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Background: Programmed cell death protein-1 inhibitors combined with lenvatinib have become a popular treatment option for patients with unresectable hepatocellular carcinoma. Transarterial chemoembolization combined with programmed cell death protein-1 inhibitors and lenvatinib has also shown preliminary efficacy in the unresectable hepatocellular carcinoma. We conducted this observational, retrospective, cohort study to compare the clinical outcomes and safety of transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib versus programmed cell death protein-1 inhibitors plus lenvatinib in patients with unresectable hepatocellular carcinoma. Methods: Between November 2019 and November 2021, patients who were diagnosed with unresectable hepatocellular carcinoma and received transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib or programmed cell death protein-1 inhibitors plus lenvatinib treatment were reviewed for eligibility. The primary endpoints included objective response rate, overall survival, and progression-free survival. The secondary endpoint was the frequency of key adverse events. Results: In total, 105 patients were eligible for the present study, and they were divided into the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group (n = 46) and the programmed cell death protein-1 inhibitors plus lenvatinib group (n = 59). The patient cohort after a one-to-one propensity score matching (n = 86) was also analyzed. The transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had a higher objective response rate both in the patient cohort before propensity score matching (54.3% vs 25.4%, P = .002) and after propensity score matching (55.8% vs 30.2%, P = .017). The patients in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group had prolonged overall survival (median, 20.5 vs 12.6 months, P = .015) and progression-free survival (median, 10.2 vs 7.4 months, P = .035). For patient cohort- propensity score matching, the overall survival (20.5 vs 12.8 months, P = .013) and progression-free survival (12.1 vs 7.8 months, P = .030) were also significantly better in the transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib group than in the programmed cell death protein-1 inhibitors plus lenvatinib group. There were no significant differences between the 2 groups concerning adverse reactions caused by immunotherapy and lenvatinib. The adverse reactions caused by transarterial chemoembolization were transient and were quickly reversed. Conclusions: Compared to programmed cell death protein-1 inhibitors plus lenvatinib, transarterial chemoembolization combined with programmed cell death protein-1 inhibitors plus lenvatinib may provide better treatment response and survival benefits for patients with unresectable hepatocellular carcinoma, and the adverse events were manageable.

Background: Elevated level of interleukin-8 (IL-8) promotes hepatocellular carcinoma (HCC) development and contributes to poor prognosis. Previously, we have proved that Dicer inhibits HCC progression. In this study, we evaluated the potential interaction between IL-8 and Dicer as well as their influence on HCC. Methods: Hepatocellular carcinoma cells of SMMC-7721 were divided into 2 groups for subsequent analysis: pCMV-Dicer group for Dicer-overexpressing lentivirus transfected cells (pCMV-Dicer cells) and pCMV-NC group for empty lentivirus transfected cells (pCMV-NC cells). Cell Counting kit-8 (CCK8), wound healing, and transwell were used to evaluate the inhibitory effect of Dicer overexpression on proliferation, migration, and invasion of HCC cells. The level of IL-8 was measured by flow cytometry bead-based immunoassays. Male nude BALB/c mice injected with pCMV-Dicer or pCMV-NC cell suspensions was used for transplant of HCC tumor. Results: We found that the secretion of IL-8 was reduced in the medium of pCMV-Dicer cells ( P = .027). Recombinant human IL-8 (rhIL-8) reversed the inhibitory effect of Dicer on proliferation ( P < .01), migration ( P = .003), and invasion ( P = .001), whereas IL-8 inhibitor of reparixin enhanced inhibitory effect of Dicer on proliferation ( P < .05), migration ( P = .008), and invasion ( P = .000). Lenvatinib downregulated the IL-8 level of HCC cells ( P = .000) as well as promote Dicer-induced inhibition for HCC cells referring to proliferation ( P < .05), migration ( P = .000), and invasion ( P = .000). Animal experiments also demonstrated that Dicer cooperated with lenvatinib to inhibit the growth of HCC tumors ( P < .05). Conclusions: Dicer cooperated with lenvatinib to inhibit HCC growth via downregulating IL-8, and Dicer displayed its potential capability to enhance the anti-tumor effect of lenvatinib.

Objective To retrospectively analyze and compare the relationship between the success rate of patient‐derived xenograft (PDX) modeling of osteosarcoma and prognosis (3‐year overall survival rate and disease‐free survival rate) and incidence of lung metastasis. Methods The sample group consisted of 57 osteosarcoma patients with definite pathological diagnoses from Shanghai General Hospital from 2015–2017. PDX models in 57 patients were analyzed by retrospective analyses. Among the patients currently inoculated, 20 were tumorigenic in the PDX model, and 37 were nontumorigenic. According to the tumorigenicity of PDXs, the corresponding osteosarcoma patients were divided into two groups. The effects of clinically related indicators on the model were retrospectively compared. The patients were followed, and the 3‐year survival, 3‐year disease‐free survival (DFS), and lung metastasis rates were collected. The relationship between the modeling success and patient prognosis was investigated. Results In the chemotherapy‐treated group, the PDX modeling success rate was 17.4%, and in the nonchemotherapy group, the success rate was 47.1%. The success of PDX modeling was related to whether patients received chemotherapy. The success rate of PDX modeling is significantly reduced after receiving chemotherapy. The 3‐year overall survival rate of the PDX‐grafted group was 49.23%, and that of the PDX‐nongrafted group was 65.71%. There was a significant difference between the two groups, showing a strong negative correlation between the 3‐year survival rate and the success rate of the PDX model. The 3‐year disease‐free survival rate of the PDX‐grafted group was 29.54%. The 3‐year DFS of the PDX‐nongrafted group was 50.34%. There was a significant difference between the two groups. Lower grafted rates indicate a higher DFS rate. The incidence of lung metastasis in the PDX‐grafted group was 32.4%, and that in the nongrafted group was 13.1%. There was a significant difference between the two groups. The successful establishment of the PDX model indicates that patients are more likely to have lung metastases. Conclusions The success of PDX modeling often indicates poor prognosis (low 3‐year overall survival rate and disease‐free survival rate) and a greater possibility of lung metastasis. Therefore, PDX modeling in osteosarcoma patients can accurately predict the prognosis of patients and the risk of lung metastasis in advance to help us develop better therapeutic strategies.

Abstract Aim The purpose of this qualitative study was to describe the health‐promoting behaviours of patients with hyperuricaemia and influencing factors. Design A descriptive qualitative design was used to gain insight into the personal experience of health promotion behaviour in patients with hyperuricaemia. Methods Sixteen patients were sampled in face‐to‐face interviews with maximum variation, and the data were transcribed verbatim. The data analysis was based on the phrases of thematic analysis outlined by Braun and Clarke (2006). Results Four main themes were identified in the data: (a) Perception of disease; (b) Motivation to change health‐promoting behaviour; (c) Strategies for health‐promoting behaviour; and (d) Encounter obstacles to change health‐promoting behaviour.

Shallowwater depth plays an important role in marine development, navigation safety, and environmental protection. It is an efficient and economical way to obtain water depth by remote sensing technology. At present, most empirical models based on multispectral image usually obtain water depth by the relationship between the sea surface reflectance (SSR) (a single pixel) and in situ water depth, it is a one-to-one correspondence between the reflectance and depth. However, seafloor substrate and inherent optical properties (IOP) will also have contribution to the SSR. In this article, we propose an adjacent pixels multilayer perceptron model (APMLP) model using adjacent pixels to weaken the influence of seafloor substrate and IOP.Datasets on Oahu Island (Sentinel-2B, LIDAR in situ data) and Saint Thomas Island (Sentinel-2A, LIDAR in situ data) are used to establish and verify the model. The APMLP model are also compared with the multilayer perceptron model (MLP) model, BP neural network model, and Log-ratio model. The overall root-mean-square error (RMSE) of APMLP model on Oahu Island is 0.72 m, which is much better than the other three models (MLP 1.07 m, BP 1.05 m, Log-ratio 1.52 m). Similar results are obtained from the Saint Thomas Island dataset, RMSE of APMLP model is 1.56 m, better than the other three (MLP 1.91 m, BP 1.89 m, Log-ratio 2.39 m). The study confirms that considering adjacent pixels in an artificial neural network model can effectively improve the performance of water depth retrieval.

