Laparoscopic lateral suspension with mesh for severe anterior and apical pelvic organ prolapse: an observational cohort study for safety and efficacy at 2-year follow-up.

PURPOSE: This study aimed to investigate the clinical safety and efficacy of laparoscopic lateral suspension (LLS) with mesh in the treatment of severe anterior and apical pelvic organ prolapse (POP) Chinese women with a 2-year follow-up. METHODS: We conducted an observational cohort study. Sixty patients who presented apical (uterovaginal or vault) and anterior prolapse at stage 3 or higher were enrolled. The LLS surgical procedure was performed in accordance with Dubuisson standard operation. The objective and subjective cures as well as the surgery-related complications were evaluated. The POP-related questionnaires were used to evaluate the quality of life before operation and at 24 months after operation follow-up. RESULTS: Objective cure rates at 2 years of follow-up were 88.3% for the anterior compartment, 100% for the apical compartment and 93.3% for the posterior compartment. The subjective cure rate reached to 93.3%. There were statistically significant lower scores of the pelvic floor impact questionnaire-7 (PFIQ-7) and the pelvic floor distress inventory-short form-20 (PFDI-20) for all women after surgery and they exhibited similar scores of the pelvic organ prolapsed-urinary incontinence sexual questionnaire-12 (PISQ-12) (P = 0.317). And no significant difference was demonstrated in international consultation on the incontinent questionnaire short form (ICI-Q-SF) (P = 0.551). No major complications associated with LLS were observed in our study. CONCLUSION: We consider that LLS with mesh operation is safe, feasible and effective to correct severe apical and anterior POP after 2-year follow-up.

Copper aggravated synaptic damage after traumatic brain injury by downregulating BNIP3-mediated mitophagy.

Synaptic damage is a crucial pathological process in traumatic brain injury. However, the mechanisms driving this process remain poorly understood. In this report, we demonstrate that the accumulation of damaged mitochondria, resulting from impaired mitphagy, plays a significant role in causing synaptic damage. Moreover, copper induced downregulation of BNIP3 is a key player in regulating mitophagy. DMSA alleviates synaptic damage and mitochondrial dysfunction by promoting urinary excretion of copper. Mechanistically, we find that copper downregulate BNIP3 by increasing the nuclear translocation of NFKB, which is triggered by TRIM25-mediated ubiquitination-dependent degradation of NFKBIA. Our study underscores the importance of copper accumulation in the regulation of BNIP3-mediated mitophagy and suggests that therapeutic targeting of the copper-TRIM25-NFKB-BNIP3 axis holds promise to attenuate synaptic damage after traumatic brain injury.

Study on the Design Method of High-Resolution Volume-Phase Holographic Gratings.

Volume-phase holographic gratings are suitable for use in greenhouse gas detection imaging spectrometers, enabling the detection instruments to achieve high spectral resolution, high signal-to-noise ratios, and high operational efficiency. However, when utilized in the infrared wavelength band with high dispersion requirements, gratings struggle to meet the demands for low polarization sensitivity due to changes in diffraction performance caused by phase delays in the incidence of light waves with distinct polarization states, and current methods for designing bulk-phase holographic gratings require a large number of calculations that complicate the balance of diffraction properties. To overcome this problem, a design method for transmissive bulk-phase holographic gratings is proposed in this study. The proposed method combines two diffraction theories (namely, Kogelnik coupled-wave theory and rigorous coupled-wave theory) and establishes a parameter optimization sequence based on the influence of design parameters on diffraction characteristics. Kogelnik coupled-wave theory is employed to establish the initial Bragg angle range, ensuring that the diffraction efficiency and phase delay of the grating thickness curve meet the requirements for incident light waves in various polarization states. Utilizing rigorous coupled-wave theory, we optimize grating settings based on criteria such as a center wavelength diffraction efficiency greater than 95%, polarization sensitivity less than 10%, maximum bandwidth, and spectral diffraction efficiency exceeding 80%. The ideal grating parameters are ultimately determined, and the manufacturing tolerances for various grating parameters are analyzed. The design results show that the grating stripe frequency is 1067 lines per millimeter, and the diffraction efficiencies of TE and TM waves are 96% and 99.89%, respectively. The diffraction efficiency of unpolarized light is more than 88% over the whole spectral range with an average efficiency of 94.49%, an effective bandwidth of 32 nm, and a polarization sensitivity of less than 7%. These characteristics meet the performance requirements for dispersive elements based on greenhouse gas detection, the spectral resolution of the detection instrument is up to 0.1 nm, and the signal-to-noise ratio and working efficiency are improved by increasing the transmittance of the instrument.

