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Abstract Background HD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new avenues for therapeutic intervention. Methods The CRISPR/CasRx system was employed to target human HTT exon 1, resulting in an efficient knockdown of HTT mRNA. This therapeutic effect was substantiated in various models: HEK 293 T cell, the HD 140Q-KI mouse, and the HD-KI pig model. The efficiency of the knockdown was analyzed through Western blot and RT-qPCR. Additionally, neuropathological changes were examined using Western blot, immunostaining, and RNA sequencing. The impact on motor abilities was assessed via behavioral experiments, providing a comprehensive evaluation of the treatment's effectiveness. Results CRISPR/CasRx system can significantly reduce HTT mRNA levels across various models, including HEK 293 T cells, HD 140Q-KI mice at various disease stages, and HD-KI pigs, and resulted in decreased expression of mHTT. Utilizing the CRISPR/CasRx system to knock down HTT RNA has shown to ameliorate gliosis in HD 140Q-KI mice and delay neurodegeneration in HD pigs. Conclusions These findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations.

Abstract Background We investigated the associations between IgM, IgG, IgA, and IgE levels and all-cause mortality risk in Chinese centenarians. Methods All participants were from the China Hainan Centenarian Cohort Study. Eligible participants were divided into quartiles based on their IgM, IgG, IgA, and IgE levels. We used restricted cubic spline analyses, Cox regression analyses, and Kaplan–Meier survival curves to analyze associations between IgM, IgG, IgA, and IgE and all-cause mortality risk. Results A total of 906 centenarian participants were included in this study (81.2% female; median age, 102 years). During a median follow-up of 30.1 months, 838 (92.5%) participants died. Restricted cubic spline analysis revealed a nonlinear relationship (“L” type) between serum IgM level and all-cause mortality. Compared with the higher three quartiles of serum IgM level, the lowest quartile was associated with a higher risk of death (Q1 versus Q2-Q4: HR, 1.365; 95% CI, 1.166–1.598; P

BackgroundExisting studies investigating the impact of serum calcium (Ca), phosphate (P), 25 hydroxyvitamin D (25[OH]D), and parathyroid hormone (PTH) levels on kidney function have produced inconsistent results. Further research is needed to establish the direct causal relationship between these factors and kidney function.MethodsThe study used genome-wide association study datasets for exposure and outcome, mainly derived from the UK Biobank and CKDGen Consortium, with sample sizes ranging from 3,310 to 480,699 individuals of European ancestry. Heritability and genetic correlations among these phenotypes were assessed using linkage disequilibrium score regression (LDSC) and phenotypes with a heritability z-score

Objectives: This study aimed to examine the relationship between anemia and all-cause mortality in Chinese centenarians. Design: Prospective cohort study. Setting and participants: We included 1002 Chinese centenarians from the China Hainan Centenarian Cohort Study (CHCCS) Measurements: Standard procedures were followed to perform blood analysis, home interviews, and physical examinations. Anemia was defined as a hemoglobin level of less than 130 g/L for men and less than 120 g/L for women. Results: During the 9-year follow-up period, a total of 929 (92.7%) deaths were identified. Cox proportional hazards regression models revealed that anemia (hazard ratio [HR] 1.289, 95% confidence interval [CI]: 1.117–1.489) was significantly associated with all-cause mortality. There was an apparent dose-response relationship between anemia and all-cause mortality. Centenarians with severe anemia had approximately 1.6 times higher likelihood of all-cause mortality than those without anemia (HR 1.662; 95% CI: 1.154–2.394). Conclusion: Anemia is associated with an increased risk of all-cause mortality in Chinese centenarians. Further research will be needed to collect more comprehensive data on the etiology of anemia and causes of death in centenarians.

Gait analysis helps clinical assessment and achieves comfortable prosthetic designs for lower limb amputees, in which accurate gait phase recognition is a key component. However, gait phase detection remains a challenge due to the individual nature of prosthetic sockets and limbs. For the first time, we present a gait phase recognition approach for transfemoral amputees based on intra-socket pressure measurement. We proposed a multiple GMM-HMM (Hidden Markov Model with Gaussian Mixture Model emissions) method to label the gait events during walking. For each of the gait phases in the gait cycle, a separate GMM-HMM model is trained from the collected pressure data. We use gait phase recognition accuracy as a primary metric. The evaluation of six human subjects during walking shows a high accuracy of over 99% for single-subject, around 97.4% for multiple-subject, and up to 84.5% for unseen-subject scenarios. We compare our approach with the widely used CHMM (Continuous HMM) and LSTM (Long Short-term Memory) based methods, demonstrating better recognition accuracy performance across all scenarios.

