Nirmatrelvir-Ritonavir Reduced Mortality in Hospitalized Patients with COVID-19 During the Omicron Outbreak: Real-World Evidence from Beijing.

Objective: The efficacy of nirmatrelvir-ritonavir for hospitalized patients with COVID-19 has not been fully established. Methods: We conducted a retrospective analysis of hospitalized COVID-19 patients with high risk for disease progression at Beijing Chaoyang Hospital from October 15, 2022, to March 31, 2023. Patients ≥18 years old who were hospitalized with COVID-19 within 5 days of symptom onset were included. Baseline data were obtained from the routine electronic health record database of the hospital information system. Outcomes were monitored at 28 days via electronic medical record reviews or telephone interviews. Results: We identified 1120 patients hospitalized with COVID-19 during the study period. After exclusions, 167 nirmatrelvir-ritonavir users and 132 controls were included. 28-day all-cause mortality rate was 12.0% (20/167) in the nirmatrelvir-ritonavir group, versus 22.7% (30/132) in the control group (unadjusted log-rank p = 0.010; HR = 0.49, 95% confidence interval [CI] = 0.28-0.86, IPTW-adjusted HR = 0.58, 95% CI = 0.40-0.86). The 28-day disease progression rates did not differ between the two groups (unadjusted HR = 0.59, 95% CI = 0.34-1.02, IPTW-adjusted HR = 0.73, 95% CI = 0.50-1.06). Nirmatrelvir-ritonavir significantly reduced all-cause mortality and disease progression within 28 days among patients aged ≥65 years without ≥2 vaccine doses. Conclusion: We found significantly reduced all-cause mortality in the nirmatrelvir-ritonavir group, particularly in elderly patients who were incompletely vaccinated. Future randomized controlled studies are needed to validate our findings.

Reliability Evaluation for Continuous-Wave Functional Near-Infrared Spectroscopy Systems: Comprehensive Testing from Bench Characterization to Human Test.

In recent years, biomedical optics technology has developed rapidly. The current widespread use of biomedical optics was made possible by the invention of optical instruments. The advantages of being non-invasive, portable, effective, low cost, and less susceptible to system noise have led to the rapid development of functional near-infrared spectroscopy (fNIRS) technology for hemodynamics detection, especially in the field of functional brain imaging. At the same time, laboratories and companies have developed various fNIRS-based systems. The safety, stability, and efficacy of fNIRS systems are key performance indicators. However, there is still a lack of comprehensive and systematic evaluation methods for fNIRS instruments. This study uses the fNIRS system developed in our laboratory as the test object. The test method established in this study includes system validation and performance testing to comprehensively assess fNIRS systems' reliability. These methods feature low cost and high practicality. Based on this study, existing or newly developed systems can be comprehensively and easily evaluated in the laboratory or workspace.

Unlocking the Potential of Oxidative Asymmetric Catalysis with Continuous Flow Electrochemistry.

In the field of catalytic asymmetric synthesis, the less-treated path lies in oxidative catalytic asymmetric transformations. The hurdles of pinpointing the appropriate chemical oxidants and addressing their compatibility issues with catalysts and functionalities present significant challenges. Organic electrochemistry, employing traceless electrons for redox reactions, is underscored as a promising solution. However, the commonly used electrolysis in batch cells introduces its own set of challenges, hindering the advancement of electrochemical asymmetric catalysis. Here we introduce a microfluidic electrochemistry platform with single-pass continuous flow reactors that exhibits a wide-ranging applicability to various oxidative asymmetric catalytic transformations. This is exemplified through the sulfenylation of 1,3-dicarbonyls, dehydrogenative C-C coupling, and dehydrogenative alkene annulation processes. The unique properties of microfluidic electrochemical reactors not only eliminate the need for chemical oxidants but also enhance reaction efficiency and reduce the use of additives and electrolytes. These salient features of microfluidic electrochemistry expedite the discovery and development of oxidative asymmetric transformations. In addition, the continuous production facilitated by parallel single-pass reactors ensures straightforward reaction upscaling, removing the necessity for reoptimization across various scales, as evidenced by direct translation from milligram screening to hectogram asymmetric synthesis.

Clinical significance of platelet mononuclear cell aggregates in patients with sepsis and acute respiratory distress syndrome.

