Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice.

Carboxylesterase 2 (CES2) is expressed mainly in liver and intestine, but most abundantly in intestine. It hydrolyzes carboxylester, thioester, and amide bonds in many exogenous and endogenous compounds, including lipids. CES2 therefore not only plays an important role in the metabolism of many (pro-)drugs, toxins and pesticides, directly influencing pharmacology and toxicology in humans, but it is also involved in energy homeostasis, affecting lipid and glucose metabolism. In this study we investigated the pharmacological and physiological functions of CES2. We constructed Ces2 cluster knockout mice lacking all eight Ces2 genes (Ces2-/- strain) as well as humanized hepatic or intestinal CES2 transgenic strains in this Ces2-/- background. We showed that oral availability and tissue disposition of capecitabine were drastically increased in Ces2-/- mice, and tissue-specifically decreased by intestinal and hepatic human CES2 (hCES2) activity. The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in Ces2-/- mice, but only marginally rescued by hCES2 expression. On the other hand, Ces2-/- mice exhibited fatty liver, adipositis, hypercholesterolemia and diminished glucose tolerance and insulin sensitivity, but without body mass changes. Paradoxically, hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size, adipose tissue mass and overall body weight, suggesting a "healthy" obesity phenotype. In contrast, intestinal hCES2 expression efficiently rescued all phenotypes, and even improved some parameters, including body weight, relative to the wild-type baseline values. Our results suggest that the induction of intestinal hCES2 may combat most, if not all, of the adverse effects of metabolic syndrome. These CES2 mouse models will provide powerful preclinical tools to enhance drug development, increase physiological insights, and explore potential solutions for metabolic syndrome-associated disorders.

Limited Social Support, but Comparable Health Literacy and Service Utilization, Among Elderly People Living Alone - Six PLADs, China, May-September 2020.

What is already known about this topic?: The proportion of elderly living alone in China is approximately 10%. Living away from family poses enormous challenges for older adults. What is added by this report?: Compared to those living with family, elderly individuals living alone exhibit a lower registration rate with general practitioners and have less social support. What are the implications for public health practice?: While the current health service system for elderly people living alone is working relatively well, there is a need for additional programs to enhance social support and improve their social well-being.

The impact of green finance on carbon productivity: The mediating effects of the quantity and quality of green innovation.

While China's economy is developing rapidly, the problem of carbon emissions is indeed more prominent. The development of green finance is conducive to supporting environmental improvement and enhancing carbon productivity. Most of the existing literature examines the relationship between green innovation and carbon productivity from the perspectives of industrial structure, technological innovation, and economic growth. However, the mechanism by which green finance (GF) affects carbon productivity and whether there is heterogeneity remains unclear. Therefore, this study utilizes panel data from 277 cities from 2010 to 2020 and employs a mediation effect model to investigate the relationship between GF and carbon productivity. The results of the study found that GF has a positive U-shaped association with carbon productivity. The quantity and the quality of green innovation have a mediating effect on the above relationship. It may be due to the fact that GF promotes the green transformation and sustainable development of the economic structure by supporting green industry and technological innovation, which provides strong support to enhance carbon productivity. In non-resource cities, the impact of GF on carbon productivity is more obvious through improving the quality of green innovation, probably because non-resource cities have the advantages of a diversified industrial structure, stronger innovation capacity, and easier access to policy support and market mechanism support than resource cities. The quantity and the quality of green innovation in the eastern, central, and western regions all play a mediating role. The findings provide policymakers with recommendations for utilizing GF in a two-carbon environment to achieve sustainable low-carbon development.

Study of Factors Affecting UV-Induced Photo-Degradation in Different Types of Polyethylene Sheets.