This paper aims to assess the latest 1 km-grid Analysis Real Time (ART_1 km) precipitation product developed by the National Meteorological Information Center of China Meteorological Administration (CMA), which can provide great support for disaster weather monitoring and warning, intelligent grid forecasting and weather services. Observed precipitation data from the independent stations (including non-uploaded regional meteorological stations and hydrometric stations) that were not integrated into the ART_1 km precipitation product as well as precipitation classification inspection are used to assess the quality of this product during twenty disastrous rainstorm cases from May to August during 2019-2022 in Guangdong. The results show that the ART_1 km precipitation product successfully reproduces the precipitation location, strength, and trends in these cases, with the best performance in the Pearl River Delta, the east of eastern Guangdong, and the north of northern Guangdong. The stronger the precipitation, the greater the correlation as well as the root mean square error (RMSE) and mean error (ME) between the ART_1 km precipitation and the observed precipitation. When the hourly precipitation is not classified, about 60% of these independent stations present a correlation efficient ≥ 0.8, more than 90% of the stations present an RMSE within the range of [1.0, 5.0) mm, and more than 60% of the stations present a ME within ±0.1 mm. When the hourly precipitation is < 5 mm, most of the stations have a correlation efficient < 0.5, an RMSE within the range of [1.0, 5.0) mm, and a ME within [0.0, 0.5] mm. When the hourly precipitation is ≥ 20 mm, 42%~56% of the stations have a correlation efficient ≥ 0.5, and most of the stations have an RMSE ≥ 10 mm and a ME < 0 mm, even when the hourly precipitation is ≥ 50 mm, most of the stations have a ME < -10 mm. Overall, ART_1 km precipitation is usually underestimated at the independent stations, and integrating observations from more sites into producing ART_1 km precipitation is helpful to improve the quality of the products.

Abstract Severe combined immunodeficiency (SCID) encompasses a range of inherited disorders that lead to a profound deterioration of the immune system. Among the pivotal genes associated with SCID, RAG1 and IL2RG play crucial roles. IL2RG is essential for the development, differentiation, and functioning of T, B, and NK cells, while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes. Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. Non-human primates (NHPs) are exceptionally well-suited models for biomedical research due to their genetic and physiological similarities to humans. Cytosine base editors (CBEs) serve as powerful tools for precisely and effectively modifying single-base mutations in the genome. Their successful implementation has been demonstrated in human cells, mice, and crop species. This study outlines the creation of an immunodeficient monkey model by deactivating both the IL2RG and RAG1 genes using the CBE4max system. The base-edited monkeys exhibited a severely compromised immune system characterized by lymphopenia, atrophy of lymphoid organs, and a deficiency of mature T cells. Furthermore, these base-edited monkeys were capable of hosting and supporting the growth of human breast cancer cells, leading to tumor formation. In summary, we have successfully developed an immunodeficient monkey model with the ability to foster tumor growth using the CBE4max system. These immunodeficiency monkeys show tremendous potential as valuable tools for advancing biomedical and translational research.

BackgroundIncreased arterial stiffness and low handgrip strength (HGS) are associated with poor health outcomes and are a severe health risk for older adults. However, there is limited evidence and mixed results on whether there is an association between them. Therefore, this study focused on the association between arterial stiffness and HGS in relatively healthy older adults in Beijing, China.MethodsIn 2016, 2,217 adult volunteers were recruited in Beijing. Brachial-ankle pulse wave velocity (baPWV) and the ankle-brachial index were measured using an automatic vascular profiling system. Carotid artery intima-media thickness and common carotid artery-internal diameter (CCAID) were evaluated using Doppler ultrasound, and HGS was measured with a dynamometer. Low HGS was determined using the Asian Sarcopenia Working Group 2019 criteria. Multivariate linear and logistic regressions evaluated the relationship between arterial stiffness and HGS.ResultsUltimately, 776 relatively healthy older adults (mean age 69.05 ± 6.46 years) were included. Based on the AWGS2019 criteria, 137 participants were defined as having low HGS. Compared to the normal HGS group, the low HGS group was older and had higher baPWV (p