BACKGROUND: The diagnosis of sepsis combined with acute respiratory distress syndrome (ARDS) has increased owing to the enhanced awareness among medical professionals and the continuous development of modern medical technologies, while early diagnosis of ARDS still lacks specific biomarkers. One of the main pathogenic mechanisms of sepsis-associated ARDS involves the actions of various pathological injuries and inflammatory factors, such as platelet and white blood cells activation, leading to an increase of surface adhesion molecules. These adhesion molecules further form platelet-white blood cell aggregates, including platelet-mononuclear cell aggregates (PMAs). PMAs has been identified as one of the markers of platelet activation, here we hypothesize that PMAs might play a potential biomarker for the early diagnosis of this complication. AIM: To investigate the expression of PMAs in the serum of patients with sepsis complicated by ARDS and its clinical significance. METHODS: We selected 72 hospitalized patients diagnosed with sepsis as the study population between March 2019 and March 2022. Among them, 30 patients with sepsis and ARDS formed the study group, while 42 sepsis patients without ARDS comprised the control group. After diagnosis, venous blood samples were immediately collected from all patients. Flow cytometry was employed to analyze the expression of PMAs, platelet neutrophil aggregates (PNAs), and platelet aggregates (PLyAs) in the serum. Additionally, the Acute Physiology and Chronic Health Evaluation (APACHE) II score was calculated for each patient, and receiver operating characteristic curves were generated to assess diagnostic value. RESULTS: The study found that the levels of PNAs and PLyAs in the serum of the study group were higher than those in the control group, but the difference was not statistically significant (P > 0.05). However, the expression of PMAs in the serum of the study group was significantly upregulated (P < 0.05) and positively correlated with the APACHE II score (r = 0.671, P < 0.05). When using PMAs as a diagnostic indicator, the area under the curve value was 0.957, indicating a high diagnostic value (P < 0.05). Furthermore, the optimal cutoff value was 8.418%, with a diagnostic sensitivity of 0.819 and specificity of 0.947. CONCLUSION: In summary, the serum levels of PMAs significantly increase in patients with sepsis and ARDS. Therefore, serum PMAs have the potential to become a new biomarker for clinically diagnosing sepsis complicated by ARDS.

Wallerian Degeneration Assessed by Multi-Modal Magnetic Resonance Imaging of Cervical Spinal Cord Is Associated With Neurological Impairment After Spinal Cord Injury.

While Wallerian degeneration (WD) is a crucial pathological process induced with spinal cord injury (SCI), its underlying mechanisms is still understudied. In this study, we aim to assess structural alterations and clinical significance of WD in the cervical cord following SCI using multi-modal magnetic resonance imaging (MRI), which combines T2*-weighted imaging and diffusion tensor imaging (DTI). T2*-weighted images allow segmentation of anatomical structures and the detection of WD on macrostructural level. DTI, on the other hand, can identify the reduction in neuroaxonal integrity by measuring the diffusion of water molecules on the microstructural level. In this prospective study, 35 SCI patients (19 paraplegic and 16 tetraplegic patients) and 12 healthy controls were recruited between July 2020 and May 2022. The hyperintensity voxels in the dorsal column was manually labeled as WD on T2*-weighted images. The mean cross-sectional area (CSA) and mean DTI indexes of WD at the C2 level were calculated and compared between groups. Correlation analysis was used to determine the associations of the magnitude of WD with lesion characteristics and clinical outcomes. Compared with controls, SCI patients showed evident hyperintensity (35/35) and decreased neuroaxonal integrity (p < 0.05) within the dorsal column at the C2 level. A higher neurological level of injury was associated with a larger mean CSA and reduction in neuroaxonal integrity within WD (p < 0.05). Smaller total and dorsal tissue bridges were related to greater mean CSA and lower fractional anisotropy values in WD (p < 0.05), respectively. Moreover, SCI participants with significantly larger CSAs and significantly lower microstructural integrity had worse sensory outcomes (p < 0.05). This comprehensive evaluation of WD can help us better understand the mechanisms of WD, monitor progression, and assess the effectiveness of therapeutic interventions after SCI.

A Wearable Fluorescence Imaging Device for Intraoperative Identification of Human Brain Tumors.