Preparations of Polyurethane Foam Composite (PUFC) Pads Containing Micro-/Nano-Crystalline Cellulose (MCC/NCC) toward the Chemical Mechanical Polishing Process.

Polyurethane foam (PUF) pads are widely used in semiconductor manufacturing, particularly for chemical mechanical polishing (CMP). This study prepares PUF composites with microcrystalline cellulose (MCC) and nanocrystalline cellulose (NCC) to improve CMP performance. MCC and NCC were characterized using scanning electron microscopy (SEM) and X-ray diffraction (XRD), showing average diameters of 129.7 ± 30.9 nm for MCC and 22.2 ± 6.7 nm for NCC, both with high crystallinity (ca. 89%). Prior to preparing composites, the study on the influence of the postbaked step on the PUF was monitored through Fourier-transform infrared spectroscopy (FTIR). After that, PUF was incorporated with MCC/NCC to afford two catalogs of polyurethane foam composites (i.e., PUFC-M and PUFC-N). These PUFCs were examined for their thermal and surface properties using a differential scanning calorimeter (DSC), thermogravimetric analysis (TGA), dynamic mechanical analyzer (DMA), and water contact angle (WCA) measurements. Tgs showed only slight changes but a notable increase in the 10% weight loss temperature (Td10%) for PUFCs, rising from 277 °C for PUF to about 298 °C for PUFCs. The value of Tan δ dropped by up to 11%, indicating improved elasticity. Afterward, tensile and abrasion tests were conducted, and we acquired significant enhancements in the abrasion performance (e.g., from 1.04 mm/h for the PUF to 0.76 mm/h for a PUFC-N) of the PUFCs. Eventually, we prepared high-performance PUFCs and demonstrated their capability toward the practical CMP process.

A phase 2 trial of gemcitabine plus toripalimab for cisplatin-ineligible patients with recurrent or metastatic nasopharyngeal carcinoma.

Cisplatin is a cornerstone chemotherapy for nasopharyngeal carcinoma (NPC); however, certain patients are ineligible for cisplatin-based regimens. This phase 2 trial (NCT04405622) evaluated the efficacy and safety of gemcitabine and toripalimab in previously untreated patients with recurrent or metastatic NPC who were either ineligible for cisplatin or had experienced severe adverse events from prior cisplatin-based treatments. Patients received gemcitabine (1,000 mg/m2) and toripalimab (240 mg) every three weeks for six cycles, followed by toripalimab monotherapy for up to two years. The primary endpoint was the incidence of grade ≥3 adverse events, while secondary endpoints included objective response rate (ORR) and overall survival (OS). Of 30 screened patients, 21 were enrolled. No treatment-related fatalities occurred, with the most frequent adverse events being headache and nausea. The ORR was 61.9%, coupled with a disease control rate of 100%. Overall, gemcitabine plus toripalimab demonstrated low toxicity and promising efficacy for this specific patient cohort.

Efficacy of brachial plexus block in reducing radial artery spasm during interventional aneurysm surgery.

