Compound heterozygous mutations in three Chinese patients of Segawa syndrome and their treatment outcomes.

Segawa syndrome is a rare autosomal recessive form of dopa-responsive dystonia resulting from TH gene dysfunction. Patients typically exhibit symptoms such as generalized dystonia, rigidity, tremors, infantile Parkinsonism, and pseudo-spastic paraplegia. Levodopa is often an effective treatment. Due to its rarity, high heterogeneity, and poorly understood pathological mutation and phenotype spectrums, as well as genotype-phenotype and genotype-treatment outcome correlations, Segawa syndrome poses diagnostic and therapeutic challenges. In our study, through clinical and molecular analyses of three Chinese Segawa patients, we re-evaluated the pathogenicity of a TH mutation (c.880G>C;p.G294R) previously categorized as "Conflicting classifications of pathogenicity" in ClinVar. Also, we summarized the clinical phenotypes of all reported Segawa syndrome cases until 2023 and compared them with our patients. We identified a novel phenotype, "cafe-au-lait macules," not previously observed in Segawa patients. Additionally, we discussed the correlation between specific genotypes and phenotypes, as well as genotypes and treatment outcomes of our three cases. Our findings aim to enhance the understanding of Segawa syndrome, contributing to improved diagnosis and treatment approaches in the future.

Review of the research status on the transmission and diffusion characteristics of indoor viral aerosol particles.

This study reviews the generation and diffusion characteristics of indoor viral aerosol particles, numerical simulation methods for the diffusion process of viral aerosols, and related research on the impact mechanism of different ventilation methods on the diffusion process of viral aerosols. Research has shown that the selection of initial conditions such as exhalation mode, initial airflow velocity, particle size, turbulence model, and calculation method for the generation of aerosol particles by the human body is of great significance for the numerical simulation of the diffusion process of viral aerosol particles. At the same time, on the basis of selecting appropriate ventilation methods, the reasonable setting of ventilation parameters (temperature, speed, height, etc.) can effectively suppress the spread of viral aerosols. This study can provide a theoretical basis for the study of related respiratory diseases, as well as technical and theoretical support for the selection of indoor ventilation methods to reduce the risk of human exposure caused by viral aerosols in the construction field. It also provides guidance and reference for aerosol transport and environmental protection in indoor atmospheric environments.

Incentive policy for the comprehensive development of young medical talents: an evolutionary game study.

Introduction: Currently in China, there is a lack of well-defined and viable incentive mechanisms at the governmental and hospital levels to support the development of young medical talents, thereby hindering their growth Existing studies primarily investigate the current state and trajectory of incentives, yet they inadequately address the distinctive characteristics of various stakeholders involved in medical talent incentive processes, particularly the lack of research on incentive mechanisms with Chinese attributes. Methods: This study adopts evolutionary game theory to investigate the dynamics of replication and the strategies for achieving evolutionary stability in the comprehensive development of young medical talents, considering both scenarios with and without supportive policies. Results: In the absence of any supportive policy measures, the evolutionarily stable strategy (ESS) point is O(0,0), the unstable equilibrium point is C(1,1), and the saddle points are A(0,1), B(1,0). The initial state of the system is at the unstable equilibrium point C(1,1), which means that the young medical talents and medical institutions adopt a combination of strategies (actively seeking comprehensive development and taking incentive measures). Under the scenario with supportive policies, the ESS point is C(1,1), the unstable equilibrium point is O(0,0), and the saddle points are A(0,1), B(1,0). The initial state of the system is at the unstable equilibrium point O(0,0), which means that young medical talents and medical institutions adopt (N,N) strategy combinations (inactively seeking comprehensive development, implementing no incentive measure). Discussion: (1) Government incentives play a crucial role in motivating young medical talents to seek comprehensive development. (2) The level of government incentive support for young medical talents should exceed the cost increment of individual efforts. Additionally, the policy support provided by the government to medical institutions should surpass the incentive support offered by these institutions to young medical talents. This will enhance the motivation and encouragement efforts of medical institutions in actively promoting comprehensive development among young medical talents. (3) With the backing of certain government incentive policies, medical institutions implementing incentive measures and young medical talents actively seeking comprehensive development will establish a virtuous cycle of mutual promotion.

The adjuvant treatment role of ω-3 fatty acids by regulating gut microbiota positively in the acne vulgaris.