Malignant glioma (MG) is the most common type of primary malignant brain tumors. Surgical resection of MG remains the cornerstone of therapy and the extent of resection correlates with patient survival. A limiting factor for resection, however, is the difficulty in differentiating the tumor from normal tissue during surgery. Fluorescence imaging is an emerging technique for real-time intraoperative visualization of MGs and their boundaries. However, most clinical grade neurosurgical operative microscopes with fluorescence imaging ability are hampered by low adoption rates due to high cost, limited portability, limited operation flexibility, and lack of skilled professionals with technical knowledge. To overcome the limitations, we innovatively integrated miniaturized light sources, flippable filters, and a recording camera to the surgical eye loupes to generate a wearable fluorescence eye loupe (FLoupe) device for intraoperative imaging of fluorescent MGs. Two FLoupe prototypes were constructed for imaging of Fluorescein and 5-aminolevulinic acid (5-ALA), respectively. The wearable FLoupe devices were tested on tumor-simulating phantoms and patients with MGs. Comparable results were observed against the standard neurosurgical operative microscope (PENTERO® 900) with fluorescence kits. The affordable and wearable FLoupe devices enable visualization of both color and fluorescence images with the same quality as the large and expensive stationary operative microscopes. The wearable FLoupe device allows for a greater range of movement, less obstruction, and faster/easier operation. Thus, it reduces surgery time and is more easily adapted to the surgical environment than unwieldy neurosurgical operative microscopes. Clinical and Translational Impact Statement-The affordable and wearable fluorescence imaging device developed in this study enables neurosurgeons to observe brain tumors with the same clarity and greater flexibility compared to bulky and costly operative microscopes.

Stomatin-like protein 2 promotes cell proliferation and survival under 5-Fluorouracil stress in hepatocellular carcinoma.

BACKGROUND: The crucial role of STOML2 in tumor progression has been documented recently in various cancers. Previous studies have shown that STOML2 promoted cancer cell proliferation, but the underlying mechanism is not fully illustrated. METHODS AND RESULTS: The expression and clinical relevance of STOML2 in pan-cancer was analyzed by TIMER2 web platform in pan-cancer. The prognostic significance of STOML2 in HCC was evaluated utilizing KM curve and a nomogram model. Signaling pathways associated with STOML2 expression were discovered by GSEA. CCK-8 assay was performed to evaluate the proliferative capacity of HCC cells after manipulating STOML2 expression. Flow cytometry was utilized to analyze cell cycle progression. Results indicated that increased STOML2 expression in HCC linked to unfavorable clinical outcomes. Cell cycle and cell division related terms were enriched under conditions of elevated STOML2 expression via GSEA analysis. A notable decrease in cell proliferation was observed in MHCC97H with STOML2 knocked-down, accompanied by G1-phase arrest, up-regulation of p21, down-regulation of CyclinD1 and its regulatory factor MYC, while STOML2 overexpression in Huh7 showed the opposite results. These results indicated that STOML2 was responsible for HCC proliferation by regulating the expression level of MYC/cyclin D1 and p21. Furthermore, an inverse correlation was found between STOML2 expression and 5-FU sensitivity. CONCLUSIONS: STOML2 promotes cell cycle progression in HCC which is associated with activation of MYC/CyclinD1/p21 pathway, and modulates the response of HCC to 5-FU.

Predictive Factors for Seizures after Revascularization in Patients with Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) is a rare and complex cerebrovascular disorder that is diagnosed through imaging studies, such as computed tomography or magnetic resonance imagin, which show progressive narrowing of the terminal portion of the internal carotid arteries and the development of compensatory capillary collaterals. The objective of our study was to identify and clarify the predictive factors for seizures in patients with MMD. METHODS: From January 2019 to March 2023, a total of 102 patients with MMD were enrolled in this study. Ten patients with seizures after surgery as the main presentation were included. Patients with epilepsy were compared to those without epilepsy in terms of their clinical characteristics. Multivariable analysis was applied to determine factors linked with postoperative seizures. RESULTS: Ten patients developed seizures after revascularization for MMD. Logistic regression analysis revealed that early seizure (odds ratio [OR], 0.068; 95% CI, 0.014-0.342; P = 0.001), cortical involvement (OR, 9.593; 95% CI, 2.256-40.783; P = 0.002), and postoperative hyperperfusion (OR, 7.417; 95% CI, 1.077-51.093; P = 0.042) were significantly associated with seizures. In a multivariate analysis, it was found that early seizures were significantly associated with a higher likelihood of experiencing seizures (OR, 5.88; 95% CI, 1.01-33.96; P = 0.048), while patients who had seizures were more likely to have cortical involvement (OR, 8.90; 95% CI, 1.55-50.96; P = 0.014) or postoperative hyperperfusion (OR, 12.44; 95% CI, 1.21-127.74; P = 0.034). CONCLUSIONS: Epilepsy in patients with MMD link with several clinical factors. In patients with MMD who undergo bypass surgery, early seizures, cortical involvement, and postoperative hyperperfusion are significant independent predictive factors for the development of epilepsy.

