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Abstract The signing of the Regional Comprehensive Economic Partnership agreement brings new opportunities for the development of international air transportation. Faced with fierce competition, it is worth studying how hub airports should enhance competitiveness, and how low-cost carriers and full-service carriers should optimize the RCEP international airline network layout for better development. Aiming at providing suggestions for the development of hub airports, low-cost and full-service carriers in the RCEP international airline network, this paper identifies the hub airports, analyzes the layout of the RCEP international airline network, and the multi-layered characteristics based on an improved contribution matrix using data from 2010 to 2019 collected from the Official Airline Guide (OAG). This method comprehensively considers attributes of hub airports and the multi-layered characteristics of the airports and routes. The layout analysis indicates that the RCEP international transportation market presents a more open environment for competition and cooperation where base carriers are often the biggest supporters of hub construction. The multi-layered characteristics analysis reveals that low-cost carriers contribute more towards opening up new RCEP routes than full-service carriers. It is advised that carriers newly entering the RCEP international aviation transportation market and low-cost carriers dedicate to establishing new routes around their hub airports to monopolize this market and enhance their market share, whilst full-service carriers consolidate existing routes and increase route density to achieve economic benefits.

Abstract Background Vast economic and healthcare status discrepancies exist among regions in China, contributing to different treatment patterns. This study was aimed to investigate the current status of pharmacotherapy for acute ischemic stroke (AIS) and outcomes in China and explore the geographic variation in stroke care. Methods This study was a multicenter prospective registry study, which collected the data of patients with AIS from 80 hospitals in 46 cities in 2015–2017 across China. Poor functional outcome defined as a modified Rankin Scale score of 3–6 was assessed at 3 and 12 months. Multivariate logistic regression was used. Results Among 9973 eligible patients, the number of receiving intravenous thrombolysis (IVT), antiplatelet agents, anticoagulants, statin and human urinary kallidinogenase was 429 (4.3%), 9363 (93.9%), 1063 (10.7%), 6828 (74.7%) and 5112 (51.2%), respectively. Multivariable analysis showed IVT use in northeastern was significantly more frequent than in eastern region (OR = 3.17, 95% CI, 2.53–3.99), while the antiplatelets agents use were less frequent (OR = 0.46, 95%CI: 0.38–0.57). The proportions of poor outcomes at 3 and 12 months were 20.7% and 15.8%, respectively. Multivariate analysis showed AIS patients from northeastern and central region had significantly lower risk of poor outcome at month 3 and 12 than those from eastern region (all P

Abstract Background The decline in the quantity and quality of mitochondria are closely associated with infertility, particularly in advanced maternal age. Transferring autologous mitochondria into the oocytes of infertile females represents an innovative and viable strategy for treating infertility, with no concerns regarding ethical considerations. As the donor cells of mitochondria, stem cells have biological advantages but research and evidence in this area are quite scarce. Methods To screen out suitable human autologous ooplasmic mitochondrial donor cells, we performed comprehensive assessment of mitochondrial physiology, function and metabolic capacity on a varity of autologous adipose, marrow, and urine-derived mesenchymal stromal cells (ADSC, BMSC and USC) and ovarian germline granulosa cells (GC). Further, to explore the biosafety, effect and mechanism of stem cell-derived mitochondria transfer on human early embryo development, randomized in-vitro basic studies were performed in both of the young and aged oocytes from infertile females. Results Compared with other types of mesenchymal stromal cells, USC demonstrated a non-fused spherical mitochondrial morphology and low oxidative stress status which resembled the oocyte stage. Moreover, USC mitochondrial content, activity and function were all higher than other cell types and less affected by age, and it also exhibited a biphasic metabolic pattern similar to the pre-implantation stage of embryonic development. After the biosafety identification of the USC mitochondrial genome, early embryos after USC mitochondrial transfer showed improvements in mitochondrial content, activity, and cytoplasmic Ca2+ levels. Further, aging embryos also showed improvements in embryonic morphological indicators, euploidy rates, and oxidative stress status. Conclusion Autologous non-invasively derived USC mitochondria transfer may be an effective strategy to improve embryonic development and metabolism, especially in infertile females with advanced age or repeated pregnancy failure. It provides evidence and possibility for the autologous treatment of infertile females without invasive and ethical concerns.

Abstract Metal–organic frameworks (MOFs) and zeolitic imidazolate frameworks (ZIFs) are promising porous materials for adsorption and storage of greenhouse gases, especially CO2. In this study, guided by the CO2 phase diagram, we explore the adsorption behavior of solid CO2 loaded with ZIF-8 framework by heating the sample under high pressures, resulting in a drastic improvement in the CO2 uptake. The behavior of CO2 under simultaneous high temperature (T) and pressure (P) conditions is directly monitored by in situ FTIR spectroscopy. The remarkable enhancement in CO2 adsorption capability observed can be attributed to the synergetic effect of high T and P: high temperature greatly enhances the transport property of solid CO2 by facilitating its diffusion into the framework; high pressure effectively modifies the pore size and shape via changing the linker orientation and creating new adsorption sites within ZIF-8. Our study thus provides important new insights into the tunability and enhancement of CO2 adsorptive capability in MOFs/ZIFs using pressure and temperature combined as a synergetic approach.

Background and aimsHypercholesterolemia has been identified as risk factor for severe acute pancreatitis (AP). We aimed to identify the common differentially expressed genes (DEGs) between a high-cholesterol diet and AP.MethodsWe retrived gene expression profiles from the GEO database. DEGs were assessed using GEO2R. For AP hub genes, we conducted functional enrichment analysis and protein–protein interaction (PPI) analysis. GeneMANIA and correlation analysis were employed to predict potential DEG mechanisms. Validation was done across various healthy human tissues, pancreatic adenocarcinoma, peripheral blood in AP patients, and Sprague–Dawley rats with AP.ResultsThe gene “Fabp5” emerged as the sole common DEG shared by a high-cholesterol diet and AP. Using the 12 topological analysis methods in PPI network analysis, Rela, Actb, Cdh1, and Vcl were identified as hub DEGs. GeneMANIA revealed 77.6% physical interactions among Fabp5, TLR4, and Rela, while genetic correlation analysis indicated moderate associations among them. Peripheral blood analysis yielded area under the ROC curve (AUC) values of 0.71, 0.63, 0.74, 0.64, and 0.91 for Fabp5, TLR4, Actb, Cdh1 genes, and artificial neural network (ANN) model respectively, in predicting severe AP. In vivo immunohistochemical analysis demonstrated higher Fabp5 expression in the hyperlipidemia-associated AP group compared to the AP and control groups.ConclusionFabp5 emerged as the common DEG connecting a high-cholesterol diet and AP. Rela was highlighted as a crucial hub gene in AP. Genetic interactions were observed among Fabp5, TLR4, and Rela. An ANN model consisting of Fabp5, TLR4, Actb, and Cdh1 was helpful in predicting severe AP.

