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Abstract Purpose To investigate the associations between the most popular social media platform WeChat usage and cognitive performance among the middle-aged and older Chinese population using data from a nationally representative survey. Methods In total, 17,472 participants (≥ 45 years old) from the China Health and Retirement Longitudinal Study (CHARLS, Wave 4, 2018) were analyzed. Cognitive performance including episodic memory and executive function was assessed using Mini-Mental Status Examination (MMSE). Other confounding variables included socio-economic characteristics, medical status, and lifestyle-related information. Multiple linear regression models were used to test the association between cognitive performance and WeChat usage by introducing covariates hierarchically. Subgroup analyses of age and gender were conducted to estimate the robustness of the primary findings. Results After adjusting for multiple confounders across all linear models, WeChat usage is significantly associated with executive function, episodic memory, and global cognitive performance (all p values

Abstract Gypsification is a common problem in weathered calcareous relics. In previous studies, the solutions of barium hydroxide in water and methanol were used as protectants for gypsification calcareous relics and showed significant differences in permeability. In this study, the underlying reasons for permeability differences between these two solutions were investigated using optical microscopy, ultraviolet–visible spectrophotometry, X-ray diffractometry, Fourier transform infrared spectroscopy, the phenolphthalein test and physical property characterizations. The results indicated that the permeability differences were primarily caused by the solutions’ reactivity. Specifically, owing to the high reactivity of barium hydroxide in water, it reacted rapidly with atmospheric CO2 and gypsum (the weathering product) to generate barium carbonate, barium sulfate and calcium hydroxide precipitates. These precipitates hindered the penetration of solution into weathered relics. In contrast, barium hydroxide in methanol did not react with atmospheric CO2 or weathered relics, which also kept the solution in a liquid state during the infiltration process. Therefore, the solution of barium hydroxide in methanol exhibited high permeability. Based on the above findings, this study is meaningful for applying barium protectants in the conservation of gypsification calcareous relics.

Abstract Temozolomide (TMZ) is a standard treatment for glioblastoma (GBM) patients. However, TMZ has moderate therapeutic effects due to chemoresistance of GBM cells through less clarified mechanisms. Here, we demonstrate that TMZ-derived 5-aminoimidazole-4-carboxamide (AICA) is converted to AICA ribosyl-5-phosphate (AICAR) in GBM cells. This conversion is catalyzed by hypoxanthine phosphoribosyl transferase 1 (HPRT1), which is highly expressed in human GBMs. As the bona fide activator of AMP-activated protein kinase (AMPK), TMZ-derived AICAR activates AMPK to phosphorylate threonine 52 (T52) of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), leading to RNR activation and increased production of dNTPs to fuel the repairment of TMZ-induced-DNA damage. RRM1 T52A expression, genetic interruption of HPRT1-mediated AICAR production, or administration of 6-mercaptopurine (6-MP), a clinically approved inhibitor of HPRT1, blocks TMZ-induced AMPK activation and sensitizes brain tumor cells to TMZ treatment in mice. In addition, HPRT1 expression levels are positively correlated with poor prognosis in GBM patients who received TMZ treatment. These results uncover a critical bifunctional role of TMZ in GBM treatment that leads to chemoresistance. Our findings underscore the potential of combined administration of clinically available 6-MP to overcome TMZ chemoresistance and improve GBM treatment.

Singlet fission (SF) is a spin-conserving process converting 1 singlet exciton into 2 triplet excitons. This exciton multiplication mechanism offers an attractive route to solar cells that circumvent the single-junction Shockley–Queisser limit. However, it remains unclear how intermolecular coupling, which is subject to the aggregation extent in thin-film morphology, controls SF pathways and dynamics. The prototype molecule 6,13-bis(triisopropylsilylethynyl)-pentacene (TIPS-pentacene) has been extensively studied to investigate SF mechanisms. However, previous literature reports have presented divergent SF mechanisms and pathways in TIPS-pentacene films. In this study, solvent vapor annealing treatment is used to deliberately adjust the aggregation extent in TIPS-pentacene films. This enables us to reproduce various SF pathways reported in the literature under the same experimental conditions, with the only variation being the level of aggregation. These results shed light on the crucial role that molecular aggregation plays in modulating both the SF mechanism and pathway and reconciles the previously contentious SF mechanisms and pathways reported in TIPS-pentacene films. Our study offers substantial insights into the understanding of the SF mechanism and provides a potential avenue for future control of SF pathways in accordance with specific application requirements.