A single center retrospective study: Comparison between centrifugal separation plasma exchange with ACD-A and membrane separation plasma exchange with heparin on acute liver failure and acute on chronic liver failure.

The purpose of this retrospective study is to compare the efficacy and safety of the centrifugal separation therapeutic plasma exchange (TPE) using citrate anticoagulant (cTPEc) with membrane separation TPE using heparin anticoagulant (mTPEh) in liver failure patients. The patients treated by cTPEc were defined as cTPEc group and those treated by mTPEh were defined as mTPEh group, respectively. Clinical characteristics were compared between the two groups. Survival analyses of two groups and subgroups classified by the model for end-stage liver disease (MELD) score were performed by Kaplan-Meier method and were compared by the log-rank test. In this study, there were 51 patients in cTPEc group and 18 patients in mTPEh group, respectively. The overall 28-day survival rate was 76% (39/51) in cTPEc group and 61% (11/18) in mTPEh group (P > .05). The 90-day survival rate was 69% (35/51) in cTPEc group and 50% (9/18) in mTPEh group (P > .05). MELD score = 30 was the best cut-off value to predict the prognosis of patients with liver failure treated with TPE, in mTPEh group as well as cTPEc group. The median of total calcium/ionized calcium ratio (2.84, range from 2.20 to 3.71) after cTPEc was significantly higher than the ratio (1.97, range from 1.73 to 3.19) before cTPEc (P < .001). However, there was no significant difference between the mean concentrations of total calcium before cTPEc and at 48 h after cTPEc. Our study concludes that there was no statistically significant difference in survival rate and complications between cTPEc and mTPEh groups. The liver failure patients tolerated cTPEc treatment via peripheral vascular access with the prognosis similar to mTPEh. The prognosis in patients with MELD score < 30 was better than in patients with MELD score ≥ 30 in both groups. In this study, the patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) treated with cTPEc tolerated the TPE frequency of every other day without significant clinical adverse event of hypocalcemia with similar outcomes to the mTPEh treatment. For liver failure patients treated with cTPEc, close clinical observation and monitoring ionized calcium are necessary to ensure the patients' safety.

Discovery of α-Ketoamide inhibitors of SARS-CoV-2 main protease derived from quaternized P1 groups.

Although the SARS-CoV-2 pandemic has ended, multiple sporadic cases still exist, posing a request for more antivirals. The main protease (Mpro) of SARS-CoV-2, a key enzyme for viral replication, is an attractive target for drug development. Here, we report the discovery of a new potent α-ketoamide-containing Mpro inhibitor, N-((R)-1-cyclohexyl-2-(((R)-3-methoxy-1-oxo-1-((1-(2-oxo-2-((thiazol-2-ylmethyl)amino)acetyl)cyclobutyl)amino)propan-2-yl)amino)-2-oxoethyl)-4,4-difluorocyclohexane-1-carboxamide (20j). This compound presented promising enzymatic inhibitory activity against SARS-CoV-2 Mpro with an IC50 value of 19.0 nM, and an excellent antiviral activity in cell-based assay with an EC50 value of 138.1 nM. This novel covalent inhibitor may be used as a lead compound for subsequent drug discovery against SARS-CoV-2.

First report on establishment and characterization of the extrahepatic cholangiocarcinoma sarcoma cell line CBC2T-2.