Objectives:We aimed to explore the potential role of omega-3 (ω-3) fatty acids on acne vulgaris by modulating gut microbiota.Materials and Methods:We randomly divided the untreated acne patients into two groups with or without ω-3 fatty acids intervention for 12 weeks. The Sprague Dawley (SD) rats with acne model were given isotretinoin, ω-3 fatty acids or their combination respectively. Then the colonic contents samples of the drug intervention SD rats were transferred to the pseudo sterile rats with acne model. The severity of the disease was assessed by the Global Acne Grading System (GAGS) score of the patients, and the swelling rate of auricle and the pathological section of the rat with acne model. The 16S rDNA gene sequencing was performed to detect the alteration of the gut microbiota.Results:ω-3 fatty acids could increase the diversity of the gut microbiota and regulate the flora structure positively both in the patients and rats, increase the abundance of butyric acid producing bacteria and GAGS score in the patients, and alleviate the inflammation and comedones of rats.Conclusion:Supplementation of ω-3 fatty acids could alleviate the inflammation of acne vulgaris by increasing the abundance of butyric acid producing bacteria.

Colloidal Self-Assembly: From Passive to Active Systems.

Self-assembly fundamentally implies the organization of small sub-units into large structures or patterns without the intervention of specific local interactions. This process is commonly observed in nature, occurring at various scales ranging from atomic/molecular assembly to the formation of complex biological structures. Colloidal particles may serve as micrometer-scale surrogates for studying assembly, particularly for the poorly understood kinetic and dynamic processes at the atomic scale. Recent advances in colloidal self-assembly have enabled the programmable creation of novel materials with tailored properties. We here provide an overview and comparison of both passive and active colloidal self-assembly, with a discussion on the energy landscape and interactions governing both types. In the realm of passive colloidal assembly, many impressive and important structures have been realized, including colloidal molecules, one-dimensional chains, two-dimensional lattices, and three-dimensional crystals. In contrast, active colloidal self-assembly, driven by optical, electric, chemical, or other fields, involves more intricate dynamic processes, offering more flexibility and potential new applications. A comparative analysis underscores the critical distinctions between passive and active colloidal assemblies, highlighting the unique collective behaviors emerging in active systems. These behaviors encompass collective motion, motility-induced phase segregation, and exotic properties arising from out-of-equilibrium thermodynamics. Through this comparison, we aim to identify the future opportunities in active assembly research, which may suggest new application domains.

How the National Health Insurance Coverage policy changed the use of lenvatinib for adult patients with advanced hepatocellular carcinoma: a retrospective cohort analysis with real world big data.

BACKGROUND: To establish a long-term mechanism to control the cost burden of drugs, the Chinese government organized seven rounds of price negotiations for the national reimbursement drug list (NRDL) from 2016 to the end of 2022. The study aimed to evaluate the impact of the National Health Insurance Coverage (NHIC) policy on the use of lenvatinib as the first-line treatment for advanced hepatocellular carcinoma (HCC) within a specific medical insurance region from the micro perspective of individual patient characteristics. METHODS: The data of HCC patients that received lenvatinib from September 2019 to August 2022 was retrieved from the Medical and Health Big Data Center and longitudinally analyzed. Contingency table chi-square statistics and binary logistic regression analysis were used to compare the differences in the categorical variables. Interrupted time-series (ITS) regression analysis was performed to evaluate the changes in the utilization of lenvatinib over 36 months. Multiple linear regression was used to analyze the impact of receiving lenvatinib on the total hospitalization expenses of hospitalized patients with advanced HCC. RESULTS: A total of 12,659 patients with advanced HCC were included in this study. The usage rate of lenvatinib increased from 6.19% to 15.28% over 36 months (P < 0.001). By controlling the other factors, consistent with this, the probability of patients with advanced HCC receiving lenvatinib increased by 2.72-fold after the implementation of the NHIC policy (OR = 2.720, 95% CI:2.396-3.088, P < 0.001). Older, residency in rural areas, lack of fixed income, treatment at hospitals below the tertiary level, and coverage by urban-rural residents' basic medical insurance (URRBMI) were the factors affecting the use of lenvatinib among patients with advanced HCC (P < 0.05). After the implementation of the NHIC policy, the total hospitalization expenses increased (Beta=-0.040, P < 0.001). However, compared to patients who received lenvatinib, the total hospitalization expenses were higher for those who did not receive the drug (US$5022.07 ± US$5488.70 vs. US$3701.63 ± US$4330.70, Beta = 0.062, P < 0.001). CONCLUSIONS: The NHIC policy has significantly increased the utilization of lenvatinib. In addition, we speculate that establishing multi-level medical insurance systems for economically disadvantaged patients would be beneficial in improving the effectiveness of the NHIC policy in the real world.

Multi-omics insights into the mechanism of the high-temperature tolerance in a thermotolerant Chlorella sorokiniana.