Radial artery spasm (RAS) occurs in around 50% of patients who undergo interventional aneurysm surgery through the radial artery approach, leading to suboptimal long-term recovery for some. We suggested using brachial plexus block (BPB) to enhance surgical impact on the radial artery, and we confirmed that preconditioning with BPB effectively reduces RAS occurrence and improves prognosis. A total of 177 patients were randomly assigned to either the BPB group or the control group. The main outcome measure was diagnosing RAS incidence through intraoperative angiography, characterized by defects at vessel edges during radial artery angiography. In the control group, RAS occurred in 62.5% (55 out of 88), while it only appeared in 9.0% (8 out of 89) in the BPB group-a significant absolute difference (-53.5 percentage points). The findings suggest that BPB may be an effective strategy to reduce intraoperative RAS incidence in patients undergoing transradial access (TRA) for intracranial aneurysm interventional surgery.

NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation.

Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture (PMR) during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis is less well elucidated. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced only by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that the ferroptosis protective effect caused by NINJ1 knockdown can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhancing cystine uptake and thereby providing protection against ferroptosis. Conversely, NINJ1 overexpression reduced xCT levels and sensitized ferroptosis. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.

Protocol for the derivation and culture of murine trophoblast organoids for CRISPR-Cas9 screening.

Murine trophoblast organoids present a more balanced array of trophoblast subtypes, rendering them a suitable platform for CRISPR-Cas9-based screening. Here, we present a protocol for the derivation and culture of murine trophoblast organoids from trophoblast stem cells or placentae. We describe steps for establishing and differentiating murine trophoblast organoids, the characterization of trophoblast organoids in both conditions, the generation of focused single guide RNA (sgRNA) libraries, and the subsequent screening using those libraries in murine trophoblast organoids. For complete details on the use and execution of this protocol, please refer to Mao et al.1.

Isolation and evaluation of the pathogenicity of a hybrid shiga toxin-producing and Enterotoxigenic Escherichia coli in pigs.

BACKGROUND: Porcine pathogenic Escherichia coli (E. coli), the globally recognized important pathogen, causes significant economic loss in the field. Enterotoxigenic E. coli (ETEC) causes porcine neonatal and post-weaning diarrhea (PWD), frequently carrying F4 adhesin, F18 adhesin, Heat-Stable toxin (ST), and Heat-Labile toxin (LT). Shiga Toxin-Producing E. coli (STEC) produces F18 adhesin and Shiga toxin type 2e (stx2e), majorly leading to systemic endothelial cell damage and edema disease. In this study, hemolytic pathogenic hybrid STEC/ETEC strains carrying ST and LT genes of ETEC and the Stx2e gene of STEC isolated from pigs with PWD in Taiwan were identified. The pathogenicity of a Taiwan hybrid STEC/ETEC strain was evaluated by oral inoculation in post-weaning pigs. RESULTS: Next generation sequencing and multilocus sequence typing of two hybrid Taiwan porcine STEC/ETEC isolates indicated that these two isolates were closely related to the ST88 porcine hybrid STEC/ETEC isolated from pigs with watery diarrhea. Furthermore, the two hybrid Taiwan porcine STEC/ETEC isolates also displayed combinations of multiple resistance genes encoding mechanisms for target modification and antibiotic inactivation. Animal experiments confirmed that the Taiwan hybrid STEC/ETEC could cause watery diarrhea in post-weaning pigs with no signs of edema disease and minimal histopathological lesions. CONCLUSION: To the best of the authors' knowledge, the present study is the first study demonstrating intestinal pathogenicity of the hybrid STEC/ETEC in pigs. The result suggests that the hybrid STEC/ETEC should be considered as a new emerging pathogen and a new target for vaccine development.

A comprehensive numerical procedure for high-intensity focused ultrasound ablation of breast tumour on an anatomically realistic breast phantom.