Abstract Thyroid-associated ophthalmopathy (TAO) is the most common autoimmune inflammatory diseases of the orbit. The CD40-CD40L pathway has been regarded as a potential molecular mechanism contributing to the development and progression of TAO, and RNA aptamers with specific binding affinity to CD40 (CD40Apt) represents a promising inhibitor of the CD40-CD40L signaling in TAO treatment. In this study, CD40Apt was confirmed to specifically recognize mouse CD40-positive ortibtal fibroblast. Mouse orbital fibroblasts were isolated from TAO mice model orbital tissues and validated. In TGF-β-induced orbital fibroblast activation model in vitro, CD40Apt administration inhibited TGF-β-induced cell viability, decreased TGF-β-induced α-SMA, Collagen I, Timp-1, and vimentin levels, and suppressed TGF-β-induced phosphorylation of Erk, p38, JNK, and NF-κB. In TAO mice model in vivo, CD40Apt caused no significant differences to the body weight of mice; furthermore, CD40Apt improved the eyelid broadening, ameliorated inflammatory infiltration and the hyperplasia in orbital muscle and adipose tissues in model mice. Concerning orbital fibroblast activation, CD40Apt reduced the levels of CD40, collagen I, TGF-β, and α-SMA in orbital muscle and adipose tissues of model mice. Finally, CD40Apt administration significantly suppressed Erk, p38, JNK, and NF-κB phosphorylation. In conclusion, CD40Apt, specifically binds to CD40 proteins in their natural state on the cell surface with high affinity, could suppress mouse orbital fibroblast activation, therefore improving TAO in mice model through the CD40 and downstream signaling pathways. CD40Apt represents a promising antagonist of the CD40-CD40L signaling for TAO treatment.

The use of human aging markers, which are physiological, biochemical and molecular indicators of structural or functional degeneration associated with aging, is the fundamental basis of individualized aging assessments. Identifying methods for selecting markers has become a primary and vital aspect of aging research. However, there is no clear consensus or uniform principle on the criteria for screening aging markers. Therefore, we combine previous research from our center and summarize the criteria for screening aging markers in previous population studies, which are discussed in three aspects: functional perspective, operational implementation perspective and methodological perspective. Finally, an evaluation framework has been established, and the criteria are categorized into three levels based on their importance, which can help assess the extent to which a candidate biomarker may be feasible, valid, and useful for a specific use context.

Abstract Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington's disease (HD) is characterized by the intracellular accumulation of mutant huntingtin (mHTT) that can be soluble and aggregated in the central nervous system and causes neuronal damage and death. Here, an intracellular antibody (intrabody) fragment is generated that can specifically bind mHTT and link to the lysosome for degradation. It is found that delivery of this peptide by either brain injection or intravenous administration can efficiently clear the soluble and aggregated mHTT by activating the lysosomal degradation pathway, resulting in amelioration of gliosis and dyskinesia in HD knock‐in (KI‐140Q) mice. These findings suggest that the small intrabody peptide linked to lysosomes can effectively lower mutant proteins and provide a new approach for treating neurodegenerative diseases that are caused by the accumulation of mutant proteins.

In this paper, a novel dual-three-phase dual-rotor flux-switching permanent magnet (PM) (DRFSPM) machine, building upon conventional FSPM machines, is proposed, where the stator is equipped with dual PMs and dual armature windings, enabling it to operate in various working modes and provide fault tolerance in the event of PM or armature winding faults. Depending on the magnetization directions of the PMs, the proposed DRFSPM machine’s structure can be categorized as 6N-DRFSPM or NS-DRFSPM. In order to assess the electromagnetic performance of the proposed DRFSPM machines with two different magnetizing modes, the topology and operating principle of the two DRFSPM machines are introduced first. Then, the no-load air-gap flux density of the two proposed machines is investigated for a more optimized and purposeful design. Finally, a comparison of the electromagnetic performance between the two proposed DRFSPM machines is conducted by finite-element analysis (FEA), and the FEA-predicted results indicate that the proposed 6N-DRFSPM machine outperforms the NS-DRFSPM machine, as it exhibits a larger back-EMF and average torque and a smaller cogging torque and torque ripple.

The ideas of transversals are important to study algebraic structures which are useful for investigating semirings structure. In this paper, we introduce and explore split additively orthodox semirings which are special semirings with transversals. After obtaining some property theorems of split additively orthodox semirings, the structure theorem for them is obtained by using idempotent semirings, additively inverse semirings, and Munn semigroup. It not only extends and strengthens the corresponding results of Clifford semirings and split orthodox semigroups but also develops a new way to study semirings.