BACKGROUND: Extrahepatic cholangiocarcinoma sarcoma is extremely rare in clinical practice. These cells consist of both epithelial and mesenchymal cells. Patient-derived cell lines that maintain tumor characteristics are valuable tools for studying the molecular mechanisms associated with carcinosarcoma. However, cholangiocarcinoma sarcoma cell lines are not available in cell banks. AIM: To establish and characterize a new extrahepatic cholangiocarcinoma sarcoma cell line, namely CBC2T-2. METHODS: We conducted a short tandem repeat (STR) test to confirm the identity of the CBC2T-2 cell line. Furthermore, we assessed the migratory and invasive properties of the cells and performed clonogenicity assay to evaluate the ability of individual cells to form colonies. The tumorigenic potential of CBC2T-2 cells was tested in vivo using non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The cells were injected subcutaneously and tumor formation was observed. In addition, immunohistochemical analysis was carried out to examine the expression of epithelial marker CK19 and mesenchymal marker vimentin in both CBC2T-2 cells and xenografts. The CBC2T-2 cell line was used to screen the potential therapeutic effects of various clinical agents in patients with cholangiocarcinoma sarcoma. Lastly, whole-exome sequencing was performed to identify genetic alterations and screen for somatic mutations in the CBC2T-2 cell line. RESULTS: The STR test showed that there was no cross-contamination and the results were identical to those of the original tissue. The cells showed round or oval-shaped epithelioid cells and mesenchymal cells with spindle-shaped or elongated morphology. The cells exhibited a high proliferation ratio with a doubling time of 47.11 h. This cell line has migratory, invasive, and clonogenic abilities. The chromosomes in the CBC2T-2 cells were polyploidy, with numbers ranging from 69 to 79. The subcutaneous tumorigenic assay confirmed the in vivo tumorigenic ability of CBC2T-2 cells in NOD/SCID mice. CBC2T-2 cells and xenografts were positive for both the epithelial marker, CK19, and the mesenchymal marker, vimentin. These results suggest that CBC2T-2 cells may have both epithelial and mesenchymal characteristics. The cells were also used to screen clinical agents in patients with cholangiocarcinoma sarcoma, and a combination of paclitaxel and gemcitabine was found to be the most effective treatment option. CONCLUSION: We established the first human cholangiocarcinoma sarcoma cell line, CBC2T-2, with stable biogenetic traits. This cell line, as a research model, has a high clinical value and would facilitate the understanding of the pathogenesis of cholangiocarcinoma sarcoma.

Risk factors of Omicron variant associated acute encephalitis/encephalopathy in children.

BACKGROUND: Outbreak of Omicron BA.2 in Taiwan led to an increased number of acute encephalitis/encephalopathy cases in children and several fatal cases drew public attention. In pre-Omicron period, pediatric cases of COVID-19-associated acute encephalitis have been reported and during Omicron epidemic, febrile convulsions, encephalitis were mentioned more frequently. The outcome of patients with neurological complications was worse. However, few studies investigated the risk factors, pathophysiology and prognosis of COVID-19-associated encephalitis/encephalopathy. Here, we describe the presentation of pediatric cases of COVID-19-associated acute encephalitis/encephalopathy and explore the associated risk factors. METHODS: Pediatric patients with confirmed SARS-CoV-2 infections were prospectively enrolled at admission at Chang Gung Memorial Hospital between April and August 2022. Patients were categorized into groups of acute encephalitis/encephalopathy, febrile convulsions or mild disease. Demographic descriptions, clinical manifestations and laboratory data were collected. RESULTS: Of 288 acute COVID-19 patients, there were 38 (13.2%) acute encephalitis/encephalopathy, 40 (13.9%) febrile convulsions, and 210 (72.9%) mild disease. Among acute encephalitis/encephalopathy group, the mean age was 68.3 ± 45.0 months. The common neurological symptoms were lethargy (65.8%), seizures (52.6%), and impaired consciousness (34.2%). Over 3 years old (adjusted odds ratio [aOR]: 7.57, p < 0.001), absolute neutrophil count ≥3150/µL (aOR: 5.46, p = 0.008), and procalcitonin ≥0.5 ng/mL (aOR: 4.32, p = 0.021) were independent factors for acute encephalitis/encephalopathy. CONCLUSIONS: Most cases of COVID-19-associated acute encephalitis/encephalopathy showed no evidence of direct viral invasion but associations with older age, increased peripheral neutrophil, and serum procalcitonin. These findings may imply the neutrophil-mediated systemic inflammatory response plays an important role on central nerve system, leading to cerebral dysfunction.