High-Intensity Focused Ultrasound (HIFU) as a promising and impactful modality for breast tumor ablation, entails the precise focalization of high-intensity ultrasonic waves onto the tumor site, culminating in the generation of extreme heat, thus ablation of malignant tissues. In this paper, a comprehensive three-dimensional (3D) Finite Element Method (FEM)-based numerical procedure is introduced, which provides exceptional capacity for simulating the intricate multiphysics phenomena associated with HIFU. Furthermore, the application of numerical procedures to an anatomically realistic breast phantom (ARBP) has not been explored before. The integrity of the present numerical procedure has been established through rigorous validation, incorporating comparative assessments with previous two-dimensional (2D) simulations and empirical data. For ARBP ablation, the administration of a 0.1 MPa pressure input pulse at a frequency of 1.5 MHz, sustained at the focal point for 10 seconds, manifests an ensuing temperature elevation to 80°C. It is noteworthy that, in contrast, the prior 2D simulation using a 2D phantom geometry reached just 72°C temperature under the identical treatment regimen, underscoring the insufficiency of 2D models, ascribed to their inherent limitations in spatially representing acoustic energy, which compromises their overall effectiveness. To underscore the versatility of this numerical platform, a simulation of a more clinically relevant HIFU therapy procedure has been conducted. This scenario involves the repositioning of the ultrasound focal point to three separate lesions, each spaced at 3 mm intervals, with ultrasound exposure durations of 6 seconds each and a 5-second interval for movement between focal points. This approach resulted in a more uniform high-temperature distribution at different areas of the tumour, leading to the ablation of almost all parts of the tumour, including its verges. In the end, the effects of different abnormal tissue shapes are investigated briefly as well. For solid mass tumors, 67.67% was successfully ablated with one lesion, while rim-enhancing tumors showed only 34.48% ablation and non-mass enhancement tumors exhibited 20.32% ablation, underscoring the need for multiple lesions and tailored treatment plans for more complex cases.

2024 Guidelines of the Taiwan Society of Cardiology on the Primary Prevention of Atherosclerotic Cardiovascular Disease --- Part I.

Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide and in Taiwan. It is highly prevalent and has a tremendous impact on global health. Therefore, the Taiwan Society of Cardiology developed these best-evidence preventive guidelines for decision-making in clinical practice involving aspects of primordial prevention including national policies, promotion of health education, primary prevention of clinical risk factors, and management and control of clinical risk factors. These guidelines cover the full spectrum of ASCVD, including chronic coronary syndrome, acute coronary syndrome, cerebrovascular disease, peripheral artery disease, and aortic aneurysm. In order to enhance medical education and health promotion not only for physicians but also for the general public, we propose a slogan (2H2L) for the primary prevention of ASCVD on the basis of the essential role of healthy dietary pattern and lifestyles: "Healthy Diet and Healthy Lifestyles to Help Your Life and Save Your Lives". We also propose an acronym of the modifiable risk factors/enhancers and relevant strategies to facilitate memory: " ABC2D2EFG-I'M2 ACE": Adiposity, Blood pressure, Cholesterol and Cigarette smoking, Diabetes mellitus and Dietary pattern, Exercise, Frailty, Gout/hyperuricemia, Inflammation/infection, Metabolic syndrome and Metabolic dysfunction-associated fatty liver disease, Atmosphere (environment), Chronic kidney disease, and Easy life (sleep well and no stress). Some imaging studies can be risk enhancers. Some risk factors/clinical conditions are deemed to be preventable, and healthy dietary pattern, physical activity, and body weight control remain the cornerstone of the preventive strategy.

Operando Decoding Ion-Conductive Switch in Stimuli-Responsive Hydrogel by Nanodiamond-Based Quantum Sensing.

Thermal-responsive hydrogels are developed as ion-conductive switchs for energy storage devices, however, the molecule mechanism of switch on/off remains unclear. Here, poly(N-isopropylacrylamide-co-acrylamide) hydrogel is synthesized as a model material and nanodiamond (ND) based quantum sensing for phase change study is developed. First, micro-scale phase separation with cross-linked mesh structure after sol-gel transition is visualized in situ and water molecules are trapped by polymer chains and on a chemically "frozen" state. Then, the nano-scale inhomogeneous distributions of viscosity, thermal conductivity and ionic mobility in hydrogel at high temperature are observed by measuring the rotation, translation and zero-field splitting of NDs. Besides, the ionic mobility of hydrogel is found to be dependent not only on temperature but also on polymer concentration. These observations suggested that the physical "wall" induced by inhomogeneous phase separation at microscopic scale blocked the ion conduction pathways, providing a potential intrinsic explanation for ion migration shut-down of ionic hydrogels at high temperature.