Abstract Solid electrolyte is vital to ensure all-solid-state batteries with improved safety, long cyclability, and feasibility at different temperatures. Herein, we report a new family of amorphous solid electrolytes, xLi2O-MCly (M = Ta or Hf, 0.8 ≤ x ≤ 2, y = 5 or 4). xLi2O-MCly amorphous solid electrolytes can achieve desirable ionic conductivities up to 6.6 × 10−3 S cm−1 at 25 °C, which is one of the highest values among all the reported amorphous solid electrolytes and comparable to those of the popular crystalline ones. The mixed-anion structural models of xLi2O-MCly amorphous SEs are well established and correlated to the ionic conductivities. It is found that the oxygen-jointed anion networks with abundant terminal chlorines in xLi2O-MCly amorphous solid electrolytes play an important role for the fast Li-ion conduction. More importantly, all-solid-state batteries using the amorphous solid electrolytes show excellent electrochemical performance at both 25 °C and −10 °C. Long cycle life (more than 2400 times of charging and discharging) can be achieved for all-solid-state batteries using the xLi2O-TaCl5 amorphous solid electrolyte at 400 mA g−1, demonstrating vast application prospects of the oxychloride amorphous solid electrolytes.

Abstract Background The combined effect of serum uric acid (SUA) and blood glucose on cognition has not been explored. This study aimed to examine the separate and combined association of SUA and fasting plasma glucose (FPG) or diabetes mellitus (DM) with cognition in a sample of Chinese middle-aged and elderly population. Methods A total of 6,509 participants aged 45 years or older who participated in the China Health and Retirement Longitudinal Study (CHARLS, 2011) were included. The three cognitive domains assessed were episodic memory, mental status, and global cognition (the sum of the first two terms). Higher scores indicated better cognition. SUA and FPG were measured. The participants were grouped based on SUA and FPG quartiles to evaluate their combined associations of cognition with SUA Q1–Q3 only (Low SUA), with FPG Q4 only (High FPG), without low SUA and high FPG levels (Non), and with low SUA and high FPG levels (Both), multivariate linear regression models were used to analyze their association. Results Lower SUA quartiles were associated with poorer performance in global cognition and episodic memory compared with the highest quartile. Although no association was found between FPG or DM and cognition, high FPG or DM combined with low SUA levels in women (βFPG = -0.983, 95% CI: -1.563–-0.402; βDM = -0.800, 95% CI: -1.369–-0.232) had poorer cognition than those with low SUA level only (βFPG = -0.469, 95% CI: -0.926–-0.013; βDM = -0.667, 95% CI: -1.060–-0.275). Conclusion Maintaining an appropriate level of SUA may be important to prevent cognitive impairment in women with high FPG.

Abstract Introduction It is well known that post‐stroke depression (PSD) is a psychiatric complication after stroke which leads to worse functional outcome and poorer quality of life. Some risk factors including gender, stroke severity, lesion location, homocysteine (HCY), and so on are associated with PSD. This study aims to further explore the possible relationship between serum levels of HCY and early‐onset PSD and the predictive value of HCY combined with stroke characteristics for early‐onset PSD. Methods Two hundred forty‐five patients with acute ischemic stroke who met the criteria were included in this study from March 2015 to March 2017. PSD was diagnosed at 2 weeks after stroke. The severity of depressive symptoms was evaluated with the Hamilton depression scale 17 items (HAMD‐17), and patients with HAMD scores ≥7 were included in the PSD group. The demographic data, clinical characteristics, serum levels of HCY, and detailed radiological variables (e.g., lesion location and quantity of the brain infarct) were also examined. Results In total, 97 (39.6%) patients of the 245 patients were diagnosed with depression. The univariate analyses suggested that patients in PSD group had a higher NIHSS score, modified Rankin Scale score, and HCY levels than patients in non‐PSD group (p < .001). The patients with PSD had higher proportion of multiple‐site acute infarcts and frontal lobe lesion (p < .05). In multivariate logistic regression analysis, NIHSS score at admission, serum levels of HCY, and multiple‐site lesions were independently related to early‐onset PSD. Based on receiver operating characteristic curves analysis, the combination of HCY, NIHSS scores, multiple‐site lesions, and lesion location revealed a highest area under the curve of 0.807 (95% confidence interval [CI]: 0.748–0.865, p < .001). Furthermore, there was a significantly increased risk of early‐onset PSD associated with serum levels of HCY ≥16.98 μmol/L (odds ratio [OR] = 10.976, 95% CI: 5.585–21.573, p < .001). Conclusions Our study indicated that higher NIHSS score, elevated serum levels of HCY, and multiple‐site lesions may be independent risk factors of early‐onset PSD. The combination of HCY, NIHSS scores, multiple‐site lesions, and lesion location may provide greater predictive value than HCY alone for early‐onset PSD. Early intervention for elevated serum levels of HCY may be a potential target for the intervention and prevention of PSD.

ObjectiveIn recent years, motor imagery-based brain–computer interfaces (MI-BCIs) have developed rapidly due to their great potential in neurological rehabilitation. However, the controllable instruction set limits its application in daily life. To extend the instruction set, we proposed a novel movement-intention encoding paradigm based on sequential finger movement.ApproachTen subjects participated in the offline experiment. During the experiment, they were required to press a key sequentially [i.e., Left→Left (LL), Right→Right (RR), Left→Right (LR), and Right→Left (RL)] using the left or right index finger at about 1 s intervals under an auditory prompt of 1 Hz. The movement-related cortical potential (MRCP) and event-related desynchronization (ERD) features were used to investigate the electroencephalography (EEG) variation induced by the sequential finger movement tasks. Twelve subjects participated in an online experiment to verify the feasibility of the proposed paradigm.Main resultsAs a result, both the MRCP and ERD features showed the specific temporal–spatial EEG patterns of different sequential finger movement tasks. For the offline experiment, the average classification accuracy of the four tasks was 71.69%, with the highest accuracy of 79.26%. For the online experiment, the average accuracies were 83.33% and 82.71% for LL-versus-RR and LR-versus-RL, respectively.SignificanceThis paper demonstrated the feasibility of the proposed sequential finger movement paradigm through offline and online experiments. This study would be helpful for optimizing the encoding method of motor-related EEG information and providing a promising approach to extending the instruction set of the movement intention-based BCIs.