The ultrastrong gradient nanostructured dual-phase high entropy alloy (DP-HEA) Fe50Mn30Co10Cr10 has been fabricated by an efficient surface nanocrystallization method, e.g. ultrasonic shot peeing (USP) at room temperature. We investigated the effect of the USP duration on the microstructure of the DP-HEA Fe50Mn30Co10Cr10 by the advanced materials characterization methods, e.g. Electron Backscatter Diffraction (EBSD), X-ray Diffraction (XRD), and Transmission Electron Microscopy (TEM). We found that the microstructure of the USPed DP-HEA Fe50Mn30Co10Cr10 can be refined into several nanometers. Additionally, the FCC γ phase is transferred into the HCP ε phase during the USP process of the DP-HEA Fe50Mn30Co10Cr10 and the portion of the HCP ε phase increases gradually with the increase of the USP duration. Nanoindentation tests indicate that the nanohardness of the nanostructured DP-HEA Fe50Mn30Co10Cr10 can reach as high as 7.49 GPa, suggesting a yield strength of 2.49 GPa, which is 10 times higher than that of the coarse-grained materials. Additionally, nanocrystallization of the DP-HEA Fe50Mn30Co10Cr10 can be triggered with a short peening duration and the transformation-induced plasticity (TRIP) effect can benefit the formation of a thick gradient nano-grained layer during USP. Micro-tensile tests revealed that the gradient nano-grained layer can significantly improve the yield strength of the DP-HEA Fe50Mn30Co10Cr10 with sacrificing ductility.

Abstract Reducing the dielectric constant and loss of cellulose insulation can make the electric field distribution uniform in oil‐paper insulation systems and decrease the heat generation in dielectric materials, thus ensuring a reliable transformer operation. To guide the experimental design from the molecular level, the fluctuation method was introduced into the molecular dynamics simulation to evaluate the static permittivity of cellulose insulation, εs. The correlation between the dynamics parameter mean square displacement (MSD) and dielectric loss induced by orientational polarization, was investigated. The simulation results and experimental values of five types of cellulose insulation were compared to verify the rationality of the proposed method. The results indicated that the simulation values of εs for five models were agreed well with the experimental values in terms of both the magnitude and the variation trend. The simulation time and permittivity of the surrounding medium εRF are two key parameters, which determine the accuracy of the simulation results of εs. Considering the convergence, 15 ns was chosen as the lower limit of simulation time. The reaction field approximation was adopted to calculate the dipole‐dipole interaction instead of true interaction, that is, εRF→∞. The MSD results reproduced the experimental trend in dielectric loss, indicating that the method can qualitatively predict the dielectric loss of cellulose insulation. Hence, these methods are sufficient to guide design experiments and provide a route to understand the mechanism of the change in dielectric properties at the molecular level.

BackgroundHand, foot, and mouth disease (HFMD) is a serious threat among children in China. Some studies have found that air pollution is associated with HFMD incidence, but the results showed heterogeneity. In this study, we aimed to explore the heterogeneity of associations between air pollutants and the number of HFMD cases and to identify significant socioeconomic effect modifiers.MethodsWe collected daily surveillance data on HFMD cases in those aged less than 15 years, air pollution variables and meteorological variables from 2015 to 2017 in the basin area of Sichuan Province. We also collected socioeconomic indicator data. We conducted a two-stage multicity time-series analysis. In the first stage, we constructed a distributed lag nonlinear model (DLNM) to obtain cumulative exposure-response curves between each air pollutant and the numbers of HFMD cases for every city. In the second stage, we carried out a multivariable meta-regression to merge the estimations in the first stage and to identify significant socioeconomic effect modifiers.ResultsWe found that PM10, NO2 and O3 concentrations were associated with the number of HFMD cases. An inverted V-shaped association between PM10 and the number of HFMD cases was observed. The overall NO2-HFMD association was a hockey-stick shape. For the relationships of PM10, SO2, NO2, O3 and CO with HFMD counts, approximately 58.5%, 48.4%, 51.0%, 55.6% and 52.5% of the heterogeneity could be explained, respectively. The proportion of primary school students, population density, urbanization rate, number of licensed physicians and number of hospital beds explained part of the heterogeneity and modified the relationships.ConclusionOur study explored the heterogeneity of associations between air pollutants and HFMD counts. The proportion of primary school students, population density, urbanization rate, number of licensed physicians and number of hospital beds could modify the relationships. The results can serve as a reference for relevant public health decision making.

Early adversity can cause malfunction of the visual system in adulthood. Adult female but not male mice undergoing early chronic mild stress (ECMS) maintain ocular dominance (OD) plasticity after the critical period. How early stressful experiences have a long-term impact on it is largely unknown. Here, we observed a wide distribution of corticotropin-releasing factor (CRF)-positive neurons, which mainly colocalized with a subpopulation of GABAergic interneurons in the mouse primary visual cortex (V1). Optogenetic activation of CRF-positive neurons transfected with AAV-ChR2 evoked inhibitory currents in nearby pyramidal cells. ECMS induced a reduction in the expression of CRF mRNA in adult mouse V1. Chemogenetic activation of V1 CRF neurons impaired OD plasticity in adult ECMS females. We further showed that local administration of the corticotropin releasing factor receptor 1 (CRFR1) antagonist via an osmotic minipump into the visual cortex mimicked OD plasticity in adult ECMS females. Whole-cell recording in layer 2/3 pyramidal neurons revealed that the CRFR1 antagonist reduced the short-term depression (STD) of evoked inhibitory postsynaptic current (IPSC) in females but not in males. Likewise, CRF agonists have the opposite effect. In summary, our findings indicate that the local CRF-CRFR1 system within V1 may mediate the long-term and sex-dependent effect of early stress experiences on visual plasticity and provide a target for the prevention of visual deficits in adults with a history of early-life adversity.

Objectives Hand, foot, and mouth disease (HFMD) is a viral infectious disease that poses a substantial threat in the Asia-Pacific region. It is widely reported that meteorological factors are associated with HFMD. However, the relationships between air pollutants and HFMD are still controversial. In addition, the interactive effects between meteorological factors and air pollutants on HFMD remain unknown. To fill this research gap, we conducted a time-series study.Design A time-series study.Setting and participants Daily cases of HFMD as well as meteorological and air pollution data were collected in Chengdu from 2011 to 2017. A total of 184 610 HFMD cases under the age of 15 were included in our study.Outcome measures Distributed lag nonlinear models were used to investigate the relationships between HFMD and environmental factors, including mean temperature, relative humidity, SO2, NO2, and PM10. Then, the relative excess risk due to interaction (RERI) and the proportion attributable to interaction were calculated to quantitatively evaluate the interactions between meteorological factors and air pollutants on HFMD. Bivariate response surface models were used to visually display the interactive effects.Results The cumulative exposure–response curves of SO2 and NO2 were inverted ‘V’-shaped and ‘M’-shaped, respectively, and the risk of HFMD gradually decreased with increasing PM10 concentrations. We found that there were synergistic interactions between mean temperature and SO2, relative humidity and SO2, as well as relative humidity and PM10 on HFMD, with individual RERIs of 0.334 (95% CI 0.119 to 0.548), 0.428 (95% CI 0.214 to 0.642) and 0.501 (95% CI 0.262 to 0.741), respectively, indicating that the effects of SO2 and PM10 on HFMD were stronger under high temperature (>17.3°C) or high humidity (>80.0%) conditions.Conclusions There were interactive effects between meteorological factors and air pollutants on HFMD. Our findings could provide guidance for targeted and timely preventive and control measures for HFMD.