Influence of sodium thiosulfate on coronary artery calcification of patients on dialysis: a meta-analysis.

Coronary artery calcification (CAC) is common in dialysis patients and is associated with a higher risk of future cardiovascular events. Sodium thiosulfate (STS) is effective for calciphylaxis in dialysis patients; however, the influence of STS on CAC in dialysis patients remains unclear. This systematic review and meta-analysis were conducted to evaluate the effects of STS on CAC in patients undergoing dialysis. PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases were searched from inception to 22 March 2023 for controlled studies comparing the influence of STS versus usual care without STS on CAC scores in dialysis patients. A random effects model incorporating the potential influence of heterogeneity was used to pool the results. Nine studies, including two non-randomized studies and seven randomized controlled trials, were included in the meta-analysis. Among these, 365 patients on dialysis were included in the study. Compared with usual care without STS, intravenous STS for 3-6 months was associated with significantly reduced CAC scores (mean difference [MD] = -180.17, 95% confidence interval [CI]: -276.64 to -83.70, p < 0.001, I2 = 0%). Sensitivity analysis limited to studies of patients on hemodialysis showed similar results (MD: -167.33, 95% CI: -266.57 to -68.09, p = 0.001; I2 = 0%). Subgroup analyses according to study design, sample size, mean age, sex, dialysis vintage of the patients, and treatment duration of STS also showed consistent results (p for subgroup differences all > 0.05). In conclusion, intravenous STS may be effective in attenuating CAC in dialysis patients.

Development and validation of a mutation-annotated prognostic score for intrahepatic cholangiocarcinoma after resection: a retrospective cohort study.

BACKGROUND: The value of existing prognostic models for intrahepatic cholangiocarcinoma is limited. The inclusion of prognostic gene mutations would enhance the predictive efficacy. METHODS: In the screening cohorts, univariable Cox regression analysis was applied to investigate the effect of individual mutant genes on overall survival (OS). In the training set, multivariable analysis was performed to evaluate the independent prognostic roles of the clinicopathological and mutational parameters, and a prognostic model was constructed. Internal and external validations were conducted to evaluate the performance of this model. RESULTS: Among the recurrent mutations, only TP53 and KRASG12 were significantly associated with OS across all three screening cohorts. In the training cohort, TP53 and KRASG12 mutations in combination with seven other clinical parameters (tumor size, tumor number, vascular invasion, lymph node metastasis, adjacent invasion, CA19-9, and CEA), were independent prognostic factors for OS. A mutation-annotated prognostic score (MAPS) was established based on the nine prognosticators. The C-indices of MAPS (0.782 and 0.731 in the internal and external validation cohorts, respectively) were statistically higher than those of other existing models ( P <0.05). Furthermore, the MAPS model also demonstrated significant value in predicting the possible benefits of upfront surgery and adjuvant therapy. CONCLUSIONS: The MAPS model demonstrated good performance in predicting the OS of intrahepatic cholangiocarcinoma patients. It may also help predict the possible benefits of upfront surgery and adjuvant therapy.

Geochemical behaviors of uranium and thorium during weathering and pedogenesis of carbonate rock: constraint from their speciation.

