSCs and hAMSCs-CM groups. However, these changes were not statistically different between the two groups. In vivo, fluorescence imaging revealed that GFP-hAMSCs were localized in the endometrial stroma and gradually underwent apoptosis. The effect of hAMSCs by vaginal injection was comparable to that by intrauterine injection assessed by H&E staining, MASSON staining and IHC. CONCLUSIONS: Our data demonstrated that hAMSCs promoted endometrial repair via paracrine, preferentially than transdifferentiation.

IUA is the crucial cause of infertility in women of childbearing age, and no satisfactory treatment measures have been found in the clinic. hAMSCs can effectively treat intrauterine adhesions through paracrine and transdifferentiation mechanisms. This study confirmed in vitro and in vivo that amniotic mesenchymal stem cells preferentially inhibited endometrial fibrosis and promoted epithelial repair through paracrine, thus effectively treating intrauterine adhesions. The level of fibrosis marker proteins in IUA-THESCs decreased significantly after co-culturing with hAMSCs for 2 days in vitro. However, the level of epithelial marker proteins in hAMSCs increased significantly, requiring at least 6 days of co-culture. hAMSCs-CM had the same efficacy as hAMSCs in inhibiting fibrosis and promoting endometrial repair in IUA rats, supporting the idea that hAMSCs promoted endometrial remodeling through paracrine in vivo. In addition, GFP-labeled hAMSCs continuously colonized the endometrial stroma instead of the epithelium and gradually underwent apoptosis. These findings prove that hAMSCs ameliorate endometrial fibrosis of IUA via paracrine, preferentially than transdifferentiation, providing the latest insights into the precision treatment of IUA with hAMSCs and a theoretical basis for promoting the "cell-free therapy" of MSCs.

Effect of tocilizumab plus corticosteroid on clinical outcome in patients hospitalized with severe fever with thrombocytopenia syndrome: A randomized clinical trial.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with high fatality rates. The blockade of pro-inflammatory cytokines presents a promising therapeutic strategy. METHODS: We conducted a randomized clinical trial at the 154th hospital, Xinyang, Henan Province. Eligible patients with severe SFTS disease were randomly assigned in a 1:2 ratio to receive either a single intravenous infusion of tocilizumab plus usual care; or usual care only. The primary outcome was the clinical status of death/survival at day 14, while secondary outcomes included improvement from baseline in liver and kidney damage and time required for hospital discharge. The efficacy of tocilizumab plus corticosteroid was compared to those receiving corticosteroid alone. The trial is registered with the Chinese Clinical Trial Registry website (ChiCTR2300076317). RESULTS: 63 eligible patients were assigned to the tocilizumab group and 126 to the control group. The addition of tocilizumab to usual care was associated with a reduced death rate (9.5%) compared to those received only usual care (23.0%), with an adjusted hazard ratio (aHR) of 0.37 (95% confidence interval [CI], 0.15 to 0.91, P = 0.029). Combination therapy of tocilizumab and corticosteroids was associated with a significantly reduced fatality (aHR, 0.21; 95% CI, 0.08 to 0.56; P = 0.002) compared to those receiving corticosteroids alone. CONCLUSIONS: A significant benefit of reducing fatality in severe SFTS patients was observed by using tocilizumab. A combined therapy of tocilizumab plus corticosteroids was recommended for the therapy of severe SFTS.

Associations of street-view greenspace with Parkinson's disease hospitalizations in an open cohort of elderly US Medicare beneficiaries.

INTRODUCTION: Protective associations of greenspace with Parkinson's disease (PD) have been observed in some studies. Visual exposure to greenspace seems to be important for some of the proposed pathways underlying these associations. However, most studies use overhead-view measures (e.g., satellite imagery, land-classification data) that do not capture street-view greenspace and cannot distinguish between specific greenspace types. We aimed to evaluate associations of street-view greenspace measures with hospitalizations with a PD diagnosis code (PD-involved hospitalization). METHODS: We created an open cohort of about 45.6 million Medicare fee-for-service beneficiaries aged 65 + years living in core based statistical areas (i.e. non-rural areas) in the contiguous US (2007-2016). We obtained 350 million Google Street View images across the US and applied deep learning algorithms to identify percentages of specific greenspace features in each image, including trees, grass, and other green features (i.e., plants, flowers, fields). We assessed yearly average street-view greenspace features for each ZIP code. A Cox-equivalent re-parameterized Poisson model adjusted for potential confounders (i.e. age, race/ethnicity, socioeconomic status) was used to evaluate associations with first PD-involved hospitalization. RESULTS: There were 506,899 first PD-involved hospitalizations over 254,917,192 person-years of follow-up. We found a hazard ratio (95% confidence interval) of 0.96 (0.95, 0.96) per interquartile range (IQR) increase for trees and a HR of 0.97 (0.96, 0.97) per IQR increase for other green features. In contrast, we found a HR of 1.06 (1.04, 1.07) per IQR increase for grass. Associations of trees were generally stronger for low-income (i.e. Medicaid eligible) individuals, Black individuals, and in areas with a lower median household income and a higher population density. CONCLUSION: Increasing exposure to trees and other green features may reduce PD-involved hospitalizations, while increasing exposure to grass may increase hospitalizations. The protective associations may be stronger for marginalized individuals and individuals living in densely populated areas.