Abstract Background Non-pharmaceutical interventions (NPIs) against coronavirus disease 2019 (COVID-19) may have suppressed the transmission of other infectious diseases. This study aimed to evaluate the impact of different degrees of NPIs during the COVID-19 pandemic on hand, foot and mouth disease (HFMD) in Guangzhou, China. Methods Weekly reported HFMD cases and pathogens information during 2015–2021 in Guangzhou were collected from the China National Notifiable Disease Reporting System. The observed number of HFMD cases in 2020 and 2021 was compared to the average level in the same period during 2015–2019. Then, an interrupted time-series segmented regression analysis was applied to estimate the impact of NPIs on HFMD, such as social distancing, suspension of schools, community management and mask wearing. The effects across different subgroups stratified by gender, children groups and enterovirus subtype of HFMD were also examined. Results A total of 13,224 and 36,353 HFMD cases were reported in 2020 and 2021, which decreased by 80.80% and 15.06% respectively compared with the average number of cases in the same period during 2015–2019. A significant drop in the number of HFMD cases during time when strict NPIs were applied (relative change: 69.07% [95% confidence interval (CI): 68.84%–69.30%]). The HFMD incidence rebounded to historical levels in 2021 as the lockdown eased. The slightest reduction of HFMD cases was found among children at kindergartens or childcare centres among the three children groups (children at kindergartens or childcare centres: 55.50% [95% CI: 54.96%–56.03%]; children living at home: 72.64% [95% CI: 72.38%–72.89%]; others: 74.06% [95% CI: 73.19%–74.91%]). Conclusions The strong NPIs during the COVID-19 epidemic may have a significant beneficial effect on mitigating HFMD. However, the incidence of HFMD rebounded as the NPIs became less stringent. Authorities should consider applying these NPIs during HFMD outbreaks and strengthening personal hygiene in routine prevention.

Feasibility checking is a step in manufacturing system engineering for verifying the normalization and effectiveness of a manufacturing system associated with a specific configuration of resources and processes. It enables factory operators to predict problems before operational time, thus preventing equipment and machinery accidents and reducing labor waste in physically organizing the shop floor. In Industry 4.0, feasibility checking becomes even more critical since emerging challenges, such as mass personalization, require reconfiguring work cells quickly and flexibly on demand. Regarding this need, digital twin technologies have emerged as an ideal candidate for practicing feasibility checking. Indeed, they are tools used to implement digital representations of manufacturing entities that can constitute a digital environment and context. Factory operators can test a manufacturing process within a digital environment in different contexts before the execution with physical resources. This approach currently receives significant attention from the manufacturing community; however, there is still a lack of sharing experiences to implement it. Thus, this paper contributes a methodology to engineer a digital environment and context for a manufacturing work cell using AAS digital twins and physics-based 3D digital twins technologies. Technically, this methodology is a specific case of N-DTs, a general methodology for engineering heterogeneous digital twins. The product assembly line case study, also presented in this paper, is a successful experiment applying the above contributions. The two methodologies and the case study can be helpful references for both public and private sectors to deploy their feasibility-checking frameworks and deal with heterogeneous digital twins in general.

BackgroundDue to disparities in medical resources in rural and urban areas as well as in different geographic regions in China, the effect of weekend versus weekday admission on the outcomes of acute ischemic stroke (AIS) patients is unknown. Our aim was to investigate whether the outcomes of AIS patients differ according to the day of admission in China.MethodsThe data were extracted from the Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR), a multicenter prospective study database of patients diagnosed with AIS. The chi-square test (χ2) and logistic regression were used to assess mortality for weekday and weekend admissions among AIS patients stratified by rural or urban status and geographic region (including the eastern, northeastern, central, and western regions).ResultsIn total, 9,256 patients were included in this study. Of these patients, 57.2% were classified as urban, and 42.8% were classified as rural. A total of 6,760 (73%) patients were admitted on weekdays, and 2,496 (27%) were admitted on weekends. There was no significant difference in the mortality rate among patients admitted on weekends compared with those admitted on weekdays in urban (7.5% versus 7.4%) or rural areas (8.8% versus 8.1%; p > 0.05). The mortality rate was the highest among patients admitted on weekends and weekdays (11.6% versus 10.3%) in the northeastern area, without statistical significance before and after adjusting for the patients’ background characteristics (p > 0.05). In addition, regression analysis revealed that the mortality of patients admitted on weekdays was more likely to be influenced by regional subgroup, hospital level and intravenous thrombolysis than that of patients admitted on weekends.ConclusionThe weekend effect was not observed in the mortality of patients with AIS regardless of rural–urban status or geographic region in China.

BackgroundPrevious studies involving uric acid (UA) in some specialized disease populations have found that high UA is associated with enhanced patient function. The mechanism to explain this association may be that UA, an important antioxidant, exerts neuroprotective effects. Patients with schizophrenia (SCZ) have severe oxidative stress abnormalities, and cognitive impairment is a major obstacle to their rehabilitation. Only few studies have been conducted on UA and cognitive impairment in SCZ. This study aims to clarify the relationship between UA and cognitive impairment and explore whether UA could be used as a potential biological marker of cognition in SCZ during maintenance period.MethodsA total of 752 cases of SCZ during maintenance period from Baiyun Jingkang Hospital were included. Cognition was measured using the Mini-Mental State Examination scale. UA was measured using the Plus method. The participants were grouped on the basis of UA to evaluate the association of cognition with low-normal (3.50–5.07 mg/dL for men, 2.50–4.19 mg/dL for women), middle-normal (5.07–6.39 mg/dL for men, 4.19–5.18 mg/dL for women), high-normal (6.39–7.00 mg/dL for men, 5.18–6.00 mg/dL for women), and high (>7.00 mg/dL for men, >6.00 mg/dL for women) levels of UA. Multiple logistic regression and linear regression models and restricted cubic spline (RCS) were utilized to evaluate the relationship.ResultsUric acid was positively associated with cognitive function. Subgroup analyses showed that high UA was associated with enhanced cognition in participants with low anticholinergic cognitive burden (ACB).ConclusionUric acid may be used as a simple objective biological indicator to assess cognition in SCZ during maintenance period.

Background and purposeCerebral small-vessel disease (CSVD) is prevalent worldwide and one of the major causes of stroke and dementia. For patients with CSVD at high altitude, a special environmental status, limited information is known about their clinical phenotype and specific neuroimaging change. We investigated the clinical and neuroimaging features of patients residing at high altitude by comparing with those in the plain, trying to explore the impact of high altitude environment on CSVD.MethodsTwo cohorts of CSVD patients from the Tibet Autonomous Region and Beijing were recruited retrospectively. In addition to the collection of clinical diagnoses, demographic information and traditional vascular risk factors, the presence, location, and severity of lacunes and white matter hyperintensities were assessed by manual counting and using age-related white matter changes (ARWMC) rating scale. Differences between the two groups and influence of long-term residing in the plateau were analyzed.ResultsA total of 169 patients in Tibet (high altitude) and 310 patients in Beijing (low altitude) were enrolled. Fewer patients in high altitude group were found with acute cerebrovascular events and concomitant traditional vascular risk factors. The median (quartiles) ARWMC score was 10 (4, 15) in high altitude group and 6 (3, 12) in low altitude group. Less lacunes were detected in high altitude group [0 (0, 4)] than in low altitude group [2 (0, 5)]. In both groups, most lesions located in the subcortical (especially frontal) and basal ganglia regions. Logistic regressions showed that age, hypertension, family history of stroke, and plateau resident were independently associated with severe white matter hyperintensities, while plateau resident was negatively correlated with lacunes.ConclusionPatients of CSVD residing at high altitude showed more severe WMH but less acute cerebrovascular events and lacunes in neuroimaging, comparing to patients residing at low altitude. Our findings suggest potential biphasic effect of high altitude on the occurrence and progression of CSVD.