TET1 overexpression affects cell proliferation and apoptosis in aging ovaries.

PURPOSE: Along with the progress of society, human life expectancy has been increasing, and late marriage and late childbearing are the current trend. Since reproductive aging affects fertility, ovarian aging in women has become a major reproductive health issue in the current society. During ovarian aging, DNA methylation levels may change. The ten-eleven translocation (TET) protein family proteins TET1, TET2, and TET3 are important DNA demethylation enzymes, and differential expression of TET1, TET2, and TET3 may affect the proliferation and apoptosis of aging ovarian cells. The aim of this study was to investigate the role of TET1 in the regulation of ovarian aging. METHODS: The expression of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) was analyzed by immunofluorescence (IF) in young and aging ovaries of six 6-8-week-old female mice and six 6-8-month-old female mice. Then, the expression pattern of the TET protein family in young and aging ovaries of mice was investigated. To determine the impact of TET1 on ovarian development, the aging of IOSE-80, KGN, and SKOV-3 cells was induced with D-galactosidase (D-gal). Cells were then transfected using the TET1 overexpression vector or si-TET1. We assessed the proliferation and apoptosis of aging cells after transfection and analyzed the regulatory effect of TET1 expression on aging cells. Additionally, we verified the Tet1 expression in Tet1-KO mice. RESULTS: The 5mC to 5hmC transition, oocyte maturation, and blastocyst rate were reduced in aging mice compared to young mice. In aging mice ovaries, the expression levels of Tet1, Tet2, and Tet3 were reduced significantly, with Tet1 being particularly pronounced. The overexpression of TET1 promoted proliferation and inhibited apoptosis in aging human ovarian cells. Furthermore, Tet1 expression was very low in Tet1-KO C57BL/6 J mice ovaries. CONCLUSION: This study demonstrates that the expression levels of TET family proteins are low in aging ovaries, and the overexpression of TET1 can promote proliferation and inhibit apoptosis in aging ovarian cells.

Stimulated Emission and Lasing from Bulk CdSe Nanocrystals.

Nanocrystals with a size in the regime of vanishing quantum confinement, or bulk nanocrystals (BNCs), have emerged recently as viable solution processable optical gain materials in the green part of the spectrum. Here, we show that these properties can be extended to the crucial red region using CdSe BNCs. Through quantitative time-resolved spectroscopy, we can model these nanocrystals as bulk semiconductors, thereby revealing that the gain originates from an unbound electron-hole plasma state. The gain is broadband in nature and is not capped by Auger processes, but by a slower second-order recombination resulting in nanosecond gain lifetimes. Finally, optically pumped lasers under femtosecond pulsed and quasi-continuous wave operation are demonstrated using a photonic crystal surface emitting laser cavity, thereby stretching from 635 to 720 nm. Our results indicate that compositional variation can indeed provide spectral versatility to the BNC concept, while preserving the excellent gain metrics associated with it.

Long non-coding RNA LNC-POTEM-4 promotes HCC progression via the LNC-POTEM-4/miR-149-5p/Wnt4 signaling axis.