Enhancing the degradability of polyethylene plastics could provide a potential solution to the overwhelming crisis of plastic waste. Conventional studies have focused on the degradation of polyethylene thin films. This study investigated UV-induced photo-degradation according to ASTM D5208-14 in polyethylene sheets with thicknesses ranging from 0.4 to 1.2 mm. The impacts of sample thickness, metal pro-oxidants, polyethylene resin types and foaming were explored through the characterization of the carbonyl index, molecular weight, tensile properties and crystallinity. As pro-oxidants, single iron or manganese stearate demonstrated a concentration-dependent trend in accelerating the photo-degradation of polyethylene sheets. The thickness, foaming and resin type-such as low-density polyethylene (LDPE) and high-density polyethylene (HDPE)-significantly impacted the rate of photo-oxidation. Thick polyethylene sheets (1.2 mm) exhibited a heterogenous and depth-dependent degradation profile. As the photo-degradation progressed, the enhanced crystallinity, reduced UV transmittance and formation of crosslinks were able to prevent further oxidative cleavage of the polyethylene chain. This study investigated the time course and factors affecting the photo-degradation of polyethylene sheets, which could provide insights into the formulation design of photo-degradable polyethylene plastics.

Mental Health Literacy Among Urban and Rural Residents of Guangdong Province, China.

Purpose: The study aims to understanding the mental health literacy level of urban and rural residents in Guangdong Province, the first major province in China, and its influencing factors is crucial. Methods: A multi-stage stratified equal-volume random sampling method was adopted in October-December 2022 to select permanent residents aged 18 years and above in Guangdong Province for the questionnaire survey, which consisted of a general demographic information questionnaire and a national mental health literacy questionnaire. Rao-Scott χ²-test with correction based on sampling design, independent samples t-test and binary multivariate logistic regression analysis were performed. Results: A total of 51744 individuals completed the questionnaire, including 31822 urban residents and 19200 rural residents. The rate of achievement of mental health literacy was 13.6% among urban residents, which was significantly higher compared to the rate of 8.6% among rural residents. Logistic regression analysis showed that female, higher education, being mental worker, being a retiree, having a higher monthly household income, maintaining a regular diet, and using electronic products for 2-6 hours per day were protective factors for mental health literacy attainment in urban residents, while having chronic diseases, being a smoker and having a history of drinking were identified as risk factors in urban residents. Among in rural residents, married, younger, higher education, being mental worker and using electronic products for 2-6 hours per day, maintaining a regular diet, and engaging in regular exercise were protective factors for achieving mental health literacy, while previous smoking was a risk factor. Conclusion: The study revealed a low level of mental health literacy among urban and rural residents of Guangdong Province, with a significant disparity between the two areas. These findings highlight the need for continuing efforts to increase the dissemination of mental health knowledge in rural communities and improve levels of mental health literacy.

Establishment of a survival predictive model for patients with two synchronous multiple primary lung cancers: a multicenter cohort analysis.

Background: The prognostic predictors of the synchronous multiple primary lung cancer (SMPLC) still remain unclear, and there is a lack of studies on the prognosis of SMPLC patients excluding those with multifocal ground-glass/lepidic (GG/L) nodules. The aim of this study is to develop an effective model for predicting survival of SMPLC patients. Methods: In this multicenter cohort study, a total of 831 SMPLC patients presenting for lung cancer resection from January 2004 to January 2018 at five institutions were included for developing and validating a nomogram model. Specifically, 499 patients from the Cancer Hospital, Chinese Academy of Medical Sciences, and Beijing Chao-Yang Hospital, Capital Medical University were served as the training cohort. A total of 332 patients from The Third Xiangya Hospital of Central South University, the First Affiliated Hospital of University of Science and Technology of China, and Beijing Liangxiang Hospital were served as the external validation cohort. The nomogram model was compared with the Tumor Node Metastasis (TNM) system for the overall survival. The C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate the model performance. A user-friendly website for SMPLC survival probability calculation was also provided for a better understanding of prognosis of patients with resected SMPLC. Results: A total of seven independent risk factors were selected by conducting a multivariate analysis on the training set. Further, a nomogram model was developed with these factors. Both the internal and external validations exhibited good discrimination (C-index: internal, 0.827; external, 0.784). The NRI and IDI of this model were 0.33 and 0.21, respectively. The survival rates for 1-year, 3-year, and 5-year were consistent with the actual observed values. A set of cutoff values were determined by grouping the patients into three different groups. For each group, we should expect a significant distinction between survival curves. Conclusions: The novel nomogram model enables accurate survival risk stratification of patients with resected SMPLC and may assist in decision-making that is conducive to patients with SMPLC at high risk.