Several studies have demonstrated the protective effect of dl-3-n-Butylphthalide (NBP) against cerebral ischemia, which may be related to the attenuation of mitochondrial dysfunction. However, the specific mechanism and targets of NBP in cerebral ischemia/reperfusion remains unclear. In this study, we used a chemical proteomics approach to search for targets of NBP and identified cytochrome C oxidase 7c (Cox7c) as a key interacting target of NBP. Our findings indicated that NBP inhibits mitochondrial apoptosis and reactive oxygen species (ROS) release and increases ATP production through upregulation of Cox7c. Subsequently, mitochondrial respiratory capacity was improved and the HIF-1α/VEGF pathway was upregulated, which contributed to the maintenance of mitochondrial membrane potential and blood brain barrier integrity and promoting angiogenesis. Therefore, our findings provided a novel insight into the mechanisms underlying the neuroprotective effects of NBP, and also proposed for the first time that Cox7c exerts a critical role by protecting mitochondrial function.

BackgroundThe association between blood lipids and cognitive function in schizophrenia is still controversial. Thus, the present study aimed to verify the association between various lipid parameters and cognitive impairment in schizophrenic patients and potential lipid pathways.MethodsA total of 447 adult inpatients with schizophrenia were divided into cognitive normal and cognitive impairment groups based on the Mini-Mental State Examination with a cut-off of 26. The blood lipid parameters were defined as abnormal levels based on the guideline. The liquid chromatography-mass spectrometry method was used to preliminarily explore the potential lipid metabolism pathway associated with cognitive impairment.ResultsThere were 368 (82.3%) patients who had cognitive impairment. Herein, apolipoprotein B was positively associated with cognitive function in overall patients and age (≥45 and

Metal-organic frameworks (MOFs) are an emerging class of porous materials with many unique properties that make them promising candidates for carbon dioxide (CO2) capture and storage. A better understanding of the behavior of CO2 adsorbed inside MOF will enable researchers to develop the ability of designing new MOF based materials with high CO2 adsorption capabilities. It is well known that presence of open metal sites (OMSs) can greatly enhance the gas adsorption capability of MOFs. MOF UTSA-74, a framework isomer of well-known MOF-74 has a unique feature that upon activation, a single metal ion has two OMSs. Therefore, it presents a unique opportunity to probe the dynamics of CO2 molecules adsorbed on these OMSs. In this work, the CO2 adsorptive properties of MOF UTSA-74 are examined with particular attention being paid to the dynamics of the CO2 adsorbed on these OMSs. Specifically, variable temperature 13C static solid-state nuclear magnetic resonance (SSNMR) experiments were conducted to directly monitor the behavior of 13CO2 in UTSA-74 at different loadings. All CO2 molecules undergo localized wobbling. At low loadings, some CO2 molecules jump among three OMSs from three different Zn atoms in the cross-section of the channel. Others hop back and forth between the two neighboring OMSs. At high loading, the three-site jump has ceased, but two-site hopping persists. The dynamical behavior of CO2 in UTSA-74 results from the unique Zn coordination environment. It was discovered that CO2 is less mobile in UTSA-74 than in its framework isomer, MOF-74-Zn.

Patients with breast cancer undergoing chemotherapy are susceptible to prolonged and severe neutropenia. Multiple biosimilars of long-acting granulocyte colony-stimulating factors (LA-G-CSFs) have been newly developed to prevent this disease. Nonetheless, which LA-G-CSF regimen has the optimal balance of efficacy and safety remains controversial. Moreover, there is a lack of evidence supporting clinical decisions on LA-G-CSF dose escalation in poor conditions. PubMed, Embase, Cochrane Library, Web of Science, and several Chinese databases were searched (December 2022) to collect randomized controlled trials (RCTs) about LA-G-CSFs preventing chemotherapy-induced neutropenia in breast cancer patients. No restrictions were imposed on language. A Bayesian network meta-analysis was performed. We assessed the incidence of severe neutropenia (SN) and febrile neutropenia (FN), the duration of SN (DSN), and the absolute neutrophil account recovery time (ANCrt) for efficacy, while the incidence of severe adverse events (SAE) was assessed for safety. The study was registered in PROSPERO (CRD42022361606). A total of 33 RCTs were included. Our network meta-analysis demonstrated that lipegfilgrastim 6 mg and eflapegrastim 13.2 mg outperformed other LA-G-CSFs with high efficacy rates and few safety concerns (SUCRA of lipegfilgrastim 6 mg: ANC rt 95.2%, FN 97.4%; eflapegrastim 13.2 mg: FN 87%, SN 89.3%). Additionally, 3.6 mg, 4.5 mg, 6 mg, and 13.2 mg dosages all performed significantly better than 1.8 mg in reducing the duration of SN (3.6 mg: DSN, SMD −0.68 [−1.13, −0.22; moderate]; 4.5 mg: −0.87 [−1.57, −0.17; low]; 6 mg: −0.89 [−1.49, −0.29; moderate]; 13.2 mg: −1.02 [1.63, −0.41; high]). Increasing the dosage from the guideline-recommended 6 mg to 13.2 mg can reduce both the duration and incidence of SN (SMD −0.13 [−0.24 to −0.03], RR 0.65 [0.43 to 0.96], respectively), with no significant difference in SAE. For patients with breast cancer, lipegfilgrastim 6 mg and eflapegrastim 13.2 mg might be the most effective regimen among LA-G-CSFs. Higher doses of LA-G-CSF may enhance efficacy without causing additional SAEs.