Background and Objective: This study aims to find the key immune genes and mechanisms of low bone mineral density (LBMD) in ankylosing spondylitis (AS) patients.Methods: AS and LBMD datasets were downloaded from the GEO database, and differential expression gene analysis was performed to obtain DEGs. Immune-related genes (IRGs) were obtained from ImmPort. Overlapping DEGs and IRGs got I-DEGs. Pearson coefficients were used to calculate DEGs and IRGs correlations in the AS and LBMD datasets. Louvain community discovery was used to cluster the co-expression network to get gene modules. The module most related to the immune module was defined as the key module. Metascape was used for enrichment analysis of key modules. Further, I-DEGs with the same trend in AS and LBMD were considered key I-DEGs. Multiple machine learning methods were used to construct diagnostic models based on key I-DEGs. IID database was used to find the context of I-DEGs, especially in the skeletal system. Gene–biological process and gene-pathway networks were constructed based on key I-DEGs. In addition, immune infiltration was analyzed on the AS dataset using the CIBERSORT algorithm.Results: A total of 19 genes were identified I-DEGs, of which IFNAR1, PIK3CG, PTGER2, TNF, and CCL3 were considered the key I-DEGs. These key I-DEGs had a good relationship with the hub genes of key modules. Multiple machine learning showed that key I-DEGs, as a signature, had an excellent diagnostic performance in both AS and LBMD, and the SVM model had the highest AUC value. Key I-DEGs were closely linked through bridge genes, especially in the skeletal system. Pathway analysis showed that PIK3CG, IFNAR1, CCL3, and TNF participated in NETs formation through pathways such as the MAPK signaling pathway. Immune infiltration analysis showed neutrophils had the most significant differences between case and control groups and a good correlation with key I-DEG.Conclusion: The key I-DEGs, TNF, CCL3, PIK3CG, PTGER2, and IFNAR1, can be utilized as biomarkers to determine the risk of LBMD in AS patients. They may affect neutrophil infiltration and NETs formation to influence the bone remodeling process in AS.

Objective: Mutations in γ-aminobutyric acid (GABA) transporter 1 (GAT-1)-encoding SLC6A1 have been associated with myoclonic atonic epilepsy and other phenotypes. We determined the patho-mechanisms of the mutant GAT-1, in order to identify treatment targets. Methods: We conducted whole-exome sequencing of patients with myoclonic atonic epilepsy (MAE) and characterized the seizure phenotypes and EEG patterns. We studied the protein stability and structural changes with homology modeling and machine learning tools. We characterized the function and trafficking of the mutant GAT-1 with 3H radioactive GABA uptake assay and confocal microscopy. We utilized different models including a knockin mouse and human astrocytes derived from induced pluripotent stem cells (iPSCs). We focused on astrocytes because of their direct impact of astrocytic GAT-1 in seizures. Results: We identified four novel SLC6A1 variants associated with MAE and 2 to 4 Hz spike-wave discharges as a common EEG feature. Machine learning tools predicted that the variant proteins are destabilized. The variant protein had reduced expression and reduced GABA uptake due to endoplasmic reticular retention. The consistent observation was made in cortical and thalamic astrocytes from variant-knockin mice and human iPSC-derived astrocytes. The Slc6a+/A288V mouse, representative of MAE, had increased 5–7 Hz spike-wave discharges and absence seizures. Interpretation: SLC6A1 variants in various locations of the protein peptides can cause MAE with similar seizure phenotypes and EEG features. Reduced GABA uptake is due to decreased functional GAT-1, which, in thalamic astrocytes, could result in increased extracellular GABA accumulation and enhanced tonic inhibition, leading to seizures and abnormal EEGs.

Finding field management techniques that increase crop output while protecting soil sustainability is essential for maintaining a long-term food supply in a changing environment. However, comprehensive evaluation of the effects of nitrogen (N) reduction combined with organic fertilizer on grain yield, N use efficiency (NUE), water use efficiency (WUE), and soil organic carbon (SOC) and total N (TN) contents of winter wheat–summer maize double cropping systems in drought-prone areas remains limited. Therefore, a 3-year field experiment (2018–2021) was conducted in a winter wheat–summer maize double cropping system with five treatments: no N fertilizer (CK), conventional farmer fertilization (CF), recommended fertilization (R), organic N substitution of 20% of the recommended synthetic N (R20), and organic N substitution of 40% of the recommended synthetic N (R40). When results were averaged from 2018 to 2021, R20 had the highest annual grain yield, which increased by 42.15%, 7.69%, 7.58%, and 12.50% compared with CK, CF, R, and R40, respectively. Compared with CF, R20 increased winter wheat and summer maize NAE, NPFP, NUE, and WUE. In addition, the soil organic carbon content of R20 and R40 treatment increased with the increase in years. In conclusion, R20 was considered ideal for improving crop yield, promoting soil fertility, and increasing the fertilizer utilization rate in a semiarid winter wheat–summer maize rotation.

The effects of electroshocking treatment (EST) direction on microstructure and hardness of TC11 alloy (Ti-6.5Al-3.5Mo-1.5Zr-0.3Si) were investigated. The results indicated that the temperature of specimens under EST along the transverse direction (T-EST) was higher than that under EST along the vertical direction (V-EST). The studies reveal the higher quantity of needle-like α martensite (αM) phases precipitated in the specimen in the case of T-EST as compared with V-EST, with a more uniform distribution of αM phases. The average Vickers hardness of specimens under T-EST and V-EST with 0.06 s were 349.3 HV and 360.8 HV, respectively, which showed an obvious increase compared to the untreated specimen. The increase in hardness was ascribed to the dispersion strengthening of needle-like αM phase, and the dispersion strengthening effect on the specimen under T-EST with 0.06 s was more obvious than on the other specimens, which was caused by a large number of evenly distributed nucleation areas for the precipitation of the αM phase and uniform distribution of the αM phase. The results indicate that a different treatment direction of EST can promote the formation of different microstructures in TC11 alloy, which demonstrates that the effect of EST cannot be simply equated with heat treatment at the same temperature.

Abstract Background SYN1 encodes synapsin I, which is a neuronal phosphoprotein involving in regulating axonogenesis and synaptogenesis. Variants in the gene have been associated with X-linked neurodevelopmental disorders in recent years. Methods In the study, we reported two male patients with familial SYN1 variants related neurodevelopmental disorders from Asian population. Previously published cases with significant SYN1 variants from the literature were also included to analyze the phenotype and genotype of the disorder. Results Two maternally inherited SYN1 variants, including c.C1076A, p.T359K in proband A and c.C1444T, p. Q482X in proband B (NM_133499) were found, which have never been described in detail. Combining with our research, all reported probands were male in the condition, whose significant SYN1 variants were inherited from their asymptomatic or mild affected mother. Although the disorder encompasses three main clinical presentations: mental deficiency, easily controlled reflex seizure and behavior problems, patients’ clinical manifestations vary in genders and individuals, even in the same pedigree. Conclusion We firstly reported two familial SYN1-related neurodevelopmental disorders in Asian pediatric patients. Gender and phenotype differences should be highly valued in the disorder.

BackgroundAttention-deficit/hyperactive disorder (ADHD) is a neurodevelopmental disorder that commonly occurs in children with a prevalence ranging from 3.4 to 7.2%. It profoundly affects academic achievement, well-being, and social interactions. As a result, this disorder is of high cost to both individuals and society. Despite the availability of knowledge regarding the mechanisms of ADHD, the pathogenesis is not clear, hence, the existence of many challenges especially in making correct early diagnosis and provision of accurate management.ObjectivesWe aimed to review the pathogenic pathways of ADHD in children. The major focus was to provide an update on the reported etiologies in humans, animal models, modulators, therapies, mechanisms, epigenetic changes, and the interaction between genetic and environmental factors.MethodsReferences for this review were identified through a systematic search in PubMed by using special keywords for all years until January 2022.ResultsSeveral genes have been reported to associate with ADHD: DRD1, DRD2, DRD4, DAT1, TPH2, HTR1A, HTR1B, SLC6A4, HTR2A, DBH, NET1, ADRA2A, ADRA2C, CHRNA4, CHRNA7, GAD1, GRM1, GRM5, GRM7, GRM8, TARBP1, ADGRL3, FGF1, MAOA, BDNF, SNAP25, STX1A, ATXN7, and SORCS2. Some of these genes have evidence both from human beings and animal models, while others have evidence in either humans or animal models only. Notably, most of these animal models are knockout and do not generate the genetic alteration of the patients. Besides, some of the gene polymorphisms reported differ according to the ethnic groups. The majority of the available animal models are related to the dopaminergic pathway. Epigenetic changes including SUMOylation, methylation, and acetylation have been reported in genes related to the dopaminergic pathway.ConclusionThe dopaminergic pathway remains to be crucial in the pathogenesis of ADHD. It can be affected by environmental factors and other pathways. Nevertheless, it is still unclear how environmental factors relate to all neurotransmitter pathways; thus, more studies are needed. Although several genes have been related to ADHD, there are few animal model studies on the majority of the genes, and they do not generate the genetic alteration of the patients. More animal models and epigenetic studies are required.