Summary: EGFRT790M mutation causes resistance to the first-generation tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, the therapeutic options for sensitizing first TKIs and delaying the emergence of EGFRT790M mutant are limited. In this study, we show that quercetin directly binds with glucose-6-phosphate dehydrogenase (G6PD) and inhibits its enzymatic activity through competitively abrogating NADP+ binding in the catalytic domain. This inhibition subsequently reduces intracellular NADPH levels, resulting in insufficient substrate for methionine reductase A (MsrA) to reduce M790 oxidization of EGFRT790M and inducing the degradation of EGFRT790M. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFRT790M-harboring NSCLCs and delays the acquisition of the EGFRT790M mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFRT790M mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFRT790M-driven TKI resistance by directly targeting G6PD.

Abstract Background HCFC1 encodes transcriptional co‐regulator HCF‐1, which undergoes an unusual proteolytic maturation at a centrally located proteolysis domain. HCFC1 variants were associated with X‐linked cobalamin metabolism disorders and mental retardation‐3. This study aimed to explore the role of HCFC1 variants in common epilepsy and the mechanism underlying phenotype heterogeneity. Methods Whole‐exome sequencing was performed in a cohort of 313 patients with idiopathic partial (focal) epilepsy. Functional studies determined the effects of the variants on the proteolytic maturation of HCF‐1, cell proliferation and MMACHC expression. The role of HCFC1 variants in partial epilepsy was validated in another cohort from multiple centers. Results We identified seven hemizygous HCFC1 variants in 11 cases and confirmed the finding in the validation cohort with additional 13 cases and six more hemizygous variants. All patients showed partial epilepsies with favorable outcome. None of them had cobalamin disorders. Functional studies demonstrated that the variants in the proteolysis domain impaired the maturation by disrupting the cleavage process with loss of inhibition of cell growth but did not affect MMACHC expression that was associated with cobalamin disorder. The degree of functional impairment was correlated with the severity of phenotype. Further analysis demonstrated that variants within the proteolysis domain were associated with common and mild partial epilepsy, whereas those in the kelch domain were associated with cobalamin disorder featured by severe and even fatal epileptic encephalopathy, and those in the basic and acidic domains were associated with mainly intellectual disability. Conclusion HCFC1 is potentially a candidate gene for common partial epilepsy with distinct underlying mechanism of proteolysis dysfunction. The HCF‐1 domains played distinct functional roles and were associated with different clinical phenotypes, suggesting a sub‐molecular effect. The distinct difference between cobalamin disorders and idiopathic partial epilepsy in phenotype and pathogenic mechanism, implied a clinical significance in early diagnosis and management.

Objectives The aims of the study were to assess the management of low-density lipoprotein cholesterol (LDL-C) and the goal achievement, as well as to investigate the association between baseline LDL-C level, lipid-lowering treatment (LLT), and stroke recurrence in patients with ischaemic stroke or transient ischaemic attack (TIA).Design Our study was a post hoc analysis of the Third China National Stroke Registry (CNSR-III).Setting We derived data from the CNSR-III - a nationwide clinical registry of ischaemic stroke and TIA based on 201 participating hospitals in mainland China.Participants 15,166 patients were included in this study with demographic characteristics, etiology, imaging, and biological markers from August 2015 to March 2018.Primary and secondary outcome measures The primary outcome was a new stroke, LDL-C goal (LDL-C

With the advent of the stock-planning era, urban renewal has gradually become an important part of urban construction. Urban renewal is essentially a process of solving the rational redistribution of space. However, blind urban renewal can easily lead to the waste of space resources. Therefore, an appropriate renewal location can maximize the space’s renewal efficiency. Based on the perspective of space benefits, this study constructs an urban renewal site selection evaluation system suitable for Macau SAR from two aspects of social and economic benefits and space benefits and uses the DEA model to verify the evaluation system. Thus, we can more objectively and directly judge the evaluation of benefits in urban renewal site selection, maximize the efficiency of spatial renewal, and provide reference for urban site selection decisions. The results are as follows: Funing Building is the best item among the four renewal projects, and it is also the most suitable target point for development; the super-rich benefit is inefficient in terms of both space benefit and production cost benefit.