Information on the potential role of the long non-coding RNA LNC-POTEM-4 in cancer progression is limited. Our preliminary study found that LNC-POTEM-4 was overexpressed in hepatocellular carcinoma (HCC) tissues, which led us to further investigate the biological function and molecular mechanism of LNC-POTEM-4 in HCC development. LNC-POTEM-4 expression in HCC tissues was examined using transcriptome sequencing and quantitative reverse transcription PCR. The relationships between LNC-POTEM-4 and the stage and prognosis of HCC in patient data from the TCGA database were analyzed. The effects of LNC-POTEM-4 on proliferation, invasion/migration, and epithelial-mesenchymal transition marker expression in HCC cells were evaluated in vitro using gain- and loss-of-function assays, while its effects on tumor growth and metastasis were explored through animal experiments. A LNC-POTEM-4/microRNA (miR)-149-5p/Wnt4 regulatory signaling axis was identified using bioinformatics analysis, and dual luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Co-transfection of LNC-POTEM-4 and Wnt4 expression plasmids was employed to confirm the new signaling pathway. We found that LNC-POTEM-4 was overexpressed in HCC tissues and was linked to poor staging and prognosis. LNC-POTEM-4 promoted proliferation, invasion, migration, and the epithelial-mesenchymal transition of HCC cells in vitro. Silencing of LNC-POTEM-4 inhibited HCC growth and distant metastasis in vivo. Mechanically, LNC-POTEM-4 was found to function as a competitive endogenous RNA, upregulating Wnt4 by sponging miR-149-5p to promote HCC progression. Wnt4 overexpression may have counteracted the tumor-inhibition effect of LNC-POTEM-4 silencing. In conclusion, LNC-POTEM-4 upregulated Wnt4 to activate the Wnt signaling pathway and stimulate the malignancy tendency of HCC by sponging miR-149-5p, providing a prospective target for the detection and therapy of HCC. However, the effects of LNC-POTEM-4 on the miR-149-5p/Wnt4 signaling axis should be further studied in animal experiments.

Associations between sleep duration, depression status, and cognitive function among Chinese elderly: A community-based study.

BACKGROUND: The associations of sleep duration and depressive status on cognitive function among the elderly remain controversial. This study aimed to investigate the associative effects and mediating mechanisms between sleep duration and depressive status on cognitive function in elderly adults. METHODS: Participants were recruited from cross-sectional and cohort surveys of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). We identified thresholds for sleep duration and depression and used logistic regression to explore their independent and joint effects on cognitive impairment. Further, we analyze the mediating effects of depressive status on the association between sleep duration and cognitive function. RESULTS: Of 13840 elderly (median age: 84 years, female: 54.6 %), 2835 (20.5 %) had cognitive impairment. Compared with those who slept 6-8 h, the ORs (95%CIs) for those who slept < 6 h and > 8 h were 0.98 (0.85, 1.12) and 1.48 (1.32, 1.66). Compared with non-depressed, the OR (95%CI) for the depressed participants was 1.74 (1.53, 1.98). Compared with those with sleep 6-8 h and none-depression, those with sleep > 8 h and depression had the highest odds of cognitive impairment (OR = 2.40, 95%CI: 1.88-3.07). Additionally, Compared with those who slept 6-8 h, the associations between depression-mediated short and long sleep and cognitive impairment were 51.1 % and 6.5 %, respectively. LIMITATIONS: Cross-sectional studies require caution in the interpretation of causal associations. CONCLUSIONS: Long sleep and depression were independently and jointly associated with higher odds of cognitive impairment among the Chinese elderly, and short sleep increased the risk of cognitive impairment by promoting the prevalence of depression.

SCG2 mediates blood-brain barrier dysfunction and schizophrenia-like behaviors after traumatic brain injury.

Traumatic brain injury (TBI), which is characterized by acute neurological dysfunction, is also one of the most widely recognized environmental risk factors for various neurological and psychiatric disorders. However, the role of TBI in neurological perturbation and the mechanisms underlying these disorders remain unknown. We evaluated transcriptional changes in cells of the frontal cortex after TBI by exploiting single-cell RNA sequencing (scRNA-Seq). We adopted the gene expression omnibus and scRNA-Seq to identify the mediation by secretogranin II (SCG2) of TBI-induced schizophrenia. Astrocytes are a principal source of SCG2 in the frontal cortex after TBI. Our analysis indicated that SCG2-triggered disruption of the blood-brain barrier (BBB) via the CypA-MMP-9 signaling pathway. Furthermore, astrocytic SCG2 knockout in the frontal cortex reduced BBB damage, mitigated inflammation, and inhibited schizophrenia after TBI. In conclusion, we identified the SCG2-CypA-MMP-9 signaling pathway in reactive astrocytes as a key switch in the protection of the BBB and provided a novel therapeutic avenue for treating psychiatric disorders after TBI.