During weathering and pedogenesis of carbonate rock with poor-uranium (U) and thorium (Th), U and Th present the characteristics of strong leaching (especially U) and significant residual enrichment, the cause of which is still unclear. In this paper, a weathering profile developed by dolomite in karst area of Guizhou province in southwest China was selected, which showed zonation characteristics of bedrock (Y), powdery rock (Yf), and soil layer (T1 to T12) from the bottom to up. Through the determination of the occurrence speciation of U and Th in Y and weathering profile, combined with mineralogical, geochemical characteristics, and element mass balance calculation, the constraints of U and Th speciation on the geochemical behavior of U and Th during the weathering of carbonate rock were revealed. The results proved that U and Th in Y preferentially existed in acid insoluble phase, for example, the contents of U and Th in Y were 0.90 mg·kg-1 and 0.28 mg·kg-1, respectively, while those in acid insoluble matter were 2.34 mg·kg-1 and 2.57 mg·kg-1, respectively, but because the mass percentage of acid insoluble matter was extremely low (0.95%), the mass percentages of U and Th in the acid soluble phase in the whole rock were absolutely superior (96% of U and 86% Th). The U and Th in the acid soluble phase of Y were mainly adsorbed on the crystal surface of carbonate minerals or existed in the cement, and the U and Th in the carbonate lattice only accounted for a small proportion. From Y to Yf with the initial dissolution, U and Th released from the surface of carbonate minerals and cements were in carbonate-rich alkaline environment, and these portions of U and Th were leached out, resulting in strong loss of U and Th in the Yf (the loss rates are 83% of U and 65% of Th, respectively). From the Yf to the overlying soil layer T1, the carbonate components were completely dissolved, and the U and Th released from the carbonate lattice showed different behaviors, where U was completely leached and Th tended to stay in the weathered residue. Thus, in the soil layer T1 formed by Y or Yf , the residual U was the inheritance of the U in the acid insoluble phase of Y; For Th, it not only inherited the Th of acid insoluble phase of Y, but also superimposed the Th from carbonate lattice in Y. On the other hand, during the evolution process from Y to Yf and to soil layer T1, with the dissolution of carbonate, the acid insoluble phase also showed a significant tendency of chemical weathering. However, the U and Th in the Y acid insoluble phase were not leached with the decomposition of the acid insoluble phase but were redistributed among the residual phases. For the geochemical behaviors of U and Th in the evolution of soil profile (T1~T12), they were subjected to the occurrence speciation of U and Th in T1 and the change of U and Th occurrence speciation with the upward direction of soil profile. The U and Th released from the carrier minerals were mainly redistributed among the residual solid phases, which weakened the intensity of their further loss. This study deepens the understanding of the geochemical behavior of radionuclides in karst environment and provides reference for the treatment of radioactive pollution in karst areas.

Lanatoside C decelerates proliferation and induces apoptosis through inhibition of STAT3 and ROS-mediated mitochondrial membrane potential transformation in cholangiocarcinoma.

Introduction: The incidence of cholangiocarcinoma (CCA) has increased worldwide in recent years. Given the poor prognosis associated with the current management approach of CCA, new therapeutic agents are warranted to improve the prognosis of this patient population. Methods: In this study, we extracted five cardiac glycosides (CGs) from natural plants: digoxin, lanatoside A, lanatoside C, lanatoside B, and gitoxin. Follow-up experiments were performed to assess the effect of these five extracts on cholangiocarcinoma cells and compounds with the best efficacy were selected. Lanatoside C (Lan C) was selected as the most potent natural extract for subsequent experiments. We explored the potential mechanism underlying the anticancer activity of Lan C on cholangiocarcinoma cells by flow cytometry, western blot, immunofluorescence, transcriptomics sequencing, network pharmacology and in vivo experiments. Results: We found that Lan C time-dependently inhibited the growth and induced apoptosis of HuCCT-1 and TFK-1 cholangiocarcinoma cells. Besides Lan C increased the reactive oxygen species (ROS) content in cholangiocarcinoma cells, decreased the mitochondrial membrane potential (MMP) and resulted in apoptosis. Besides, Lan C downregulated the protein expression of STAT3, leading to decreased expression of Bcl-2 and Bcl-xl, increased expression of Bax, activation of caspase-3, and initiation of apoptosis. N-acetyl-L-cysteine (NAC) pretreatment reversed the effect of Lan C. In vivo, we found that Lan C inhibited the growth of cholangiocarcinoma xenografts without toxic effects on normal cells. Tumor immunohistochemistry showed that nude mice transplanted with human cholangiocarcinoma cells treated with Lan C exhibited decreased STAT3 expression and increased caspase-9 and caspase-3 expression in tumors, consistent with the in vitro results. Conclusion: In summary, our results substantiates that cardiac glycosides have strong anti-CCA effects. Interestingly the biological activity of Lan C provides a new anticancer candidate for the treatment of cholangiocarcinoma.

Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease.

The SARS-CoV-2 main protease (Mpro, also named 3CLpro) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of α-ketoamide derivatives as a new class of SARS-CoV-2 Mpro inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent Mpro inhibitor (27h) with an IC50 value of 10.9 nM. The crystal structure of Mpro in complex with 27h revealed that α-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro antiviral assay, 27h showed excellent activity with an EC50 value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for Mpro against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV-2 Mpro and deserves further in-depth studies.