Caffeic acid phenethyl ester restores mitochondrial homeostasis against peritoneal fibrosis induced by peritoneal dialysis through the AMPK/SIRT1 pathway.

Increasing evidence suggests that peritoneal fibrosis induced by peritoneal dialysis (PD) is linked to oxidative stress. However, there are currently no effective interventions for peritoneal fibrosis. In the present study, we explored whether adding caffeic acid phenethyl ester (CAPE) to peritoneal dialysis fluid (PDF) improved peritoneal fibrosis caused by PD and explored the molecular mechanism. We established a peritoneal fibrosis model in Sprague-Dawley rats through intraperitoneal injection of PDF and lipopolysaccharide (LPS). Rats in the PD group showed increased peritoneal thickness, submesothelial collagen deposition, and the expression of TGFß1 and α-SMA. Adding CAPE to PDF significantly inhibited PD-induced submesothelial thickening, reduced TGFß1 and α-SMA expression, alleviated peritoneal fibrosis, and improved the peritoneal ultrafiltration function. In vitro, peritoneal mesothelial cells (PMCs) treated with PDF showed inhibition of the AMPK/SIRT1 pathway, mitochondrial membrane potential depolarization, overproduction of mitochondrial reactive oxygen species (ROS), decreased ATP synthesis, and induction of mesothelial-mesenchymal transition (MMT). CAPE activated the AMPK/SIRT1 pathway, thereby inhibiting mitochondrial membrane potential depolarization, reducing mitochondrial ROS generation, and maintaining ATP synthesis. However, the beneficial effects of CAPE were counteracted by an AMPK inhibitor and siSIRT1. Our results suggest that CAPE maintains mitochondrial homeostasis by upregulating the AMPK/SIRT1 pathway, which alleviates oxidative stress and MMT, thereby mitigating the damage to the peritoneal structure and function caused by PD. These findings suggest that adding CAPE to PDF may prevent and treat peritoneal fibrosis.

Tumor-derived extracellular vesicles as a biomarker for breast cancer diagnosis and metastasis monitoring.

It is imperative to explore biomarkers that are both precise and readily accessible in the comprehensive management of breast cancer. A multicenter cohort, including 512 breast cancer patients and 198 nonneoplastic individuals, was recruited to detect the level of tumor-derived extracellular vesicles using our method based on dual DNA tetrahedral nanostructures. The level of tumor-derived extracellular vesicles was significantly higher in newly diagnosed breast cancer patients than in nonneoplastic individuals at a cutoff value of 3.58 U/µL. For postoperative metastasis monitoring, the level of tumor-derived extracellular vesicles was significantly higher in breast cancer patients with metastasis than in those without metastasis at a cutoff value of 3.91 U/µL. Its efficacy of diagnosis and metastasis monitoring was superior to traditional tumor markers. Elevated level of tumor-derived extracellular vesicles served as a predictive biomarker for diagnosis and metastasis monitoring in breast cancer patients.

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.

BACKGROUND: Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) and related emotional responses. CGRP antibodies and receptor antagonists have been approved for CM treatment. However, the underlying CGRP-related signaling pathways in the pain-related cortex remain poorly understood. METHODS: The SD rats were used to establish the CM model by dural infusions of inflammatory soup. Periorbital mechanical thresholds were assessed using von-Frey filaments, and anxiety-like behaviors were observed via open field and elevated plus maze tests. Expression of c-Fos, CGRP and NMDA GluN2B receptors was detected using immunofluorescence and western blotting analyses. The excitatory synaptic transmission was detected by whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, was applied via insula stereotaxic and intraperitoneal injections in CM rats. RESULTS: The insular cortex (IC) was activated in the migraine model rats. Glutamate-mediated excitatory transmission and NMDA GluN2B receptors in the IC were potentiated. CGRP levels in the IC significantly increased during nociceptive and anxiety-like activities. Locally applied hNB001 in the IC or intraperitoneally alleviated periorbital mechanical thresholds and anxiety behaviors in migraine rats. Furthermore, CGRP expression in the IC decreased after the hNB001 application. CONCLUSIONS: Our study indicated that AC1-dependent IC plasticity contributes to migraine and AC1 may be a promising target for treating migraine in the future.