Myasthenia gravis is an organ-specific autoimmune disease. Currently there is no universal guidelines for childhood-onset myasthenia gravis, therefore, treatment strategies are usually based on the guidelines from adult myasthenia gravis patients. In order to contribute in the process of the development of the universal childhood-onset myasthenia gravis guideline, we have summarized the clinical characteristics, treatment strategies, outcome and the related predictors of childhood-onset myasthenia gravis. We recruited 343 childhood-onset myasthenia gravis cases who were followed up at the Department of Pediatrics, Xiangya Hospital from June, 2010 to December, 2019. The data about clinical characteristics, treatments and outcome were collected and analyzed. Among of the 343 cases, 164 cases were followed up for longer than 2 years, of whom 142 still remained with ocular myasthenia gravis at the endpoint. About the treatments, 27 cases (27/164) accepted pyridostigmine only while the rest accepted glucocorticoid and/or other immunosuppressants. At the endpoint, the proportion of optimal outcome was 66.2% in the group remaining with ocular myasthenia gravis and 31.8% in the generalized myasthenia gravis group. Multivariate logistic regression analysis revealed that generalized myasthenia gravis type and positive status of antibodies against acetylcholine receptors were the independent risk factors for poor outcome. In conclusion, our childhood-onset myasthenia gravis patients present mainly as ocular myasthenia gravis, adequate immunotherapy improve the long-term outcome, and generalized myasthenia gravis phenotype as well as positive status of antibodies against acetylcholine receptors relate to poor outcome.

ObjectiveAlthough many unexplained intellectual disability/global developmental delay (ID/GDD) individuals have benefited from the excellent detection yield of copy number variations and next-generation sequencing testing, many individuals still who suffer from ID/GDD of unexplained etiology. In this study, we investigated the applicability of fragile X syndrome (FXS) testing in unexplained ID/GDD individuals with negative or absent genetic testing.MethodsIn this study, we used the triplet repeat primed polymerase chain reaction to evaluate the value and application of fragile X testing in unexplained ID/GDD individuals with negative or absent genetic testing (n = 681) from three hospitals.ResultsOf the 681 ID/GDD individuals with negative or absent genetic testing results detected by FXS testing, 12 men and one woman were positive. This corresponded to a diagnostic yield of 1.9% for FXS testing in our cohort. All FXS individuals had either a family history of ID/GDD or suggestive clinical features. The detection yield of FXS testing in ID/GDD individuals who completed genetic testing (2.70%, 12/438) was significantly higher than in individuals without any genetic testing (0.40%, 1/243).ConclusionsThis is the first report of FXS testing in ID/GDD individuals who lacked previous genetic testing, which promotes standardization of the FXS diagnostic process. These results highlight the utility of FXS testing of unexplained ID/GDD individuals with negative results from standard genetic testing. In the era of next-generation sequencing, FXS testing is more suitable as a second-tier choice and provides clinicians and geneticists with auxiliary references for tracing the etiology of ID/GDD.

Abstract Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

Abstract The WHO has described coronavirus disease 2019 (COVID-19) as a pandemic due to the speed and scale of its transmission. Without effective interventions, the rapidly increasing number of COVID-19 cases would greatly increase the burden of clinical treatments. Identifying the transmission sources and pathways is of vital importance to block transmission and allocate limited public health resources. According to the relationships among cases, we constructed disease transmission network graphs for the COVID-19 epidemic through a visualization technique based on individual reports of epidemiological data. We proposed an analysis strategy of the transmission network with the epidemiological data in Tianjin and Chengdu. The transmission networks showed different transmission characteristics. In Tianjin, an imported case of COVID-19 can produce an average of 2.9 secondary infections and ultimately produce as many as 4 generations of infections, with a maximum of 6 cases being generated before the imported case is identified. In Chengdu, 45 noninformative cases and 24 cases with vague exposure information made accurate information about the transmission network difficult to provide. The proposed analysis framework of visualized transmission networks can trace the transmission source and contacts, assess the current situation of transmission and prevention, and provide evidence for the global response and control of the COVID-19 pandemic.

The frequent occurrence of meteorological disasters in China has caused huge losses to agriculture. Risk assessment serves as a bridge from disaster crisis management to disaster risk management. Therefore, it is necessary to carry out a refined comprehensive risk assessment of meteorological disasters in typical areas. However, several limitations remain in the disaster loss risk research, such as too coarse resolution and too single risk indicator. Additionally, less research has examined geographical information on risk clustering and barycenter migration, as well as temporal information on the sustainability of trends. Consequently, it is significant to unearth the geographical and temporal information on disaster loss and identify the refined spatial and temporal evolution pattern of crop risk. For this reason, we evaluated the risk of corn production in Gansu Province. First, based on maize yield data, a risk evaluation index system was constructed using the characteristics of variation trends, fluctuations, and extreme values of disaster losses. Then, the spatial distribution patterns and temporal evolution characteristics of maize production risks on a county scale in Gansu Province were determined using spatial analysis and climate diagnosis technology. The results show that there is a large interdecadal fluctuation in risk. In the 1980s, 1990s, 2000s, and 2010s, the average yield reduction rates of maize in Gansu Province were −11.8%, −12.6%, −8.7%, and −8.5%, and the proportions of counties with severe yield reduction were 34.8%, 44.4%, 20.8%, and 9.7%, respectively. Second, most counties belong to medium-low or low-risk areas for maize production. High-risk counties are primarily located in eastern and southern Gansu, whereas low-risk counties are mostly found along the Hexi Corridor. Third, most risk indicators exhibit some geographical aggregation. The Jiuquan region falls within the low-low-risk aggregation zone. In contrast, the Qingyang region is a high-high aggregation zone with a gradual expansion trend. Four, each risk indicator’s geographical barycenter migrates over a complicated path, but the direction and distance vary considerably. The comprehensive risk migrates along the south-northwest-southeast trajectory, albeit at a shorter distance. Five, the proportion of counties with a medium, medium-severe, severe, and total yield reduction tended to decline. In addition, the annual precipitation is significantly or very significantly correlated with most risk indicators and the comprehensive risk level. The results can guide agricultural production processes at all levels, as well as government disaster prevention.

Mesanophrys sp. is reported to be highly pathogenic to marine crustaceans. This study presents the first report of Mesanophrys sp. infection in the mud crab (Scylla paramamosain). In this study, we first recorded the survival rates of an experimentally infected group and a control group; the cumulative survival rate in the infected group was significantly lower compared to the control group after 72 h (73.20% vs. 94.19%), while the highest mortality of S. paramamosain occurred within the first 24 h post-infection. Then, we investigated the dynamic distribution and tissue tropism of the Mesanophrys sp. in the infected S. paramamosain by a quantitative real-time polymerase chain reaction (qPCR). The result showed that a significant increase in the number of Mesanophrys sp. could be detected in all tested tissues (obtained from the eyestalks, gills, heart, nerves, muscles and hepatopancreas) at 3 h post-infection. The numbers of Mesanophrys sp. in the gill, eyestalk and nerve tissues were relatively higher than in the other tissues. The gill tissue showed the highest numbers from 6 to 48 h. Histopathological observation found a severe collapse in the filament structure, which indicated tissue-specific pathogen infection. Furthermore, the antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) in three representative tissues (gill, muscle and hepatopancreas) were compared between the infected and control groups, and a significant increase in enzyme activity was observed in all three tested tissues in the infected group, indicating a relatively strong innate immune defense reaction that could have been induced by Mesanophrys sp. infection. These results will be helpful to Mesanophrys sp. pathogenicity-related research and the control of this pathogen in S. Paramamosain in the future.