Chronic ß-adrenergic stress contributes to cardiomyopathy in rodents with collagen-induced arthritis.

Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic drug therapy. In this study, we investigated dynamic changes in cardiac function in classic animal models of RA and examined the potential effectors of RA-induced heart failure (HF). Collagen-induced arthritis (CIA) models were established in rats and mice. The cardiac function of CIA animals was dynamically monitored using echocardiography and haemodynamics. We showed that cardiac diastolic and systolic dysfunction occurred in CIA animals and persisted after joint inflammation and that serum proinflammatory cytokine (IL-1ß, TNF-α) levels were decreased. We did not find evidence of atherosclerosis (AS) in arthritic animals even though cardiomyopathy was significant. We observed that an impaired cardiac ß1AR-excitation contraction coupling signal was accompanied by sustained increases in blood epinephrine levels in CIA rats. Furthermore, serum epinephrine concentrations were positively correlated with the heart failure biomarker NT-proBNP in RA patients (r2 = +0.53, P < 0.0001). In CIA mice, treatment with the nonselective ßAR blocker carvedilol (2.5 mg·kg-1·d-1, for 4 weeks) or the specific GRK2 inhibitor paroxetine (2.5 mg·kg-1·d-1, for 4 weeks) effectively rescued heart function. We conclude that chronic and persistent ß-adrenergic stress in CIA animals is a significant contributor to cardiomyopathy, which may be a potential target for protecting RA patients against HF.

M2 macrophage-derived exosomes carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-ß1.

Radiotherapy is essential to cancer treatment, while it inevitably injures surrounding normal tissues, and bone tissue is one of the most common sites prone to irradiation. Bone marrow mesenchymal stem cells (BMMSCs) are sensitive to irradiation and the irradiated dysfunction of BMMSCs may be closely related to irradiation-induced bone damage. Macropahges play important role in regulating stem cell function, bone metabolic balance and irradiation response, but the effects of macrophages on irradiated BMMSCs are still unclear. This study aimed to investigate the role of macrophages and macrophage-derived exosomes in restoring irradiated BMMSCs function. The effects of macrophage conditioned medium (CM) and macrophage-derived exosomes on osteogenic and fibrogenic differentiation capacities of irradiated BMMSCs were detected. The key microribonucleic acids (miRNAs) and targeted proteins in exosomes were also determined. The results showed that irradiation significantly inhibited the proliferation of BMMSCs, and caused differentiation imbalance of BMMSCs, with decreased osteogenic differentiation and increased fibrogenic differentiation. M2 macrophage-derived exosomes (M2D-exos) inhibited the fibrogenic differentiation and promoted the osteogenic differentiation of irradiated BMMSCs. We identified that miR-142-3p was significantly overexpressed in M2D-exos and irradiated BMMSCs treated with M2D-exos. After inhibition of miR-142-3p in M2 macrophage, the effects of M2D-exos on irradiated BMMSCs differentiation were eliminated. Furthermore, transforming growth factor beta 1 (TGF-ß1), as a direct target of miR-142-3p, was significantly decreased in irradiated BMMSCs treated with M2D-exos. This study indicated that M2D-exos could carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-ß1. These findings pave a new way for promising and cell-free method to treat irradiation-induced bone damage.

Prehistoric population expansion in Central Asia promoted by the Altai Holocene Climatic Optimum.

How climate change in the middle to late Holocene has influenced the early human migrations in Central Asian Steppe remains poorly understood. To address this issue, we reconstructed a multiproxy-based Holocene climate history from the sediments of Kanas Lake and neighboring Tiewaike Lake in the southern Altai Mountains. The results show an exceptionally warm climate during ~6.5-3.6 kyr is indicated by the silicon isotope composition of diatom silica (δ30Sidiatom) and the biogenic silica (BSi) content. During 4.7-4.3 kyr, a peak in δ30Sidiatom reflects enhanced lake thermal stratification and periodic nutrient limitation as indicated by concomitant decreasing BSi content. Our geochemical results indicate a significantly warm and wet climate in the Altai Mountain region during 6.5-3.6 kyr, corresponding to the Altai Holocene Climatic Optimum (AHCO), which is critical for promoting prehistoric human population expansion and intensified cultural exchanges across the Central Asian steppe during the Bronze Age.