BackgroundAs a form of severe combined immunodeficiency (SCID), Janus kinase 3 (JAK3) deficiency can be fatal during severe infections in children, especially after inoculation of live-attenuated vaccines. We report a unique case of JAK3 deficiency with two compound heterozygous JAK3 mutations complicated by disseminated Bacille Calmette–Guérin (BCG) disease and Pneumocystis pneumonia.Case descriptionA 5-month-old Chinese girl presented with recurring fever and productive cough after BCG vaccination and ineffective antibiotic treatment. Chest CT demonstrated bilateral infiltrations, enlarged mediastinal and axillary lymph nodes, and hypoplasia of the thymus. Mycobacterium tuberculosis and Pneumocystis jirovecii were detected from blood samples by sequencing. Acid-fast bacilli were also found from the sputum aspirate and gastric aspirate. Lymphocyte subset analyses indicated T-B+NK- immunodeficiency, and gene sequencing identified two heterozygous missense mutations (one unreported globally) in the Janus homology 7 (JH7) domain of JAK3. The patient received rifampicin, isoniazid, ethambutol, and trimethoprim/sulfamethoxazole and was discharged after improvements but against advice.OutcomeThe patient died at 13 months of age due to severe infections and hepatic damage.DiscussionSCID should be recognized before inoculation of live-attenuated vaccines in children. Newborn screening for SCID is advocated. Further investigations are needed to better understand the pathogenicity of the variants and molecular mechanism of the JH7 domain of JAK3.

Background Small single subcortical infarction (SSSI) may be classified as parent artery disease-related or only branch involved according to the stenosis of parent artery. The study aimed to evaluate short-term and long-term prognoses and the effectiveness of antiplatelet therapy in SSSI.Methods We prospectively enrolled 2890 patients with SSSI from the Third China National Stroke Registry (CNSR-III) database from August 2015 to March 2018. We assessed clinical outcomes and antiplatelet treatment effects in patients with SSSI with and without parent artery stenosis (PAS) identified by magnetic resonance angiography.Results Among 2890 patients with SSSI in the perforator territory of the middle cerebral artery and the basilar artery, there were 680 (23.53%) patients with PAS and 2210 (76.47%) patients without PAS, respectively. After adjusting for potential confounders, the PAS group had a greater initial stroke severity (OR 1.262, 95% CI 1.058 to 1.505; p=0.0097) and a higher risk of ischaemic stroke recurrence at 3 months (OR 2.266, 95% CI 1.631 to 3.149; p

Abstract Background Malaria is still a serious public health problem on Bioko Island (Equatorial Guinea), although the number of annual cases has been greatly reduced since 2004 through the Bioko Island Malaria Control Project (BIMCP). A better understanding of malaria parasite population diversity and transmission dynamics is critical for assessing the effectiveness of malaria control measures. The objective of this study is to investigate the genetic diversity of Plasmodium falciparum populations and multiplicity of infection (MOI) on Bioko Island 7 years after BIMCP. Methods A total of 181 patients with uncomplicated P. falciparum malaria diagnosed with microscopy were collected from Bioko Island from January 2011 to December 2014. Parasite DNA was extracted using chelex-100 and species were identified using a real-time PCR followed by high-resolution melting. Plasmodium falciparum msp1 and msp2 allelic families were determined using nested PCR. Results Three msp1 alleles (K1, MAD20, and RO33) and two msp2 alleles (FC27 and 3D7) were analysed in all samples. In msp1, the MAD20 allelic family was predominant with 96.69% (175/178) followed respectively by the K1 allelic family with 96.07% (171/178) and R033 allelic family with 70.78% (126/178). In msp2, the FC27 allelic family was the most frequently detected with 97.69% (169/173) compared to 3D7 with 72.25% (125/173). Twenty-six different alleles were observed in msp1 with 9 alleles for K1, 9 alleles for MAD20 and 8 alleles for R033. In msp2, 25 individual alleles were detected with 5 alleles for FC27 and 20 alleles for 3D7. The overall MOI was 5.51 with respectively 3.5 and 2.01 for msp1 and msp2. A significant increase in overall MOI was correlated with the age group of the patients (P = 0.026) or parasite densities (P = 0.04). Conclusions The present data showed high genetic diversity and MOI values among the P. falciparum population in the study, reflecting both the high endemic level and malaria transmission on Bioko Island. These data provide valuable information for surveillance of P. falciparum infection and for assessing the appropriateness of the current malarial control strategies in the endemic area.

An accurate second-order spatial and temporal finite-difference scheme is applied to solve the dynamics model of a depth-averaged avalanche. Within the framework of the MacCormack scheme, a total variation diminishing term supplements the corrector step to suppress large oscillations in domains with steep gradients. The greatest strength of the scheme lies in its high computational efficiency while maintaining satisfactory accuracy. The performance of the scheme is tested on a granular flume flow–obstacle interaction scenario and a granular dam breaking scenario. In the former, the flume flow splits into two granular streams when an obstacle is encountered. The opening between the two granular streams widens when the side length of the obstacle increases. In the simulation, shock waves with a fan-shaped configuration are captured, and successive waves in the tail of the avalanche between the two streams are observed. In the latter scenario, the average values and the fluctuations in the flow rate and velocity (at relatively steady state) decrease with the width of the breach. The capture of complex and typical granular-flow phenomena indicates the applicability and effectiveness of combining the TVD-MacCormack Scheme and S-H model to simulate dam breaking and inclined flow–obstacle interaction cases. In this study, the dense granular flow strikes on a rigid obstacle that is described by a wall boundary, rather than a topographic feature with a finite slope. This shows that the TVD-MacCormack scheme has a shock-capturing ability. The results of granular dam break simulations also revealed that the boundary conditions (open or closed) affect the collapse of the granular pile, i.e., the grains evenly breached out under closed boundary conditions, whereas the granules breaching out of the opening were mostly grains adjacent to the boundaries under open boundary conditions.