Comparison of HBV-specific T cell reactivity across the pregnant, postpartum and non-pregnant women with chronic HBV infection.

Objective: To investigate the features of HBV-specific T cell reactivity across the pregnant, postpartum or non-pregnant women with chronic HBV infection. Methods: A total of 283 patients with chronic HBV infection were enrolled in this study, including 129 patients during pregnancy, 58 patients during postpartum less than 6 months and 96 non-pregnant patients at childbearing age. A universal ELISpot assay was set up using a broad-spectrum T-cell epitope peptide library which containing 103 functionally validated CD8+ T-cell epitopes derived from overall HBsAg, HBc/eAg, HBx and HBpol proteins and fitting to the human leukocyte antigen polymorphisms of Chinese population. Then, The functional HBV-specific T cells in peripheral blood were detected. Results: The spot-forming units (SFUs) of HBV-specific T cells in the pregnant group showed no statistical difference from the postpartum group, but significantly less than that in the non-pregnant group (p = 0.046). In the untreated patients, the pregnant group displayed HBe/cAg-specific T cells (SFUs) less than the non-pregnant group (P = 0.025) and the postpartum group (P = 0.045). Meanwhile, in the NUCs-treated patients, the three groups presented similar HBV-specific T cell reactivity. Furthermore, the SFUs in the NUCs-treated pregnant group were similar to that in the NUCs-untreated pregnant group. Importantly, ROC analysis demonstrated that the HBV-specific T cells (SFUs) (AUC = 0.742) and combined with HBsAg levels (AUC = 0.775) or with HBeAg level (AUC = 0.78) had a good predictive performance for hepatitis progression during pregnancy group. Conclusion: Pregnancy can reduce HBV-specific T cell reactivity in the women with chronic HBV infection, and NUCs treatment cannot improve their HBV-specific T cells reactivity. Routine monitoring of HBV-specific T cells during pregnant and postpartum period can provide precise evaluation for immune function and valuable guidance for treatments.

Mental health status of Chinese residents and its associated factors in the aftermath of the COVID-19 pandemic: A cross-sectional study.

Background: During the COVID-19 pandemic, numerous studies focused on mental health, but few considered both positive and negative aspects within the dual-factor model of psychological well-being. In China, a highly populous country, limited evidence exists regarding mental health and its associated factors following the surge and decline of COVID-19 cases after the loosening of COVID-19 control measures. This study aims to investigate the mental health status of Chinese residents in the aftermath of the pandemic and factors influencing positive and negative indicators using the System-Based Model of Stress. Methods: A cross-sectional online survey of 1,026 participants was conducted in China from March 2-31, 2023, using quota sampling. Structural equation modeling (SEM) was performed to test the conceptual model, where social support, perceived susceptibility, perceived severity, pandemic-related events, coping style, and concern about COVID-19 were considered as predictors, and psychological distress and subjective well-being as outcomes. Results: The results revealed high prevalence rates of psychological distress (23 %) with either of anxiety (15 %) or depression (20 %), and poor subjective well-being (23 %) among Chinese residents after the COVID-19 pandemic. Social support was negatively correlated with psychological distress, and negative coping style, pandemic-related events, and concern about COVID-19 were positively correlated with psychological distress. Moreover, social support was positively correlated with subjective well-being, and negative coping style and pandemic-related events were negatively correlated with subjective well-being. Conclusions: These findings enhance our understanding of the differing correlates of positive and negative mental health, suggesting targeted psychological interventions for post-pandemic and future public health events.

An MXene-supported NH2CNT and BiOCl composite as a sulfur reservoir for Li-S batteries with high energy density.

To solve the intractable challenges of Li-S batteries, we synthesized MXene-NH2CNT-BiOCl-x to be used as a sulfur host. The M-N-B-10%-S electrode exhibited superior electrochemical performance. In situ XRD measurement confirmed that the M-N-B-10%-S electrode displayed good cycle stability.

Simulation of Polymer Fractal Formation Using a Triangular Network Growth Model.