Catalytic Edges in One-Dimensional Covalent Organic Frameworks for the Oxygen Reduction Reaction.

Metal-free covalent organic frameworks (COFs) are employed in oxygen reduction reactions (ORR) because of their diverse structural units and controllable catalytic sites, and the edge sites have high catalytic activity than the basal sites. However, it is still challenge to modulate the edge sites in COFs, because the extended frameworks in two- or three-dimensional topologies resulted in limited edge parts. In this study, we have demonstrated the edge site modulation engineering based on one dimensional (1D) COFs to catalyze the ORR, which featured distinct edge groups-carbonyl, diaminopyrazine, phenylimidazole, and benzaldehyde imidazole units. The synthesized COFs have same ordered frameworks, similar pore structure, but had different electronic states of the carbons along the edge sites, which results in tailored catalytic properties. Notably, the COF functionalized with a phenylimidazole edge group exhibited superior catalytic performance compared to the other synthesized COFs. And the theoretical calculation further revealed the different edge sites had tunable binding ability of the intermediates OOH*, which contributed modulated activity. Our findings introduce a novel way for designing COFs optimized for ORR applications through molecular level control of edge sites.

Thrombopoietin improves the functions of bone marrow endothelial progenitor cells via METTL16/Akt signalling of haematological patients with chemotherapy-induced thrombocytopenia.

Bone marrow endothelial progenitor cells (BM EPCs) are crucial in supporting haematopoietic regeneration, while the BM EPCs of haematological patients with chemotherapy-induced thrombocytopenia (CIT) are unavoidably damaged. Therefore, the present study aimed to examine the effect of thrombopoietin (TPO) on the recovery of BM EPCs of CIT patients and to identify the underlying mechanisms. The cell functions were determined by 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil)-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake and fluorescein isothiocyanate (FITC)-labeled Ulex europaeus agglutinin-I (FITC-UEA-I) binding assay, as well as proliferation, migration and tube formation experiments. Endothelial cells were transfected with METTL16 lentivirus, followed by methylated RNA immunoprecipitation sequencing. Zebrafish with vascular defect was used as the in vivo model. TPO significantly improved the quantity and functions of BM EPCs from CIT patients in vitro and restored the subintestinal vein area of zebrafish with vascular defect in vivo. Mechanically, TPO enhanced the BM EPC functions through Akt signal mediated by METTL16, which was downregulated in BM EPCs of CIT patients and involved in the regulation of endothelial functions. The present study demonstrates that TPO improves the recovery of BM EPCs from CIT patients with haematological malignancies via METTL16/Akt signalling, which provides new insights into the role of TPO in treating CIT in addition to direct megakaryopoiesis.

Impact of clonal TP53 mutations with loss of heterozygosity on adjuvant chemotherapy and immunotherapy in gastric cancer.

BACKGROUND: This study aimed to reveal the effect of TP53 status on clinical outcomes and underlying mechanism in gastric cancer (GC) patients. METHODS: TP53 status was divided into three groups according to genome sequencing, namely clonal mutations with LOH (C-LOH), clonal diploid or subclonal mutations (CD-SC), and wild type (WT). The p53 protein activity was divided into over-expression (OE), Null and WT according to immunohistochemical staining. Four cohorts, including the TCGA, SMC, ZSHS and FUSCC cohort, were analyzed for association between TP53 mutation status and clinical outcomes and the underlying mechanism. RESULTS: In TCGA cohort, TP53 CD-SC were associated with superior overall survival compared to TP53 C-LOH cases. GC patients could benefit from ACT only in TP53 CD-SC/ p53 OE and TP53/ p53 WT subgroups, and TP53 C-LOH subgroup demonstrated the worst response to pembrolizumab among three subgroups. Genomic and immunophenotypic deconvolution revealed that TP53 C-LOH, CD-SC and WT differed for genomic and immune-related features. CONCLUSIONS: TP53 C-LOH GCs with genomic instability and immune evasion phenotype have poor clinical outcomes in patients treated with ACT or immunotherapy.