Objective To study the characteristics of cerebral hemodynamics and the correlation with cognitive function in patients with mild cognitive impairment (MCI). Methods A total of 80 cases were divided into MCI group (N = 40) and control group (N = 40). Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate the cognitive function of 2 groups. Bilateral middle cerebral artery (MCA) and basilar artery (BA) were examined by means of transcranial Doppler (TCD) ultrasound to obtain mean flow velocity (MFV), pulsatility index (PI), resistance index (RI) and the ratio of peak systolic velocity to end-diastolic velocity (S/D) in all subjects. Results Compared with control group, PI (P = 0.023) and RI (P = 0.035) of MCA were significantly increased in MCI group. The differences in MFV, S/D and hemodynamic indexes of BA had no significance between 2 groups (P > 0.05, for all). The rate of abnormal PI of MCA in MCI group was higher than that in control group [45% (18/40) vs. 20% (8/40); χ2 = 4.615, P = 0.032]. Pearson correlation analysis showed that PI of MCA had negative correlation with MoCA score in MCI group (r = -0.382, P = 0.036), and no correlation with MMSE score (P > 0.05). MFV, RI and S/D of MCA and MFV, PI, RI and S/D of BA had no correlation with MoCA and MMSE scores (P > 0.05, for all). MCI group was further divided into subgroups according to PI, and MoCA score was significantly lower in abnormal PI subgroup than that in normal PI subgroup [(18.57 ± 3.02) score vs. (23.41 ± 2.78) score; t = 3.914, P = 0.015]. Conclusions Cerebral hemodynamics in MCI patients was changed. The cognitive impairment was closely related to the increase of PI in MCA. DOI: 10.3969/j.issn.1672-6731.2017.01.011

BACKGROUND:Guidelines from the U.S. National Comprehensive Cancer Network have recommended use of concurrent chemoradiotherapy (CCRT), followed by a 3-cycles combination of platinum and 5-fluorouracil chemotherapy as standard treatment for nasopharyngeal carcinoma (NPC). The benefits of CCRT for treatment of locally advanced NPC have been established. Whether platinum and 5-fluorouracil chemotherapy should be routinely added to locally advanced NPC after CCRT is still open to debate. Whether adjuvant chemotherapy provides an additional survival benefit for the subgroup of patients with residual nasopharyngeal carcinoma who have undergone CCRT is also unclear. This retrospective study was initiated to determine the survival benefit of adjuvant chemotherapy (AC) in residual NPC patients who have undergone concurrent chemoradiotherapy. METHODS:The retrospective study included 155 nasopharyngeal carcinoma patients who had local residual lesions after the platinum-based CCRT without or with AC. Kaplan-Meier analysis and the log-rank test were used to estimate overall survival (OS), failure-free survival (FFS), local relapse-free survival (LRFS) and distant metastasis-free survival (DMFS). RESULTS:Median follow-up was 47 months. Adjuvant cisplatin or nedaplatin plus 5-fluorouracil chemotherapy did not significantly improve 3-year OS, LRFS, FFS, and DMFS for patients with residual nasopharyngeal carcinoma after undergoing CCRT. The 3-year OS rates for the no-AC group and AC group were 71.6% and 73.7%, respectively (P= 0.44). The 3-year FFS rates for no-AC group and AC group were 57.5% and 66.9%, respectively ((P= 0.19). The 3-year LRFS rates for no-AC group and AC group were 84.7% and 87.9%, respectively ((P= 0.51). The 3-year DMFS rates for no-AC group and AC group were 71.4% and 77.4%, respectively ((P= 0.23). CONCLUSIONS:Since we did not find sufficient data to support significant survival in 3-year OS, LRFS, FFS, and DMFS, whether Adjuvant cisplatin or nedaplatin and 5-fluorouracil chemotherapy should be routinely added to residual nasopharyngeal carcinoma patients after undergoing CCRT remain uncertain.