Biological age (BA) is a common model to evaluate the function of aging individuals as it may provide a more accurate measure of the extent of human aging than chronological age (CA). Biological age is influenced by the used biomarkers and standards in selected aging biomarkers and the statistical method to construct BA. Traditional used BA estimation approaches include multiple linear regression (MLR), principal component analysis (PCA), Klemera and Doubal’s method (KDM), and, in recent years, deep learning methods. This review summarizes the markers for each organ/system used to construct biological age and published literature using methods in BA research. Future research needs to explore the new aging markers and the standard in select markers and new methods in building BA models.

A semiring (S,+,⋅) is called additively orthodox semiring if its additive reduct (S,+) is a orthodox semigroup. In this paper, by introducing some special semiring transversals as the tools, the constructions of additively orthodox semirings with a skew-ring transversal or with a generalized Clifford semiring transversal are established. Meanwhile, it is shown that an additively orthodox semiring with a generalized Clifford semiring transversal is a b-lattice of additively orthodox semirings with skew-ring transversals. Consequently, the corresponding results of Clifford semirings and generalized Clifford semirings in reference (M. K. Sen, S. K. Maity, K. P. Shum, Clifford semirings and generalized Clifford semirings, Taiwan. J. Math., 9 (2005), 433–444) and completely regular semirings in reference (S. K. Maity, M. K. Sen, K. P. Shum, On completely regular semirings, Bull. Cal. Math. Soc., 98 (2006), 319–328) are extended and strengthened.

Animal models are important for understanding the pathogenesis of human diseases and for developing and testing new drugs. Pigs have been widely used in the research on the cardiovascular, skin barrier, gastrointestinal, and central nervous systems as well as organ transplantation. Recently, pigs also become an attractive large animal model for the study of neurodegenerative diseases because their brains are very similar to human brains in terms of mass, gully pattern, vascularization, and the proportions of the gray and white matters. Although adeno-associated virus type 9 (AAV9) has been widely used to deliver transgenes in the brain, its utilization in large animal models remains to be fully characterized. Here, we report that intravenous injection of AAV9-GFP can lead to widespread expression of transgene in various organs in the pig. Importantly, GFP was highly expressed in various brain regions, especially the striatum, cortex, cerebellum, hippocampus, without detectable inflammatory responses. These results suggest that intravenous AAV9 administration can be used to establish large animal models of neurodegenerative diseases caused by gene mutations and to treat these animal models as well.

Background and objectiveMetabolic syndrome (MetS) is an important risk factor for cardiovascular complications and kidney damage. Obesity- and lipid-related indices are closely related to MetS, and different indices have different predictive abilities for MetS. This study aimed to evaluate the predictive value of eight obesity- and lipid-related indicators, namely, body mass index (BMI), lipid accumulation product (LAP), body roundness index (BRI), Chinese visceral adiposity index (CVAI), body adiposity index (BAI), abdominal volume index (AVI), triglyceride glucose index (TYG), and visceral adiposity index (VAI), for MetS.MethodsA total of 1,452 relatively healthy people in Beijing were enrolled in 2016, and the correlation between the eight indicators and MetS was analyzed by multivariate logistic regression. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to analyze the predictive ability of the eight indicators for MetS. The Delong test was used to compare the AUC values of the eight indicators. MetS was defined according to the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 edition), the revised National Cholesterol Education Program Adult Treatment Group (NCEP-ATPIII), and the International Diabetes Federation (IDF).ResultsUsing these three sets of criteria, LAP, TYG, CVAI, and VAI, which are based on blood lipids, had higher AUC values for MetS prediction than BMI, BRI, AVI, and BAI, which are based on anthropometry. LAP had the highest AUC values of 0.893 (0.874–0.912), 0.886 (0.869–0.903), and 0.882 (0.864–0.899), separately, based on the three sets of criteria.ConclusionThe eight obesity- and lipid-related indicators had screening value for MetS in relatively healthy people, and of the eight indicators, LAP performed the best.

Photovoltaic (PV) power generation is considered to be a clean energy source. Solar modules suffer from nonlinear behavior, which makes the maximum power point tracking (MPPT) technique for efficient PV systems particularly important. Conventional MPPT techniques are easy to implement but require fine tuning of their fixed step size. Unlike conventional MPPT, the MPPT based on reinforcement learning (RL-MPPT) has the potential to self-learn to tune step size, which is more adaptable to changing environments. As one of the typical RL algorithms, the Q-learning algorithm can find the optimal control strategy through the learned experiences stored in a Q-table. Thus, as the cornerstone of this algorithm, the Q-table has a significant impact on control ability. In this paper, a novel Q-table of reinforcement learning is proposed to maximize tracking efficiency with improved Q-table update technology. The proposed method discards the traditional MPPT idea and makes full use of the inherent characteristics of the Q-learning algorithm such as its fast dynamic response and simple algorithm principle. By establishing six kinds of Q-tables based on the RL-MPPT method, the optimal discretized state of a photovoltaic system is found to make full use of the energy of the photovoltaic system and reduce power loss. Therefore, under the En50530 dynamic test standard, this work compares the simulation and experimental results and their tracking efficiency using six kinds of Q-table, individually.