Fractal formation in spin-coated thin-film polymers is of experimental and theoretical interest. Modeling the determinants and dynamics of this process will deepen our understanding of polymer aggregation and the predictability of thin-film structures. This is especially true if the model used has readily interpretable parameters and has been demonstrated to yield a close match to experimental processes under a variety of conditions. In this work, we adapted and applied a relatively new model of fractal growth comprised of a spreading and contracting triangular network, to model spin-coated, thin-film polymers made of poly(vinyl alcohol) on polydimethylsiloxane substrates. We drew clear connections between model parameters and the process of polymer aggregation and we demonstrated the ability of the model to simulate fractal formation under a wide variety of conditions including varying the degree of hydrolysis of the polymer, changing the spin-coating process, and solvent annealing and reforming of polymer fractals under different drying conditions. We also showed how the model is able to replicate idiosyncratic experimental settings yielding novel fractal patterns.

Bimetallic Coupling Strategy Modulating Electronic Construction to Accelerate Sulfur Redox Reaction Kinetics for High-Energy Flexible Li-S Batteries.

Lithium-sulfur (Li-S) batteries are considered the most promising energy storage battery due to their low cost and high theoretical energy density. However, the low utilization rate of sulfur and slow redox kinetics have seriously limited the development of Li-S batteries. Herein, the electronic state modulation of metal selenides induced by the bi-metallic coupling strategy is reported to enhance the redox reaction kinetics and sulfur utilization, thereby improving the electrochemical performance of Li-S batteries. Theoretical calculations reveal that the electronic structure can be modulated by Ni-Co coupling, thus lowering the conversion barrier of lithium polysulfides (LiPSs) and Li+, and the synergistic interaction between NiCoSe nanoparticles and nitrogen-doped porous carbon (NPC) is facilitating to enhance electron transport and ion transfer kinetics of the NiCoSe@NPC-S electrodes. As a result, the assembled Li-S batteries based on NiCoSe@NPC-S exhibit high capacities (1020 mAh g-1 at 1 C) and stable cycle performance (80.37% capacity retention after 500 cycles). The special structural design and bimetallic coupling strategy promote the batteries working even under lean electrolyte (7.2 µL mg-1) with a high sulfur loading (6.5 mg cm-2). The proposed bimetallic coupling strategy modulating electronic construction with N-doping porous carbon has jointly contributed the good redox reaction kinetics and high sulfur utilization.

Human behavior-based COVID-19 transmission in two dining spaces.

Since December 2019, the COVID-19 pandemic has rapidly disseminated globally, posing significant threats to the world. The dining spaces are high-risk indoor environments for the transmission of SARS-CoV-2, posing challenges for intervention and control. This study, based on surveillance videos from two COVID-19 outbreak cases in restaurants, obtained real data on human behaviors of close contact and surface touch. A respiratory infectious disease transmission model was developed, incorporating four transmission routes: short-range airborne, long-range airborne, fomite and large droplet. The results indicate that diners and staff spent 21.9 %-28.7 % and 17.5 %-27.8 % of their time on speaking, respectively, while spending 85.9 %-90.7 % and 83.4 %-87.6 % of their time on surface touching. The primary transmission routes were short-range (contributing 5.8 %-70.9 %) and long-range airborne (contributing 28.4 %-93.0 %), with fomite and large droplet routes contributing less than 12.0 %. Staff-only mask wearing reduced infection risk by 12.8 %-31.8 %. It is recommended that mandatory mask wearing for staff is necessary, while diners should wear masks as much as possible, and that the equivalent ventilation rate of clean fresh air is suggested to 30.0 m3/ (h·person). This study provides a scientific support to make non-pharmaceutical interventions in dinning spaces.

Exploring the impact of variable power outputs on the efficacy and safety during microwave ablation for lung carcinoma: a real-world study.

Background: Microwave ablation (MWA) is an important method for the treatment of lung cancer, but there is still a lack of standard guidelines for the selection of power. This study aimed to explore the effectiveness and safety of MWA at different power levels. Methods: The study gathered individuals underwent MWA for lung cancer between January 2012 and December 2020. All patients were divided into low power group and high power group based on the power of MWA. By intergroup comparisons, we clarified the differences between the two groups. Results: In this study, 265 participants were involved, with 192 in the low power group and 73 in the high power group. Compared to the low power group, the high power group had a significantly higher incidence of postoperative complications (63.0% vs. 24.0%). In the Kaplan-Meier analysis, overall survival (OS) and disease-free survival (DFS) of the high power group were both better than the low power group. We found through Cox regression analysis that smoking, tumor volume, tumor differentiation, gene mutation, neutrophil count, and lymphocyte count were independent factors affecting the OS of patients. Based on the above factors, we constructed a nomogram, with areas under the curve (AUCs) of 0.941, 0.903, and 0.905 for predicting 1-, 2-, and 3-year OS after MWA, respectively. Conclusions: While high-power MWA brings better long-term prognosis to patients, it also leads to an increase in postoperative complications. The application of a nomogram for stratifying the prognosis of patients may be a more feasible approach to further develop individualized treatment plans.