Aiming at the problem of accurately locating and identifying multi-scale and differently shaped apple leaf diseases from a complex background in natural scenes, this study proposed an apple leaf disease detection method based on an improved YOLOv5s model. Firstly, the model utilized the bidirectional feature pyramid network (BiFPN) to achieve multi-scale feature fusion efficiently. Then, the transformer and convolutional block attention module (CBAM) attention mechanisms were added to reduce the interference from invalid background information, improving disease characteristics’ expression ability and increasing the accuracy and recall of the model. Experimental results showed that the proposed BTC-YOLOv5s model (with a model size of 15.8M) can effectively detect four types of apple leaf diseases in natural scenes, with 84.3% mean average precision (mAP). With an octa-core CPU, the model could process 8.7 leaf images per second on average. Compared with classic detection models of SSD, Faster R-CNN, YOLOv4-tiny, and YOLOx, the mAP of the proposed model was increased by 12.74%, 48.84%, 24.44%, and 4.2%, respectively, and offered higher detection accuracy and faster detection speed. Furthermore, the proposed model demonstrated strong robustness and mAP exceeding 80% under strong noise conditions, such as exposure to bright lights, dim lights, and fuzzy images. In conclusion, the new BTC-YOLOv5s was found to be lightweight, accurate, and efficient, making it suitable for application on mobile devices. The proposed method could provide technical support for early intervention and treatment of apple leaf diseases.

Postmenopausal osteoporosis (PMOP) is one of the most common metabolic bone diseases in postmenopausal women. Increasing evidence has indicated that microRNAs (miRNAs) play vital regulatory roles during osteoporosis progression. This study aimed to investigate the potential function of miR-23b-3p in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). PMOP was induced in mice by bilateral ovariectomy. X-ray absorptiometry was applied to detect BMD and BMC in PMOP mice. Luciferase reporter assay and RIP assay were utilized to investigate the relationship between miR-23b-3p and MRC2. We found the upregulation of miR-23b-3p in bone tissues of PMOP mice. Silencing of miR-23b-3p relieved PMOP in mice. Moreover, miR-23b-3p knockdown facilitated the osteogenic differentiation of hMSCs by increasing the expression of Runx2, OCN, Osterix and promoting ALP activity. Mechanistically, MRC2 is a downstream target gene of miR-23b-3p. MRC2 knockdown significantly rescued the promoting effect of lenti-miR-23b-3p inhibitor on osteogenic differentiation of hMSCs. Furthermore, miR-23b-3p targeted MRC2 to inhibit the Wnt/β-catenin pathway during the osteogenic differentiation of hMSCs. In summary, inhibition of miR-23b-3p alleviates PMOP by targeting MRC2 to inhibit the Wnt/β-catenin signaling, which may provide a novel molecular insight for osteoporosis therapy.

The log-ratio model (LRM) with three model parameters (${\boldsymbol{n}}$, ${{\boldsymbol{m}}_1},$ and ${{\boldsymbol{m}}_0}$) has been widely used in shallow water bathymetry of multispectral images. At present, obtaining LRM model parameters by optimization algorithms depends on the setting of initial values [${\boldsymbol{n}}(0)$, ${{\boldsymbol{m}}_1}(0),$ and ${{\boldsymbol{m}}_0}(0)$] or initial value ranges. However, how to set the initial value can obtain model parameters more effectively and credibly, and the significance of each initial value in the optimization process is very important for LRM bathymetric retrieval method. In this article, remote sensing images and bathymetric data were used to determine the initial value ranges of credible model parameters, and then the sensitivity of each parameter was analyzed in the algorithm optimization process from the partial differential perspective, and the bathymetry was retrieved in the sea area near Ganquan Island. The results show that according to the partial differential analysis of model parameters, ${\boldsymbol{n}}$, with the smallest change rate in three LRM parameters and the rate of ${{\boldsymbol{m}}_1}$ and ${{\boldsymbol{m}}_0}$ is at least five times of it. So ${\boldsymbol{n}}(0)$ needs more iterations to achieve the optimal. Therefore, the initial value ${\boldsymbol{n}}(0)$ determines whether the optimization method can obtain credible LRM model parameters and the algorithm convergence speed. And when ${\boldsymbol{n}}(0) \in ({1/{{\boldsymbol{R}}_{{{\bf min}}}},\ 1000} ]$ (${{\boldsymbol{R}}_{{{\bf min}}}}$ is the minimum reflectance in blue and green bands), there must be a credible model parameter solution. The bathymetric retrieval results of the sea area with coral and sand substrates show the applicability of our initial value ranges in different substrate area.

Abstract Coronavirus disease-2019 (COVID-19) pandemic has affected millions of people since December 2019. Summarizing the development of COVID-19 and assessing the effects of control measures are very critical to China and other countries. A logistic growth curve model was employed to compare the development of COVID-19 before and after the emergency response took effect. We found that the number of confirmed cases peaked 9–14 days after the first detection of an imported case, but there was a peak lag in the province where the outbreak was concentrated. Results of the growth curves indicated that the fitted cumulative confirmed cases were close to the actual observed cases, and the R 2 of all models was above 0.95. The average growth rate decreased by 44.42% nationally and by 32.5% outside Hubei Province. The average growth rate in the 12 high-risk areas decreased by 29.9%. The average growth rate of cumulative confirmed cases decreased by approximately 50% after the emergency response. Areas with frequent population migration have a high risk of outbreak. The emergency response taken by the Chinese government was able to effectively control the COVID-19 outbreak. Our study provides references for other countries and regions to control the COVID-19 outbreak.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel plays a critical role in regulating the resting membrane potential and integrating synaptic transmission. Variants of HCN1 have been recognized as causes of epilepsy, and mutant HCN1 channels could act with loss-of-function (LOF), loss- and gain-of-function (LOF and GOF) and gain-of-function (GOF) mechanisms. However, phenotypes and pathogenesis of HCN1-related epilepsy are still poorly understood. This study enrolled five epileptic cases carrying five different HCN1 variants: two pathogenic variants (I380F and S710Rfs*71), two likely pathogenic variants (E240G and A395G), and a paternally inherited variant (V572A). Four variants were novel. Electrophysiological experiments revealed impaired biophysical properties of the identified mutants, including current densities and activation/deactivation kinetics. Moreover, three variants exerted effects on the biophysical properties of wild-type HCN1 channels in heterozygous conditions. Immunofluorescence experiments showed that two variants reduced the protein expression of HCN1channels in neurons. Neurons expressing E240G (GOF) variant showed increased input resistance. However, the variant of I380F (LOF) increased the neuronal firing rate, thus leading to neuronal hyperexcitability. In conclusion, the present study expands the genotypic and phenotypic spectrum of patients with HCN1-related epilepsy and clarifies the underlying mechanisms. We reported five new cases including four unreported likely/pathogenic variants. We provided assessments of biophysical function for each variant, which could help patients to receive individual therapy in the future. We confirmed that HCN1 variants contributed to neuronal hyperexcitability by regulating input resistance and the action potential firing rate, and we have shown that they can affect protein expression in neurons for the first time.

CSNK2B has recently been identified as the causative gene for Poirier–Bienvenu neurodevelopmental syndrome (POBINDS). POBINDS is a rare neurodevelopmental disorder characterized by early-onset epilepsy, developmental delay, hypotonia, and dysmorphism. Limited by the scarcity of patients, the genotype–phenotype correlations in POBINDS are still unclear. In the present study, we describe the clinical and genetic characteristics of eight individuals with POBINDS, most of whom suffered developmental delay, generalized epilepsy, and hypotonia. Minigene experiments confirmed that two intron variants (c.367+5G>A and c.367+6T>C) resulted in the skipping of exon 5, leading to a premature termination of mRNA transcription. Combining our data with the available literature, the types of POBINDS-causing variants included missense, nonsense, frameshift, and splicing, but the variant types do not reflect the clinical severity. Reduced casein kinase 2 holoenzyme activity may represent a unifying pathogenesis. We also found that individuals with missense variants in the zinc finger domain had manageable seizures (p = 0.009) and milder intellectual disability (p = 0.003) than those with missense variants in other domains of CSNK2B. This is the first study of genotype–phenotype correlations in POBINDS, drawing attention to the pathogenicity of intron variants and expanding the understanding of neurodevelopmental disorders.

BackgroundHyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.ObjectivesThis systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype–phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.MethodsThe review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.ResultsWe identified pathogenic variants of HCN1 (n = 24), HCN2 (n = 8), HCN3 (n = 2), and HCN4 (n = 6) that were associated with epilepsy in 74 cases (43 HCN1, 20 HCN2, 2 HCN3, and 9 HCN4). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising HCN1 (n = 4), HCN2 (n = 2), HCN3 (n = 2), and HCN4 (n = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults (n = 10) than children (n = 2). HCN1 variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as HCN2 variants p.S632W and delPPP (p.719–721), were associated with different phenotypes. HCN1 p.L157V and HCN4 p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.ConclusionWe recommend clinicians to include HCN genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.

Glutamate-induced excitotoxicity is a pathological basis of many acute/chronic neurodegenerative diseases. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2b) is a membrane-embedded P-type ATPase pump that manages the translocation of calcium ions (Ca2+) from cytosol into the lumen of the endoplasmic reticulum (ER) calcium stores. It participates in a wide range of biological functions in the central nervous system (CNS). However, the role of SERCA2b in glutamate-induced excitotoxicity and its mechanism must be elucidated. Herein, we demonstrate that SERCA2b mutants exacerbate the excitotoxicity of hypo-glutamate stimulation on HT22 cells. In this study, SERCA2b mutants accelerated Ca2+ depletion through loss-of-function (reduced pumping capacity) or gain-of-function (acquired leakage), resulting in ER stress. In addition, the occurrence of ER Ca2+ depletion increased mitochondria-associated membrane formation, which led to mitochondrial Ca2+ overload and dysfunction. Moreover, the enhancement of SERCA2b pumping capacity or inhibition of Ca2+ leakage attenuated Ca2+ depletion and impeded excitotoxicity in response to hypo-glutamate stimulation. In conclusion, SERCA2b mutants exacerbate ER Ca2+-depletion-mediated excitotoxicity in glutamate-sensitive HT22 cells. The mechanism of disruption is mainly related to the heterogeneity of SERCA2b mutation sites. Stabilization of SRECA2b function is a critical therapeutic approach against glutamate-induced excitotoxicity. These data will expand understanding of organelle regulatory networks and facilitate the discovery and creation of drugs against excitatory/inhibitory imbalance in the CNS.

BackgroundSystemic therapies, including immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), have challenged the use of conventional therapies for hepatocellular carcinoma (HCC). It is crucial to determine which patients could benefit most from combination therapy. This study aims to examine the associations of sarcopenia and systemic inflammation response index (SIRI) with the treatment responses and efficacies in patients with HCC treated with ICIs and tyrosine kinase inhibitors TKIs, as well as investigate the correlation between sarcopenia and inflammatory or immune states.MethodsWe reviewed 160 patients with HCC treated with TKIs and ICIs. The patients’ psoas muscle size was measured on axial computed tomography scans and normalized for the patients’ height squared. This value was referred to as the psoas muscle index (PMI). Sarcopenia was determined from PMI and their relationships with patients’ clinicopathological characteristics, inflammation indexes, peripheral blood T-cell subsets and survival were evaluated.ResultsSarcopenia and systemic inflammation response index (SIRI) were independent predictors for overall survival and progression-free survival. Patients with high PMI and low SIRI demonstrated significantly better median overall survival and progression-free survival (36.0 months and 9.6 months, respectively) than those with either low PMI or high SIRI (20.8 months and 6.0 months, respectively) and those with both high SIRI and low PMI (18.6 months and 3.0 months, respectively). Portal vein tumor thrombus (P=0.003), eastern cooperative oncology group performance status score of 1 (P=0.048), high alkaline phosphatase (P=0.037), high neutrophil-to-lymphocyte ratio (NLR) (P=0.012), low lymphocyte-to-monocyte ratio (LMR) (P=0.031), high platelet-to-lymphocyte ratio (PLR) (P=0.022) and high SIRI (P=0.012) were closely associated with an increased incidence of sarcopenia. PMI was negatively correlated with SIRI (r = -0.175, P=0.003), NLR (r = -0.169, P=0.036), and PLR (r = -0.328, P=0.000) and was significantly positively correlated with LMR (r = 0.232, P=0.004). The CD3+ and CD4+ T-cell counts of the high PMI group were significantly higher than those of the low PMI group.ConclusionSarcopenia and high SIRI were associated with reduced survival in patients with HCC treated with ICIs and TKIs. Sarcopenia could affect inflammatory states and the immune microenvironment.

In this paper, a fast and effective method based on multiple image features and a weighted K-means clustering algorithm is proposed to achieve the automatic grading of apples. The method provides a novel way of using four images (top, bottom and two sides) and average gray values for each apple to distinguish between the apple defects, stem and calyx. Furthermore, weighted features (MCSAD (maximum cross-sectional average diameter), circularity, PRA (proportion of red area) and defect regions) were carefully selected according to the requirements of the national apple grading standard, which improves the practicality of the proposed method. Finally, qualitative and quantitative evaluation results demonstrate that the total accuracy of the proposed multi-feature grading method is greater than 96%, which provides encouragement for the additional research and implementation of multi-feature automatic grading for the fruit industry.

Abstract Background Cerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism. Case presentation Here we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well. Conclusions One novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.

Abstract Background Trilobatin, a natural compound, has been found to exhibit anti-diabetic properties in high-fat diet (HFD) and streptozotocin (STZ) induced type 2 diabetic mice. But up to now no research has been reported on the effect of trilobatin on insulin resistance in peripheral tissues. Herein, we determined the effects of trilobatin on insulin resistance in palmitate-treated C2C12 myotubes and ob/ob mice. Methods Male ob/ob mice (8-10 weeks) and same background C57BL/6 mice were used to evaluate the role of trilobatin on insulin resistance; protein expression and phosphorylation were measured by western blot; glucose uptake was determined a fluorescent test. Results Treatment with trilobatin prevented palmitate-induced insulin resistance by enhancing glucose uptake and the phosphorylation of insulin resistance substrate 1 (IRS1) and protein Kinase B, (PKB/AKT), recovered the translocation of GLUT4 from cytoplasm to membrane, but preincubation with LY294002, an inhibitor of PI3K, blocked the effects of trilobatin on glucose uptake and the distribution of GLUT4 in C2C12 myotubes. Furthermore, administration with trilobatin for 4 weeks significantly improved insulin resistance by decreasing fasting blood glucose and insulin in serum, enhancing the phosphorylation of IRS1 and AKT, and recovering the expression and translocation of GLUT4 in ob/ob mice. Conclusions IRS-AKT-GLUT4 signaling pathway might be involved in trilobatin ameliorating insulin resistance in skeletal muscle of obese animal models.

Abstract Background Infantile spasms (IS) are the most common childhood epileptic encephalopathy. Focal cortical dysplasia (FCD) and gray matter heterotopias (GH) are common structural causes of IS. The recommended first-line treatment for IS patients with structural causes is surgical intervention, according to the International League Against Epilepsy (ILAE) commission guidelines. However, there is currently no consensus on appropriate timings of surgery. Case presentations Two structural IS cases are presented here: one was caused by FCD, and the other by GH. Both patients exhibited recurrent seizures at the age of 2 months, had poor responses to various antiepileptic drugs (AEDs) and displayed severe mental and motor developmental retardation. Seizure types included focal seizures and spasms. Brain magnetic resonance imaging showed abnormal gray signal or suspicious FCD lesions that coincided with the origin of the focal seizures. The patients underwent lesion resection before the age of 6 months. Follow-up observation showed that seizures of both patients were completely controlled several days after the surgery. All AEDs were gradually reduced in dosage within 1 year, and the mental and motor development almost returned to normal. Conclusion Early resection of lesions in structural IS patients has benefits of effectively controlling convulsions and improving developmental retardation. Infants at several months of age can well tolerate craniotomy, and their cognitive development is more likely to return to normal after early surgery.