BackgroundThe disease pathology for diabetes mellitus patients with chronic kidney disease (CKD) may be diabetic nephropathy (DN), non-diabetic renal disease (NDRD), or DN combined with NDRD. Considering that the prognosis and treatment of DN and NDRD differ, their differential diagnosis is of significance. Renal pathological biopsy is the gold standard for diagnosing DN and NDRD. However, it is invasive and cannot be implemented in many patients due to contraindications. This article constructed a new noninvasive evaluation model for differentiating DN and NDRD.MethodsWe retrospectively screened 1,030 patients with type 2 diabetes who has undergone kidney biopsy from January 2005 to March 2017 in a single center. Variables were ranked according to importance, and the machine learning methods (random forest, RF, and support vector machine, SVM) were then used to construct the model. The final model was validated with an external group (338 patients, April 2017–April 2019).ResultsIn total, 929 patients were assigned. Ten variables were selected for model development. The areas under the receiver operating characteristic curves (AUCROCs) for the RF and SVM methods were 0.953 and 0.947, respectively. Additionally, 329 patients were analyzed for external validation. The AUCROCs for the external validation of the RF and SVM methods were 0.920 and 0.911, respectively.ConclusionWe successfully constructed a predictive model for DN and NDRD using machine learning methods, which were better than our regression methods.Clinical Trial RegistrationClinicalTrial.gov, NCT03865914.

Background: A meta-analysis was performed to evaluate the association of chronic kidney disease (CKD) and acute kidney injury (AKI) with the clinical prognosis of patients with coronavirus disease 2019 (COVID-19). Methods: The PubMed, EMBASE, Cochrane Library, medRxiv, Social Science Research Network, and Research Square databases (from December 1, 2019 to May 15, 2020) were searched to identify studies that reported the associations of CKD/AKI and disease severity/mortality. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and meta-regression was performed. Results: In total, 42 studies enrolling 8,932 participants were included in this meta-analysis. The quality of most included studies was moderate to high. Compared with patients without previously diagnosed CKD, those with CKD had a significantly increased risk of progressing to a severe condition (OR 2.31, 95% CI 1.64–3.24) or death (OR 5.11, 95% CI 3.36–7.77). Similarly, compared with patients without AKI, those with AKI had a significantly increased risk of progressing to a severe condition (OR 11.88, 95% CI 9.29–15.19) or death (OR 30.46, 95% CI 18.33–50.59). Compared with patients with previously diagnosed CKD, those with AKI were more likely to progress to a severe condition (pgroup < 0.001, I2 = 98.3%) and even to death (pgroup < 0.001, I2 = 96.5%). Age had a significant impact on the association between CKD and disease severity (p = 0.001) but had no impact on the associations between AKI and disease severity (p = 0.80), between CKD and mortality (p = 0.51), or between AKI and mortality (p = 0.86). Four important complications (cardiac injury, shock, acute respiratory distress syndrome, and liver injury) did not significantly affect the associations between CKD/AKI and disease severity/mortality, indicating that CKD/AKI may be independent clinical prognostic indicators for patients with COVID-19. Conclusions: In COVID-19 patients, CKD/AKI was associated with worse outcomes compared with those without CKD/AKI. AKI was associated with higher risks of severity and mortality than CKD.

Let Σ+ be the set of all finite words over a finite alphabet Σ. A word u is called a strict prefix of a word v, if u is a prefix of v and there is no other way to show that u is a subword of v. A language L⊆Σ+ is said to be prefix-strict, if for any u,v∈L, u is a subword of v always implies that u is a strict prefix of v. Denote the class of all prefix-strict languages in Σ+ by P(Σ+). This paper characterizes P(Σ+) as a universe of a model of the free object for the ai-semiring variety satisfying the additional identities x+yx≈x and x+yxz≈x. Furthermore, the analogous results for so-called suffix-strict languages and infix-strict languages are introduced.