Single-cell transcriptomics reveals writers of RNA modification-mediated immune microenvironment and cardiac resident Macro-MYL2 macrophages in heart failure.

BACKGROUND: Heart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown. METHODS: We comprehensively characterized the expressions of 28 WRMs using datasets GSE145154 and GSE141910 to map the cardiac immunological microenvironment in HF patients. Based on the expression of WRMs, the immunological cells in the datasets were scored. RESULTS: Single-cell transcriptomics analysis (GSE145154) revealed immunological dysregulation in HF as well as differential expression of WRMs in immunological cells from HF and non-HF (NHF) samples. WRM-scored immunological cells were positively correlated with the immunological response, and the high WRM score group exhibited elevated immunological cell infiltration. WRMs are involved in the differentiation of T cells and myeloid cells. WRM scores of T cell and myeloid cell subtypes were significantly reduced in the HF group compared to the NHF group. We identified a myogenesis-related resident macrophage population in the heart, Macro-MYL2, that was characterized by an increased expression of cardiomyocyte structural genes (MYL2, TNNI3, TNNC1, TCAP, and TNNT2) and was regulated by TRMT10C. Based on the WRM expression pattern, the transcriptomics data (GSE141910) identified two distinct clusters of HF samples, each with distinct functional enrichments and immunological characteristics. CONCLUSION: Our study demonstrated a significant relationship between the WRMs and immunological microenvironment in HF, as well as a novel resident macrophage population, Macro-MYL2, characterized by myogenesis. These results provide a novel perspective on the underlying mechanisms and therapeutic targets for HF. Further experiments are required to validate the regulation of WRMs and Macro-MYL2 macrophage subtype in the cardiac immunological milieu.

Efficient Deep-Blue Fluorescent OLEDs Based on a D-π-A Emitter Profiting From Intramolecular Hydrogen Bonds and a Hybridized Excited State.

High performance deep-blue emitters with a Commission International de l'Eclairage (CIE) coordinate of CIEy≤0.08 are highly desired in ultrahigh-definition displays. Herein, we designed and synthesized an efficient D-π-A deep-blue emitter, 2-(6-([1,1' : 3',1''-terphenyl]-5'-yl)pyridin-3-yl)-1-phenyl-1H-phenanthro[9,10-d] imidazole (mPTPH), using the synergistic effect of intramolecular hydrogen bond (H-bond) and hybridized excited state. Single-crystal structure analysis confirmed that there exist intra- and intermolecular H-bond interactions which could inhibit the structure vibration and increase photoluminescence efficiency. The photophysical and theoretical results show that mPTPH exhibited hybridized local and charge-transfer (HLCT) feature with strong deep-blue emission. Ultimately, the non-doped device based on mPTPH exhibited high maximum luminance of 20610 cd m-2. The doped device achieved high maximum external quantum efficiency of 5.4 % and small efficiency roll-off with deep-blue emission peak of 413 nm and CIE coordinate of (0.16, 0.08).

Analysis of the thermal insulation performance of cement with waste glass powder in geothermal well.

To improve the heat extraction efficiency from the wellbore fluids to the stratum in the geothermal well, thermal insulation cement, which contains of waste glass powder as a heat-insulating material, is proposed to apply in geothermal well's middle and upper sections in the paper. Effect of such glass powers on mechanic and thermal property of thermal insulation cement was then investigated. Various tests were carried out to measure compressive strength, thermal conductivity, microstructure porosity etc. parameters of the thermal insulation cement. Results showed that the waste glass powder would enhance its the compressive strength and improve its the thermal insulation performance. Correlation study between contents of the added waste glass powder in geothermal cements and its mechanic and thermal property was conducted. It was found that thermal insulation cement exhibited its optimum performance when the added content of glass powers was 20% in weight. Analysis of the microstructure porosity with SEM found that the pores in thermal insulation cement with added waste glass powders were mostly closed, tiny and even, and therefore contributed to the compressive strength of the thermal insulation cement; such pores would be also beneficial to improving its thermal insulation performance.