VISTA (PD-1H) is an immune regulatory molecule considered part of the next wave of immuno-oncology targets. VISTA is an immunoglobulin (Ig) superfamily cell surface molecule mainly expressed on myeloid cells, and to some extent on NK cells and T cells. In previous preclinical studies, some VISTA-targeting antibodies provided immune inhibitory signals, while other antibodies triggered immune stimulatory signals. Importantly, for therapeutic antibodies, the isotype backbone can have a strong impact on antibody function. To elucidate the mode of action of immune stimulatory anti-VISTA antibodies, we studied three different anti-human VISTA antibody clones, each on three different IgG isotypes currently used for therapeutic antibodies: unaltered IgG1 (IgG1-WT), IgG1-KO (IgG1-LL234,235AA-variant with reduced Fc-effector function), and IgG4-Pro (IgG4- S228P-variant with stabilized hinge region). Antibody functionality was analysed in mixed leukocyte reaction (MLR) of human peripheral blood mononuclear cells (PBMCs), as a model system for ongoing immune reactions, on unstimulated human PBMCs, as a model system for a resting immune system, and also on acute myeloid leukemia (AML) patient samples to evaluate anti-VISTA antibody effects on primary tumor material. The functions of three anti-human VISTA antibodies were determined by their IgG isotype backbones. An MLR of healthy donor PBMCs was effectively augmented by anti-VISTA-IgG4-Pro and anti-VISTA-IgG1-WT antibodies, as indicated by increased levels of cytokines, T cell activation markers and T cell proliferation. However, in a culture of unstimulated PBMCs of single healthy donors, only anti-VISTA-IgG1-WT antibodies increased the activation marker HLA-DR on resting myeloid cells, and chemokine levels. Interestingly, interactions with different Fc-receptors were required for these effects, namely CD64 for augmentation of MLR, and CD16 for activation of resting myeloid cells. Furthermore, anti-VISTA-IgG1-KO antibodies had nearly no impact in any model system. Similarly, in AML patient samples, anti-VISTA-antibody on IgG4-Pro backbone, but not on IgG1-KO backbone, increased interactions, as a novel readout of activity, between immune cells and CD34+ AML cancer cells. In conclusion, the immune stimulatory effects of antagonistic anti-VISTA antibodies are defined by the antibody isotype and interaction with different Fc-gamma-receptors, highlighting the importance of understanding these interactions when designing immune stimulatory antibody therapeutics for immuno-oncology applications.

Tacrolimus is a major immunosuppressor against post-transplant rejection in kidney transplant recipients. However, the narrow therapeutic index of tacrolimus and considerable variability among individuals are challenges for therapeutic outcomes. The aim of this study was to compare different machine learning and deep learning algorithms and establish individualized dose prediction models by using the best performing algorithm. Therefore, among the 10 commonly used algorithms we compared, the TabNet algorithm outperformed other algorithms with the highest R2 (0.824), the lowest prediction error [mean absolute error (MAE) 0.468, mean square error (MSE) 0.558, and root mean square error (RMSE) 0.745], and good performance of overestimated (5.29%) or underestimated dose percentage (8.52%). In the final prediction model, the last tacrolimus daily dose, the last tacrolimus therapeutic drug monitoring value, time after transplantation, hematocrit, serum creatinine, aspartate aminotransferase, weight, CYP3A5, body mass index, and uric acid were the most influential variables on tacrolimus daily dose. Our study provides a reference for the application of deep learning technique in tacrolimus dose estimation, and the TabNet model with desirable predictive performance is expected to be expanded and applied in future clinical practice.

The relationship between body mass index (BMI) and cognitive impairment remains controversial, especially in older people. This study aims to confirm the association of phenotypic and genetic obesity with cognitive impairment and the benefits of adhering to a healthy lifestyle. This prospective study included 10,798 participants (aged ≥ 50 years) with normal cognitive function from the Health and Retirement Study in the United States. Participants were divided into low (lowest quintile), intermediate (quintiles 2–4), and high (highest quintile) groups according to their polygenic risk score (PRS) for BMI. The risk of cognitive impairment was estimated using Cox proportional hazard models. Higher PRS for BMI was associated with an increased risk, whereas phenotypic obesity was related to a decreased risk of cognitive impairment. Never smoking, moderate drinking, and active physical activity were considered favourable and associated with a lower risk of cognitive impairment compared with current smoking, never drinking, and inactive, respectively. A favourable lifestyle was associated with a low risk of cognitive impairment, even in subjects with low BMI and high PRS for BMI. This study suggest that regardless of obesity status, including phenotypic and genetic, adhering to a favourable lifestyle is beneficial to cognitive function.

Background and Purpose: Studies on the regional differences in hospital costs of acute ischemic stroke (AIS) are scarce in China. We aimed to explore the regional differences in hospital costs and identify the determinants of hospital costs in each region.Methods: Data were collected from the Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR), a multicenter prospective study on patients diagnosed with AIS and hospitalized from 2015 to 2017. Univariate and multivariate analyses were undertaken to identify the determinants of hospital costs of AIS.Results: A total of 8,547 patients were included in the study, of whom 3,700 were from the eastern area, 2,534 were from the northeastern area, 1,819 were from the central area, and 494 were from the western area. The median hospital costs presented a significant difference among each region, which were 2175.9, 2175.1, 2477.7, and 2282.4 dollars in each area, respectively. Each region showed a similar hospital cost proportion size order of cost components, which was Western medicine costs, other costs, diagnostic costs, and traditional medicine costs, in descending order. Male sex, diabetes mellitus, severe stroke symptoms, longer length of stay, admission to the intensive care unit, in-hospital complications of hemorrhage, and thrombectomy were independently associated with hospital costs in most regions.Conclusion: Hospital costs in different regions showed a similar proportion size order of components in China. Each region had different determinants of hospital costs, which reflected its current medical conditions and provided potential determinants for increasing medical efficiency according to each region's situation.

Abstract Background Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. Methods Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. Results In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. Conclusions The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. Trial registration Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019.

Abstract Background Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. Methods Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function. Results Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein. Conclusion In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

Myeloid-derived growth factor (MYDGF) is an angiogenic growth factor with therapeutic potential for ischemic tissue repair and the receptor is still unknown. Here the authors present the crystal structure of human MYDGF and identify its functional epitope through mutagenesis studies.

Background and Purpose: There is limited information on symptomatic intracranial hemorrhage (sICH) in stroke patients without thrombolysis. This study aimed to evaluate the risk factors of sICH and the association between sICH and the prognosis at 3 and 12 months in acute ischemic stroke patients without thrombolysis.Methods: Data originated from the Chinese Acute Ischemic Stroke Treatment Outcome Registry. Univariate analysis and multivariate logistic regression were used to screen the risk factors of sICH. Multivariable logistic regression models were used to assess the association of sICH with poor outcome and all-cause mortality.Results: Totally, 9,484 patients were included, of which 69 (0.73%) had sICH. Atrial fibrillation (odds ratio [OR], 3.682; 95% confidence interval [CI], 1.945–6.971; p < 0.001), history of tumors (OR, 2.956; 95% CI, 1.115–7.593; p = 0.024), and the National Institutes of Health Stroke Scale (NIHSS) score on admission ([6–15: OR, 2.344; 95% CI, 1.365–4.024; p = 0.002] [>15: OR, 4.731; 95% CI, 1.648–13.583; p = 0.004]) were independently associated with sICH. After adjustment of the confounders, patients with sICH had a higher risk of poor outcome (OR, 1.983; 95% CI, 1.117–3.521; p = 0.018) at 3 months and that of all-cause mortality at 3 (OR, 6.135; 95% CI, 2.328–16.169; p < 0.001) and 12 months (OR, 3.720; 95% CI, 1.513–9.148; p = 0.004).Conclusion: sICH occurred in 0.73% of acute ischemic stroke patients without thrombolysis and was associated with a worse prognosis at 3 and 12 months. Atrial fibrillation, history of tumors, and NIHSS score at admission were independent risk factors of sICH.