There is lack of prospective evidence regarding vagal nerve stimulator (VNS) in younger children with intractable epilepsy. Here, we report the outcomes of using VNS in two pre-school patients for pediatric intractable epilepsy (VNS-PIE) study. Medical treatment was ineffective in both the patients, and they underwent VNS implantation. Seizure frequency, score on the Gesell scale, and heart rate variability (HRV) were assessed following VNS therapy. After 6 months VNS treatment, the seizure frequency in the two patients decreased by 50% from that at baseline, based on the records in their epileptic diary. Video electroencephalography (EEG) examinations showed that abnormal fast waves diminished in the background in Patient 1, and captured seizure frequency in Patient 2 remarkably decreased. The adaptability, language, and individual and social interaction on their Gesell scales increased slightly, suggesting that VNS had a positive effect on the development of these two children. Moreover, the changes in the different HRV indices indicated improved cardiac autonomic function. In conclusion, these two cases indicated that VNS may not only be a superior therapy for pre-school children with intractable epilepsy, but also may exert a positive effect on their mental development and cardiac autonomic function.

Gene therapy now provides a novel approach for treating inherited monogenetic disorders, including nuclear gene mutations associated with mitochondrial diseases. In this study, we have utilized a mouse model carrying a p.Arg389Gln mutation of the mitochondrial Ferredoxin Reductase gene (Fdxr) and treated them with neurotropic AAV-PHP.B vector loaded with the mouse Fdxr cDNA sequence. We then used immunofluorescence staining and western blot to test the transduction efficiency of this vector. Toluidine blue staining and electronic microscopy were also utilized to assess the morphology of optic and sciatic nerves, and the mitochondrial respiratory chain activity was determined as well. The AAV vector effectively transduced in the central nervous system and peripheral organs, and AAV-Fdxr treatment reversed almost all the symptoms of the mutants (FdxrR389Q/R389Q). This therapy also improved the electronic conductivity of the sciatic nerves, prevented optic atrophy, improved mobility, and restored mitochondrial complex function. Most notably, the sensory neuropathy, neurodegeneration, and chronic neuroinflammation in the brain were alleviated. Overall, we present the first demonstration of a potential definitive treatment that significantly improves optic and sciatic nerve atrophy, sensory neuropathy, and mitochondrial dysfunction in FDXR-related mitochondriopathy. Our study provides substantial support for the translation of AAV-based Fdxr gene therapy into clinical applications.

Abstract Background Wheat yield is influenced by the number of ears per unit area, and manual counting has traditionally been used to estimate wheat yield. To realize rapid and accurate wheat ear counting, K-means clustering was used for the automatic segmentation of wheat ear images captured by hand-held devices. The segmented data set was constructed by creating four categories of image labels: non-wheat ear, one wheat ear, two wheat ears, and three wheat ears, which was then was sent into the convolution neural network (CNN) model for training and testing to reduce the complexity of the model. Results The recognition accuracy of non-wheat, one wheat, two wheat ears, and three wheat ears were 99.8, 97.5, 98.07, and 98.5%, respectively. The model R 2 reached 0.96, the root mean square error (RMSE) was 10.84 ears, the macro F1-score and micro F1-score both achieved 98.47%, and the best performance was observed during late grain-filling stage (R 2 = 0.99, RMSE = 3.24 ears). The model could also be applied to the UAV platform (R 2 = 0.97, RMSE = 9.47 ears). Conclusions The classification of segmented images as opposed to target recognition not only reduces the workload of manual annotation but also improves significantly the efficiency and accuracy of wheat ear counting, thus meeting the requirements of wheat yield estimation in the field environment.

Objective: This aim of this study was to analyze the correlations between clinical manifestations, treatment strategies, and the prognosis in cryptococcal meningitis (CM) in China. Methods: This was a retrospective analysis of the clinical data of CM patients treated during the years 2002–2019. The clinical features and supplementary examinations, treatment strategies, and prognosis were summarized and then a correlation analysis was performed. Results: Fifty patients were enrolled. The most common symptoms were fever, headache, and vomiting. Five of these patients died and five had visual impairment sequelae; nine of these patients were treated before 2010. Correlation analysis suggested that cerebral hernia, consciousness disorder, visual impairment, hydrocephalus, and an intracranial pressure >300 mmH2O in cerebrospinal fluid (CSF) were associated with a poor prognosis. Whether or not the application of intrathecal administration had little effect on prognosis. Early surgical intervention with internal drainage helped to reduce the mortality and incidence of visual impairment sequelae, whether or not Cryptococcus was present in the CSF before surgery. Conclusions: Clinically, the presence of a cerebral hernia, consciousness disorder, hydrocephalus, visual impairment, or intracranial pressure >300 mmH2O often indicates a poor prognosis in patients with CM. The prognosis improved significantly after 2010, following an adjustment of the treatment strategy. Early internal drainage is the key factor, and CSF positive for Cryptococcus before surgery is not a contraindication.

Abstract Glycosylphosphatidylinositol biosynthesis defects cause rare genetic disorders characterised by developmental delay/intellectual disability, seizures, dysmorphic features, and diverse congenital anomalies associated with a wide range of additional features (hypotonia, hearing loss, elevated alkaline phosphatase, and several other features). Glycosylphosphatidylinositol functions as an anchor to link cell membranes and protein. These proteins function as enzymes, adhesion molecules, complement regulators, or co-receptors in signal transduction pathways. Biallelic variants involved in the glycosylphosphatidylinositol anchored proteins biosynthetic pathway are responsible for a growing number of disorders, including multiple congenital anomalies-hypotonia-seizures syndrome; hyperphosphatasia with mental retardation syndrome/Mabry syndrome; coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies/epilepsy syndrome; and early infantile epileptic encephalopathy-55. This review focuses on the current understanding of Glycosylphosphatidylinositol biosynthesis defects and the associated genes to further understand its wide phenotype spectrum.

Abstract Background Spinal cord ischemia-reperfusion injury (SCIRI) often leads to neurological damage and mortality. In this regard, understanding the pathology of SCIRI and preventing its development are of great clinic value. Methods Herein, we analyzed the role of bone marrow mesenchymal stem cell (BMMSC)-derived exosomal microRNA (miR)-124-3p in SCIRI. A SCIRI rat model was established, and the expression of Ern1 and M2 macrophage polarization markers (Arg1, Ym1, and Fizz) was determined using immunohistochemistry, immunofluorescence assay, RT-qPCR, and western blot analysis. Targeting relationship between miR-124-3p and Ern1 was predicted using bioinformatic analysis and verified by dual-luciferase reporter assay. Macrophages were co-cultured with miR-124-3p-containing BMMSC-derived exosomes. M2 macrophages were identified using flow cytometry, and the expression of Arg1, Ym1, and Fizz was determined. In addition, SCIRI rats were injected with miR-124-3p-containing exosomes, spinal cord cell apoptosis was observed using TUNEL assay, and the pathological condition was evaluated with H&E staining. Results In SCIRI, Ern1 was highly expressed and M2 polarization markers were poorly expressed. Silencing Ern1 led to elevated expression of M2 polarization markers. MiR-124-3p targeted and negatively regulated Ern1. Exosomal miR-124-3p enhanced M2 polarization. Highly expressed exosomal miR-124-3p impeded cell apoptosis and attenuated SCIRI-induced tissue impairment and nerve injury. miR-124-3p from BMMSC-derived exosomes ameliorated SCIRI and its associated nerve injury through inhibiting Ern1 and promoting M2 polarization. Conclusion In summary, exosomal miR-124-3p derived from BMMSCs attenuated nerve injury induced by SCIRI by regulating Ern1 and M2 macrophage polarization.

Intermittent fasting (IF) has been shown beneficial in reducing metabolic diseases. Here, using a multi-omics approach in a T2D mouse model, the authors report that IF alters the composition of the gut microbiota and improves metabolic phenotypes that correlate with cognitive behavior.

Neurology: Seeking salvation for spines after surgery Therapeutic strategies that protect neurological function could prevent serious side effects associated with surgery of the aorta. Patients undergoing aortic surgery for aneurysm or other conditions are at risk of spinal cord damage associated with reduced blood flow during surgery and the subsequent restoration of normal circulation. Researchers led by Fei Yin at Jilin University in Changchun, China, have identified molecular mechanisms that can potentially increase this neurological harm. They show that the combination of low oxygen and reperfusion triggers production of a protein called Foxd3, which switches off cellular pathways that otherwise protect and repair vulnerable tissues. By interfering with this Foxd3-mediated response, Yin’s team was able to protect motor function and preserve the survival of spinal cord neurons in a rat model of this condition, suggesting a potential therapeutic avenue for heart surgery patients.