Prevalence of nicotine dependence among smokers aged 40 years and older in China.

Background: Nicotine dependence, also known as tobacco dependence, is a common chronic disease and a major risk factor for chronic respiratory diseases. The present study was designed to determine the prevalence of nicotine dependence and its changes among smokers aged 40 years and older in China, to analyze the characteristics of nicotine dependence among smokers, and to provide a reference for smoking cessation interventions. Methods: The data were sourced from nationally representative large-sample surveys conducted during 2014-2015 and 2019-2020 in the Chinese population, covering 125 counties (districts) in 31 provinces, autonomous regions and municipalities. Variables related to smoking and nicotine dependence among residents ≥40 years old were collected in face-to-face interviews. A total of 20,062 and 18,975 daily smokers were included in the 2014-2015 and 2019-2020 surveys, respectively. The severity of nicotine dependence was evaluated according to the Fagerström Test for Nicotine Dependence and Heaviness of Smoking Index. The level and change in nicotine dependence among daily smokers aged ≥40 years were estimated using a complex weighted sampling design, and their influencing factors were analyzed. Results: Levels of nicotine dependence among daily smokers aged ≥40 years in China could be divided into very low, low, medium, high, and very high, accounting for 31.1%, 27.9%, 13.4%, 20.5%, and 7.1% of the total, respectively. The average Fagerström Test for Nicotine Dependence score was 3.9 (95% confidence interval [CI]: 3.8-4.0), with the prevalence of medium-high nicotine dependence being 41.0% (95% CI: 39.0-42.9%) and that of high and very high nicotine dependence being 27.6% (95% CI: 26.0-29.3%), both of which were significantly higher in men than in women (both P < 0.001). Among daily smokers, those with a low education level, age at smoking initiation <18 years, and with smoking duration of ≥20 years had a higher degree of nicotine dependence. In terms of geographic region, the level of medium-high nicotine dependence in South China was higher than in other areas, and the decline in the prevalence of high nicotine dependence was the greatest in Northwest China (P < 0.001). The prevalence of medium-high and high and very high nicotine dependence was significantly higher in men with chronic respiratory symptoms, chronic obstructive pulmonary disease (COPD), and/or chronic respiratory diseases than in men without these conditions (all P < 0.05). The prevalence of high and very high nicotine dependence in women with chronic respiratory symptoms and chronic respiratory diseases was significantly higher than that in women without these conditions (both P < 0.05). Compared with that during 2014-2015, the prevalence of high nicotine dependence among daily smokers decreased during 2019-2020 by 4.5 percentage points in the total population (P < 0.001) and by 4.8 percentage points in men (P < 0.001), with no significant change seen in women (P > 0.05). Additionally, the prevalence of high nicotine dependence in men with chronic respiratory symptoms and COPD decreased by 6.7 and 4.7 percentage points, respectively (P < 0.05), but showed no significant change in women with these conditions (P > 0.05). Multivariate logistic regression analysis showed that the risk of medium-high nicotine dependence was higher among daily smokers who were male; 50-59 years old; unmarried/divorced/widowed/separated; engaged in agriculture, forestry, husbandry, fishery and water conservancy; had a low education level; started smoking before the age of 18 years; and smoked for more than 20 years. Conclusions: The past few years have seen a slight decline in the prevalence of high (severe) nicotine dependence among smokers aged ≥40 years in China. However, 41.0% of daily smokers had medium-high nicotine dependence, and 27.6% had high or very high nicotine dependence, with notable differences in population and geographic distributions. Development of tailored interventions, optimization of smoking cessation service systems, and integration of smoking cessation into the management of chronic diseases will effectively reduce the burden of nicotine dependence in China.

GGC repeat expansions in NOTCH2NLC cause uN2CpolyG cerebral amyloid angiopathy.