The pathogenic mechanisms underlying vascular cognitive impairment and dementia (VCID) remain controversial due to the heterogeneity of vascular causes and complexity of disease neuropathology. However, one common feature shared among all these vascular causes is cerebral blood flow (CBF) dysregulation, and chronic cerebral hypoperfusion (CCH) is the universal consequence of CBF dysregulation, which subsequently results in an insufficient blood supply to the brain, ultimately contributing to VCID. The purpose of this comprehensive review is to emphasize the important contributions of CCH to VCID and illustrate the current findings about the mechanisms involved in CCH-induced VCID pathological changes. Specifically, evidence is mainly provided to support the molecular mechanisms, including Aβ accumulation, inflammation, oxidative stress, blood-brain barrier (BBB) disruption, trophic uncoupling and white matter lesions (WMLs). Notably, there are close interactions among these multiple mechanisms, and further research is necessary to elucidate the hitherto unsolved questions regarding these interactions. An enhanced understanding of the pathological features in preclinical models could provide a theoretical basis, ultimately achieving the shift from treatment to prevention.

Objective: This study evaluated iron overload after intracerebral hemorrhage (ICH) using ESWAN sequences.Methods: This single-center prospective observational cohort study enrolled supratentorial ICH patients. MRI was obtained with a 3.0-T scanner at day 1, day 14, day 30, and follow-up (300 days or later). R2* mapping was generated based on the ESWAN. R2* value of the ipsilateral side represented iron deposition, and the R2* value of the contralateral side served as control. R2* value was adjusted by volume and used to assess total iron overload. Brain edema was measured on T2 FLAIR-weighted images. Brain atrophy was calculated as the contralateral hemisphere volume minus the injured hemisphere volume.Results: Twnety-seven patients with a spontaneous supratentorial ICH were included in this analysis. The ipsilateral R2* value was 40.27 ± 11.62, 41.92 ± 13.56, and 60.89 ± 14.09 at days 1, 14, and 30, respectively. The R2* value was significantly higher in the ICH side than the contralateral side (p < 0.01). Increased R2* value was seen on day 30 compared to day 14 (p < 0.01). The R2* value showed logistic decay with the distance to the hematoma margin (p < 0.01). Brain edema at day 14 and brain atrophy at follow-up correlated with R2* value adjusted by volume at day 14 (p < 0.01).Conclusions: After ICH, the iron deposition in the perihematomal region was progressively increased during the first month. R2* value adjusted by volume predicted acute brain edema and chronic brain atrophy.

Vascular endothelial cell (EC) and blood–brain barrier (BBB) dysfunction is the core pathogenesis of cerebral small vessel disease (CSVD). Moreover, animal experiments have shown the importance of connexin (Cx)-43 in EC and BBB function. In this study, we recruited 200 patients diagnosed with sporadic CSVD. Initially, we examined imaging scores of white matter hyperintensities (WMH), lacunar infarction (LI), and cerebral microbleeds (CMB). Additionally, we performed next-generation sequencing of the GJA1 gene (Cx43 coding gene) to examine correlation between these single-nucleotide polymorphisms and the burden and distribution of CSVD. Fourteen target loci were chosen. Of these, 13 loci (92.9%) contributed toward risk for cerebellar LI, one locus (7.1%) was shown to be a protective factor for lobar CMB after FDR adjustment. In conclusion, single-nucleotide polymorphisms in the GJA1 gene appear to affect the distribution but not severity of CSVD.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. More than 25 ALS-related genes have been identified, accounting for approximately 10% of sporadic ALS (SALS) and two-thirds of familial ALS (FALS) cases. Several recent studies showed that genetic factors might have a larger contribution to young-onset ALS than to ALS cases overall. However, the genetic profile of young-onset ALS patients is not yet fully understood. Here, we investigated a cohort of 27 young-onset ALS patients (onset age < 45 years) through whole-exome sequencing (WES). Genetic analysis identified pathogenic variants of FUS (25.9%), SOD1 (22.2%), TARDBP (3.7%), and VCP (3.7%) in 27 young-onset ALS patients. Of 12 identified types of mutations, c.1528A > C in FUS and c.266G > A in VCP were novel. All of the cases in this study reflect a monogenic origin with an autosomal dominant mode of inheritance. Notably, a novel de novo missense mutation, c.1528A > C (p.K510Q), in FUS was identified in a 29-year-old ALS patient. Expression of the K510Q mutant FUS resulted in cytoplasmic mislocalization of FUS in cultured cells and induced neural toxicity in a fly model. This study provides further evidence of the genetic profile of young-onset ALS patients from China and expands the mutational spectrum of the FUS gene, with one new K510Q mutation identified.

The urokinase-type plasminogen activator (uPA) loaded hollow nanogels (nUK) were synthesized by a one-step reaction of glycol chitosan and aldehyde capped poly (ethylene oxide). The resultant formulation is sensitive to diagnostic ultrasound (US) of 2 MHz. Herein, we evaluated the in vivo sonothrombolysis performance of the nUK on acute ischemic stroke rat model which was established by suture embolization of middle cerebral artery (MCA). Via intravenous (i.v.) administration, the experimental data prove a controlled release of the therapeutic protein around the clots under ultrasound stimulation, leading to enhanced thrombolysis efficiency of the nUK, evidenced from smaller infarct volume and better clinical scores when compared to the i.v. dose of free uPA no matter with or without US intervention. Meanwhile, the preservation ability of the nanogels not only prolonged the circulation duration of the protein, but also resulted in the better blood-brain barrier protection of the nUK formulation, showing no increased risk on the hemorrhagic transformation than the controls. This work suggests that the nUK is a safe sonothrombolytic formulation for the treatment of acute ischemic stroke.