ObjectiveTo explore the etiology of infantile spasms (IS) in a large Chinese cohort based on the United States National Infantile Spasms Consortium (NISC) classification.MethodsIn the present study, we recruited IS patients diagnosed at a single center (Xiangya Hospital, Central South University) between Jan 2010 and Aug 2019. Thereafter, we collected their clinical and genetic information retrospectively. Their underlying etiologies were classified according to the NISC classification and then compared in different scenarios to understand their distribution.ResultsA total of 541 patients with IS from 18 provinces were included in this study. The underlying etiology was identified in 53.2% of the cases: structural-acquired, 25.3%; genetic, 12.9%; genetic-structural, 7.2%; structural-congenital, 5.0%; metabolic, 2.4%; infections, 0.4% and immune, 0%. Whole-exome sequencing (WES) provided the highest diagnostic yield (26.9%). In structural-acquired IS, the proportion of hypoglycemic brain injuries was significant, second only to hypoxic-ischemic encephalopathy. There was no patient discovered to have Down syndrome. STXBP1, CDKL5, TSC2, KCNQ2, IRF2BPL, and TSC1 were the most frequently implicated genes. Genetic causes were found to be the most common cause of IS in the early onset group, while structural-acquired etiologies were common in males and preterm babies. Patients with pre-spasm seizures were associated with a higher proportion of identified causes than those without. Non-acquired structural etiologies were more common in patients without hypsarrhythmia than in those with hypsarrhythmia.SignificanceThe most prevalent cause of IS was structural acquired followed by genetic causes. When brain MRI fails to detect the etiology, we propose WES as the next step. Structural-acquired IS and cases with genetic disorders are characteristic of the Chinese cohort, however, the etiology differs with the patient's age of onset, gestation age at birth, sex, and the presence/absence of both pre-spasm seizures, and hypsarrhythmia.

ObjectiveThe limitations of adrenocorticotrophic hormone (ACTH) treatment for infantile spasms (ISs), such as high costs, limited availability, and adverse effects (AEs), make it necessary to explore whether corticosteroids are optimal alternatives. Many other compelling treatments have gone through trials due to the suboptimal effectiveness of hormonal therapy. A systematic review and meta-analysis were performed to evaluate the effectiveness and safety of hormonal therapy for patients with ISs.MethodsEMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and online registers were searched through April 2021 for randomized controlled trials (RCTs).ResultsA total of 19 RCTs (N = 1,279) were included. There was no significant difference in the effectiveness of oral corticosteroids and ACTH in electro-clinical response (risk ratio [RR] = 0.85, 95% CI 0.41–1.76). Low-dose ACTH had similar effectiveness in electro-clinical response compared to usual-dose group (RR = 0.94, 95% CI 0.60–1.47) but conferred a lower risk of AEs (RR = 1.71, 95% CI 1.08–2.71). ACTH was more beneficial in controlling spasms than vigabatrin (VGB) (RR = 1.31, 95% CI 1.05–1.64) for patients without tuberous sclerosis complex (TSC). All RCTs were connected through network meta-analysis, and we found that ketogenic diet (KD), zonisamide, methylprednisolone, or combined treatment of hormonal therapy with topiramate (TPM) or pyridoxine was not different in electro-clinical response compared to usual-dose ACTH.ConclusionOur analysis showed that oral corticosteroids could be optional alternatives when ACTH is not applicable, and ACTH is more beneficial for patients without TSC. Moreover, low-dose ACTH is recommended due to comparative effectiveness but lower risk of AEs. However, due to the high heterogeneity of included patients and treatment protocols, these results must be interpreted with caution. RCTs with multicentric involvement and larger sample size are needed for solid evaluation of other alternative treatments.

Background Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis, alendronate (ALE) and teriparatide (TPTD) are widely used in the treatment of GIOP. However, which of these two drugs has a better curative effect needs the support of evidence-based medicine. Methods We searched PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar for randomized controlled trials of ALE and TPTD in the treatment of glucocorticoid-induced osteoporosis until February 2022. These patients included in the study took glucocorticoid doses greater than 7.5 mg/d for more than 3 months before treatment with ALE and TPTD. The risk ratio (RR) and its 95% confidence interval (CI) are used as the influence index of discontinuous data, and the standardized mean difference (SMD) and its 95% CI are used as the influence index of continuous data. Results A total of 4102 patients were enrolled in all 5 studies that met the admission criteria. We found that compared with ALE, TPTD could reduce the rate of new vertebral fracture (RR = 0.13, 95% CI: 0.05–0.34, PConclusions Compared with ALE, TPTD is an effective drug to reduce vertebral fracture risk in patients with GIOP. Furthermore, long-term use of TPTD can increase the bone mineral density of LS, FN, and TH.

Purpose The ongoing coronavirus disease 2019 (COVID-19) epidemic increasingly threatens the public health security worldwide. We aimed to identify high-risk areas of COVID-19 and understand how socioeconomic factors are associated with the spatial distribution of COVID-19 in China, which may help other countries control the epidemic. Methods We analyzed the data of COVID-19 cases from 30 provinces in mainland China (outside of Hubei) from 16 January 2020 to 31 March 2020, considering the data of demographic, economic, health, and transportation factors. Global autocorrelation analysis and Bayesian spatial models were used to present the spatial pattern of COVID-19 and explore the relationship between COVID-19 risk and various factors. Results Global Moran’s I statistics of COVID-19 incidences was 0.31 (PConclusion Our results suggested that COVID-19 risk was positively associated with the level of economic development and population movements. Blocking population movement and reducing local exposures are effective in preventing the local transmission of COVID-19.

Objective:Vitro functional analyses of KCNB1 variants have been done to disclose possible pathogenic mechanisms in KCNB1-related neurodevelopmental disorder. “Complete or partial loss of function (LoF),” “dominant-negative (DN) effect” are applied to describe KCNB1 variant's molecular phenotypes. The study here aimed to investigate clinical presentations and variant effects associations in the disorder.Methods: We reported 10 Chinese pediatric patients with KCNB1-related neurodevelopmental disorder here. Functional experiments on newly reported variants, including electrophysiology and protein expression, were performed in vitro. Phenotypic, functional, and genetic data in the cohort and published literature were collected. According to their variants' molecular phenotypes, patients were grouped into complete or partial LoF, and DN effect or non-dominant-negative (non-DN) effect to compare their clinical features.Results: Nine causative KCNB1 variants in 10 patients were identified in the cohort, including eight novel and one reported. Epilepsy (9/10), global developmental delay (10/10), and behavior issues (7/10) were common clinical features in our patients. Functional analyses of 8 novel variants indicated three partial and five complete LoF variants, five DN and three non-DN effect variants. Patient 1 in our series with truncated variants, whose functional results supported haploinsufficiency, had the best prognosis. Cases in complete LoF group had earlier seizure onset age (64.3 vs. 16.7%, p = 0.01) and worse seizure outcomes (18.8 vs. 66.7%, p = 0.03), and patients in DN effect subgroup had multiple seizure types compared to those in non-DN effect subgroup (65.5 vs. 30.8%, p = 0.039).Conclusion: Patients with KCNB1 variants in the Asian cohort have similar clinical manifestations to those of other races. Truncated KCNB1 variants exhibiting with haploinsufficiency molecular phenotype are linked to milder phenotypes. Individuals with complete LoF and DN effect KCNB1 variants have more severe seizure attacks than the other two subgroups.

Magnetic nanomaterials are widely used in biosynthesis, catalysis, as electronic and microwave-absorbing materials, and in environmental treatment because of their high specific surface area, strong magnetism, chemical stability, and good biocompatibility. The chemical coprecipitation method is widely used for the preparation of magnetic nanomaterials due to its simplicity, low cost, and easily-controlled operating conditions. The magnetic nanomaterials prepared by the chemical coprecipitation method are summarized according to the different compositions, including the basic preparation principles, and the factors affecting their morphology, size, and microstructure. The mechanisms of preparing magnetic nanomaterials by chemical precipitation and the process control factors are emphasized. Finally, the preparation of magnetic nanomaterials by chemical coprecipitation is summarized and prospected.