The expansion of GGC repeats within NOTCH2NLC leads to the translation of the uN2CpolyG protein, the primary pathogenic factor in neuronal intranuclear inclusion disease (NIID). This study aims to explore the deposition of uN2CpolyG as an amyloid in the vessel wall, leading to uN2CpolyG cerebral amyloid angiopathy (CAA)-related cerebral microbleeds (CMBs). A total of 97 patients with genetically confirmed NIID were enrolled in this study. We analyzed the presence of CMBs using susceptibility-weighted imaging sequences and compared general clinical information, cerebrovascular risk factors, stroke history, antiplatelet medication use, and MRI features between NIID patients with and without CMBs. We further performed hematoxylin and eosin (H&E), Perl's, Congo red, and Thioflavin S staining, ubiquitin, p62 and uN2CpolyG immunostaining on brain tissue obtained from four NIID patients. A total of 354 CMBs were detected among 41 patients with NIID, with nearly half located in the deep brain, one-third in the lobes, and approximately 20% in the infratentorial area. No significant differences in cerebrovascular disease risk factors or history of antiplatelet drug use were observed between patients with and without CMBs. However, patients with CMBs suffered a higher incidence of previous ischemic and hemorrhagic stroke events. This group also had a higher incidence of recent subcortical infarcts and a higher proportion of white matter lesions in the external capsule and temporal pole. Conversely, patients without CMBs showed higher detection of high signals at the corticomedullary junction on diffusion-weighted imaging and more pronounced brain atrophy. H&E staining showed blood vessel leakage and hemosiderin-laden macrophage clusters, and Prussian blue staining revealed brain tissue iron deposition. CMBs occurred more frequently in small vessels lacking intranuclear inclusions, and extensive degeneration of endothelial cells and smooth muscle fibres was observed mainly in vessels lacking inclusions. Congo red-positive amyloid deposition was observed in the cerebral vessels of NIID patients, with disordered filamentous fibres appearing under an electron microscope. Additionally, the co-localization of Thioflavin S-labeled amyloid and uN2CpolyG protein in the cerebral vascular walls of NIID patients further suggested that uN2CpolyG is the main pathogenic protein in this form of amyloid angiopathy. In conclusion, we reviewed patients with GGC repeat expansion of NOTCH2NLC from a novel perspective, providing initial clinical, neuroimaging, and pathological evidence suggesting that uN2CpolyG may contribute to a distinct type of CAA.

The meniscotibial ligament does exist: An anatomic and histological description.

Purpose: To describe the anatomical and histological characteristics of the human MTL (meniscotibial ligament) that keeps the meniscus stable and are rarely discussed. Study design: Descriptive laboratory study. Methods: In total, six fresh-frozen adult cadaver knees were dissected, and the dissection protocol were designed by two experienced anatomy professors. The anatomical morphology of MTL was observed. The main anatomical specimens included meniscus, tibial plateau, MTL. The osteotome was used to excise the portion of the tibial plateau, which could obtain the complex including partial meniscus, MTL, and a tibial fragment. A histopathologic study was performed by two experienced pathologists. Results: Macroscopically, the MTL could be divided into two parts: medial meniscotibial ligament (MMTL)and lateral meniscotibial ligament (LMTL). The MMTL is distributed continuously, whereas the LMTL is discontinuous on the tibial plateau. The average length from the tibial attachment of the LMTL to the articular surface was 19 ± 1.0mm (mean ± SD). The average length from the tibial attachment of the MMTL to the articular surface was 10 ± 1.2 mm (mean ± SD). Microscopy of the MTL showed that the MTL is a ligamentous tissue, composed of a network of oriented collagenous fibers. Conclusions: In all knees, the MTL was inserted on the outer edge of the meniscus, attaching to the tibia below the level of articular cartilage, which was key to maintaining the rotational stability of knee and the meniscus in the physiological position on the tibial plateau. Histological analysis of this ligament demonstrated that the MTL is a veritable ligamentous structure, which is made up of collagen type I-expressing fibroblasts. Clinical relevance: This article contributes to the understanding of the anatomical and histological characteristics of the MTL. It is beneficial to promote the development of relevant surgical techniques for the MTL lesion.