Abstract Background The present study aimed to investigate the prevalence and risk factors for extracranial carotid artery stenosis (ECAS) and intracranial carotid artery stenosis (ICAS) simultaneously in asymptomatic Chinese pure rural population. Methods We analyzed 2589 asymptomatic subjects aged over 30 yr. by ultrasonography and transcranial Doppler simultaneously in 13 isolated villages by door-to-door investigation. Both ECAS and ICAS were defined as more than 50% stenosis. Demographics, medical history documentation, and investigation of biochemical results were performed for each subject. Univariate and multivariate logistic regression analyses were employed to assess the risk factors associated with ECAS and ICAS, respectively. Results One hundred twenty-two (4.7%) residents with ICAS and 56 (2.2%) with ECAS were found in 2589 subjects. Three factors emerged as independent risk factors for ICAS: age (95% confidence interval [CI] = 1.01–1.04, odds ratio [OR] = 1.07), hypertension (95% CI = 1.98–4.37, OR = 2.94), and diabetes mellitus (95% CI = 1.72–4.38, OR = 2.75). As for ECAS, five factors presented as independent risk factors: age (95% CI = 1.09–1.11, OR = 1.10), male sex (95% CI = 1.01–1.02, OR = 1.01), diabetes mellitus (95% CI = 1.10–2.12, OR = 1.53), systolic blood pressure (95% CI = 1.95–2.88, OR = 2.37), and total cholesterol (95% CI = 1.00–1.13, OR = 1.06). Conclusions ICAS and ECAS were relatively common among asymptomatic rural Chinese subjects. Although they shared similar risk factors, differences still existed between them.

Abstract Rationale Stroke presents a serious health problem in China. Despite progresses made in recent years, there is still a lack of effective treatments for acute ischemic stroke (AIS) in clinical practices. Aims The Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR) is designed to evaluate the patterns and cost-effectiveness of current treatments for AIS in real-world settings in China. Design CASTOR is a prospective, multi-center study registered with ClinicalTrials.gov (NCT02470624) with a target sample size of 10,000 patients who are experiencing AIS. The patients are treated for AIS following the Chinese stroke guideline and local practice. Real-world data on treatment regimens, outcomes and costs are collected at baseline (Visit 1) and during subsequent visits (Visit 2 to Visit 5) after medication treatments. Outcome The primary objective of the present study is to analyze the current treatment status of AIS in real world settings. The secondary objectives include: 1) to compare the effectiveness of common treatment regimens, 2) to analyze the cost-effectiveness of different treatment regimens for AIS, 3) to analyze the incidence of adverse events and complications in enrolled patients with AIS, 4) to analyze the effect of Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification on the specific therapies during acute phase treatment period. Discussion In face of changing treatment patterns and increasing demand from medical insurers for cost-effectiveness data in China, a large-scale registry study examining the real-world patterns of AIS in hospitals is needed. The CASTOR study will help to find favorable cost-utility treatment regimens for AIS and improve the overall treatment outcome of Chinese patients with AIS.

Abstract The relation between obesity and stroke outcome has been disputed. This study was aimed to determine the association of body mass index (BMI) with mortality and functional outcome in patients with acute ischemic stroke. Data were from a national, multi-centre, prospective, hospital-based register: the ChinaQUEST (Quality Evaluation of Stroke Care and Treatment) study. Of 4782 acute ischemic stroke patients, 282 were underweight (BMI

BACKGROUND:Olfactory testing is a useful tool in the differential diagnosis of Parkinson's Disease (PD). Although fast and easy to use, the high intercultural variability of odor detection limits the world-wide use of the most common test sets. OBJECTIVE:The aim of this study was to test one of the most commonly used olfactory tests (Sniffin' Sticks 12-identification test) in an adapted version for a Chinese population of healthy subjects and PD patients. METHODS:For this purpose, cohorts of 39 Chinese and 41 German PD patients as well as 70 Chinese and 100 German healthy subjects have been examined both with the original and the adapted version of the Sniffin' Sticks test, the latter being designed according to the regional culture. RESULTS:The adapted Chinese version of the Sniffin' Sticks 12 identification test proved to discriminate Chinese PD patients from controls with a high specificity but relatively low sensitivity. Yet not all odor exchanges would have been necessary as the original odors including liquorice and coffee showed an equally high identification rate in the Chinese and German cohorts. CONCLUSIONS:The results showed that the newly adapted test could be used as a screening test for PD related olfactory dysfunction in a Chinese population. However further investigation will be necessary to optimize the selection of odors for the Chinese version of the test.

Background The optimal range of blood pressure variability remains unclear. We aimed to stratify the degree of risk of stroke based on visit‐to‐visit systolic blood pressure (SBP) variability in a large Chinese hypertensive population in 32 communities. Methods and Results We retrospectively analyzed the data of 20 702 hypertensive patients from the China Stroke Primary Prevention Trial. The participants were randomized into 2 treatment groups to receive either enalapril or enalapril plus folic acid. Their blood pressures were measured every 3 months. The outcome was the first stroke. Three parameters of SBP variability were calculated: standard deviation, coefficient of variation, and average real variability. The records of first 4, 6, 8, 10 and 12 visits at which SBP was measured were used to calculate SBP variability and to predict subsequent stroke risk in adjusted Cox regression models. After median follow‐up of 4.5 years, 597 patients had experienced stroke. Visit‐to‐visit SBP variability was an independent predictor of subsequent stroke (eg, the hazard ratio for the highest quintile of average real variability [22.67–61.07 mm Hg] over 6 visits was 1.55, 95% CI 1.07–2.25, P=0.021), independent of mean SBP over the follow‐up period. Its value was more predictive when more blood pressure records were used. Conclusions Visit‐to‐visit SBP variability is an independent predictor of primary stroke in Chinese hypertensive patients. This predictive value depends on the number of blood pressure measurements used to calculate variability but is independent of mean SBP. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Black rice (Oryza sativa L.), whose pericarp is rich in anthocyanins (ACNs), is considered as a healthier alternative to white rice. Molecular species of ACNs in black rice have been well documented in previous studies; however, information about the metabolic mechanisms underlying ACN biosynthesis during black rice grain development is unclear.The aim of the present study was to determine changes in the metabolic pathways that are involved in the dynamic grain proteome during the development of black rice indica cultivar, (Oryza sativa L. indica var. SSP). Isobaric tags for relative and absolute quantification (iTRAQ) MS/MS were employed to identify statistically significant alterations in the grain proteome. Approximately 928 proteins were detected, of which 230 were differentially expressed throughout 5 successive developmental stages, starting from 3 to 20 days after flowering (DAF). The greatest number of differentially expressed proteins was observed on 7 and 10 DAF, including 76 proteins that were upregulated and 39 that were downregulated. The biological process analysis of gene ontology revealed that the 230 differentially expressed proteins could be sorted into 14 functional groups. Proteins in the largest group were related to metabolic process, which could be integrated into multiple biochemical pathways. Specifically, proteins with a role in ACN biosynthesis, sugar synthesis, and the regulation of gene expression were upregulated, particularly from the onset of black rice grain development and during development. In contrast, the expression of proteins related to signal transduction, redox homeostasis, photosynthesis and N-metabolism decreased during grain maturation. Finally, 8 representative genes encoding different metabolic proteins were verified via quantitative real-time polymerase chain reaction (qRT-PCR) analysis, these genes had differed in transcriptional and translational expression during grain development.Expression analyses of metabolism-related protein groups belonging to different functional categories and subcategories indicated that significantly upregulated proteins were related to flavonoid and starch synthesis. On the other hand, the downregulated proteins were determined to be related to nitrogen metabolism, as well as other functional categories and subcategories, including photosynthesis, redox homeostasis, tocopherol biosynthetic, and signal transduction. The results provide valuable new insights into the characterization and understanding of ACN pigment production in black rice.

BACKGROUND:Rates of acute intracerebral hemorrhage (ICH) increase in winter months but the magnitude of risk is unknown. We aimed to quantify the association of ambient temperature with the risk of ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) participants on an hourly timescale. METHODS:INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of patients with spontaneous ICH (

Stroke is the second most common cause of mortality in China. Although most subtypes of ischemic stroke share similar risk factors, they have different etiologies. Our study aimed to evaluate the different risk factor profiles between the stroke subtypes, lacunar infarcts (LI) and large-artery atherosclerosis (LAA), and clarify the characteristics of current acute ischemic stroke in China.In this cross-sectional study, we analyzed the clinical characteristics of 1982 patients with acute ischemic stroke who were admitted to the neurology department at the Peking University First Hospital between 2007 and 2014. Ischemic stroke was further classified into LAA, LI, cardioembolism (CE) and undetermined causes of infarction (UDI) according to TOAST classification. Demographic characteristics, risk factors, as well as the findings of laboratory and imaging tests of 1773 patients with LAA and LI, were analyzed by univariate and multivariate logistic analysis.Of the 1982 ischemic stroke patients included in this study, 1207 were diagnosed with LAA, 566 with LI, 173 with cardioembolism (CE) and 36 with undetermined causes of infarction (UDI). By comparing the risk factors in multivariate logistic regression analysis, hypertension [odds ratio (OR) = 1.832] and white matter leukoaraiosis (WML) (OR = 1.865) were found to be more strongly correlated with LI than LAA. Low density lipoprotein- cholesterol (LDL-c) (OR = 0.774) were more strongly related to LAA than LI.This study found that hypertension and WML were more strongly correlated with LI than LAA. LDL-c was more strongly related to LAA than LI.

The yeast Ipi3p is required for DNA replication and cell viability in Sacharomyces cerevisiae. It is an essential component of the Rix1 complex (Rix1p/Ipi2p-Ipi1p-Ipi3p) that is required for the processing of 35S pre-rRNA in pre-60S ribosomal particles and for the initiation of DNA replication. The human IPI3 homolog is WDR18 (WD repeat domain 18), which shares significant homology with yIpi3p. Here we report that knockdown of hIPI3 resulted in substantial defects in the chromatin association of the MCM complex, DNA replication, cell cycle progression and cell proliferation. Importantly, hIPI3 silencing did not result in a reduction of the protein level of hCDC6, hMCM7, or the ectopically expressed GFP protein, indicating that protein synthesis was not defective in the same time frame of the DNA replication and cell cycle defects. Furthermore, the mRNA and protein levels of hIPI3 fluctuate in the cell cycle, with the highest levels from M phase to early G1 phase, similar to other pre-replicative (pre-RC) proteins. Moreover, hIPI3 interacts with other replication-initiation proteins, co-localizes with hMCM7 in the nucleus, and is important for the nuclear localization of hMCM7. We also found that hIPI3 preferentially binds to the origins of DNA replication including those at the c-Myc, Lamin-B2 and β-Globin loci. These results indicate that hIPI3 is involved in human DNA replication licensing independent of its role in ribosome biogenesis.

Black rice (Oryza sativa L.) is considered to be a healthy food due to its high content of anthocyanins in the pericarp. The synthetic pathway of anthocyanins in black rice grains has been identified, however, the proteomic profile of leaves during grain development is still unclear. Here, isobaric Tags Relative and Absolute Quantification (iTRAQ) MS/MS was carried out to identify statistically significant changes of leaf proteome in the black rice during grain development. Throughout three sequential developmental stages, a total of 3562 proteins were detected and 24 functional proteins were differentially expressed 3–10 days after flowering (DAF). The detected proteins are known to be involved in various biological processes and most of these proteins were related to gene expression regulatory (33.3%), signal transduction (16.7%) and developmental regulation and hormone-like proteins (12.5%). The coordinated changes were consistent with changes in regulatory proteins playing a leading role in leaves during black rice grain development. This indicated that signal transduction between leaves and grains may have an important role in anthocyanin biosynthesis and accumulation during grain development of black rice. In addition, four identified up-regulated proteins associated with starch metabolism suggested that the remobilization of nutrients for starch synthesis plays a potential role in anthocyanin biosynthesis of grain. The mRNA transcription for eight selected proteins was validated with quantitative real-time PCR. Our results explored the proteomics of the coordination between leaf and grain in anthocyanins biosynthesis of grain, which might be regulated by signal transduction and sugar metabolism in black rice leaf.

BACKGROUND: The burden of stroke is high and increasing in China. We modelled variations in, and predictors of, the costs of hospital care for patients with acute stroke in China. METHODS AND FINDINGS: Baseline characteristics and hospital costs for 5,255 patients were collected using the prospective register-based ChinaQUEST study, conducted in 48 Level 3 and 14 Level 2 hospitals in China during 2006-2007. Ordinary least squares estimation was used to determine factors associated with hospital costs. Overall mean cost of hospitalisation was 11,216 Chinese Yuan Renminbi (CNY) (≈US$1,602) per patient, which equates to more than half the average annual wage in China. Variations in cost were largely attributable to stroke severity and length of hospital stay (LOS). Model forecasts showed that reducing LOS from the mean of 20 days for Level 3 and 18 days for Level 2 hospitals to a duration of 1 week, which is common among Western countries, afforded cost reductions of 49% and 19%, respectively. Other lesser determinants varied by hospital level: in Level 3 hospitals, health insurance and the occurrence of in-hospital complications were each associated with 10% and 18% increases in cost, respectively, whilst treatment in a teaching hospital was associated with approximately 39% decrease in cost on average. For Level 2 hospitals, stroke due to intracerebral haemorrhage was associated with a 19% greater cost than for ischaemic stroke. CONCLUSIONS: Changes to hospital policies to standardise resource use and reduce the variation in LOS could attenuate costs and improve efficiencies for acute stroke management in China. The success of these strategies will be enhanced by broader policy initiatives currently underway to reform hospital reimbursement systems.