Improving high-temperature tolerance of microalgae is crucial to enhance the robustness and economy of microalgae industrial production. Herein, a continuous adaptive laboratory evolution (ALE) system was developed to generate the thermotolerant strain of Chlorella sorokiniana. The resulting thermotolerant strain TR42 exhibited excellent cell growth and biomass production at 42 °C, the temperature that the original strain (OS) could not survive. The high-temperature resistant mechanism of TR42 was investigated by integrating the physiology, transcriptome, proteome and metabolome analyses, which involved enhancing antioxidant capacity, maintaining protein homeostasis, remodeling photosynthetic metabolism, and regulating the synthesis of heat-stress related metabolites. The proof-of-concept high-temperature outdoor cultivation demonstrated that TR42 exhibited 1.15- to 5.72-fold increases in biomass production and 1.62- to 7.04-fold increases in lipid productivity compared to those of OS, respectively, which provided a promising platform for microalgae industrial production. Thus, the multi-system thermotolerant mechanism of TR42 offered potential targets for enhancing high-temperature tolerance of microalgae.

Tunable Self-Thermophoretic Nanomotors with Polymeric Coating.

Thermophoretic micro/nanomotors (MNMs) generate self-propulsion without a chemical reaction. Intrinsically, this promises excellent biocompatibility and is thus suitable for biomedical applications. However, their propulsion efficiency is severely limited due to the poor understanding of the thermophoretic process, which dominates the conversion from thermal energy into mechanical movement. We here developed a series of self-thermophoresis light-powered MNMs with variable surface coatings and discovered obvious self-thermophoresis propulsion enhancement of the polymeric layer. An intrinsically negative self-thermophoretic movement is also observed for the first time in the MNM system. We propose that enthalpic contributions from polymer-solvent interactions should play a fundamental role in the self-thermophoretic MNMs. Quantitative microcalorimetry and molecular dynamics simulations are performed to support our hypothesis. The polymer solvation enthalpy and coating thickness influences on self-thermophoresis are investigated, further highlighting the essential enthalpy contributions to thermophoresis. Our work indicates that surface grafting would be important in designing high-efficiency thermally driven nanorobotic systems for biomedical applications.

Metabolomics analysis of serum lipids in patients with acne vulgaris / 中国热带医学

@#Abstract: Objective To analyze and compare the differences in serum lipid metabolomics between patients with moderate to severe acne and healthy controls to understand the characteristics of serum lipid metabolism in acne patients. Methods Serum samples were collected from 30 patients with moderate to severe acne and 30 healthy controls matched for age, gender and body mass index in the Department of Dermatology, the Affiliated Hospital of Southwest Medical University from May 2019 to Apr. 2020. Serum lipid metabolomics was analyzed by liquid chromatography-tandem mass spectrometry. Partial least squares discriminant analysis (PLS-DA) was used for multivariate statistical analysis of differentially expressed lipid metabolites. The metabolic pathways with significant differences between the two groups were screened by Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Using Mann-Whitney U test to calculate differential metabolites. Spearman correlation analysis was used to analyze the correlation between serum PC (18: 2e/20: 2) concentration and acne severity. Results The PLS-DA results showed that the composition of serum lipid metabolites in acne patients was significantly separated from that in healthy controls. Of the top 30 lipid metabolites with the most significant differences, four kinds of triglycerides (TG), two kinds of diglycerides (DG), six kinds of phosphatidylcholine (PC), one kind of MePC, two kinds of sphingomyelin (SM), two kinds of phosphatidylinositol (PI), two kinds of ceramide (monohexosyl ceramide, Hex1Cer;dihexosyl ceramide, Hex2Cer), two cardiolipin (CL) were found to be increased in the acne group (P<0.05). The levels of one kind of DG, two kinds of lysophosphatidyl ethanolamines (LPE), one kind of dimethylphosphatidyl ethanolamine (dMePE), one kind of bismethyl phosphatidic acid (BisMePA), three kinds of phosphatidyl ethanolamine (PE) and one kind of ceramide were found to be decreased in the acne group (P<0.05), and most of them belonged to phospholipid metabolites. Spearman correlation analysis showed that serum PC (18:2e/20:2) concentration was positively correlated with acne severity (r=0.456, P=0.004). KEGG enrichment function analysis revealed that the differential lipid metabolites were primarily enriched in metabolic pathways such as sphingolipid signaling pathway, cholesterol metabolism, insulin resistance, glycerophospholipid metabolism, among which the sphingolipid signaling pathway may play an important role. Conclusion There are significant differences in serum lipid metabolism between acne patients and healthy controls. Lipid metabolism disorders may be related to the pathogenesis of acne, but it’s molecular mechanism still needs further experimental exploration.

Tryptophan, an important link in regulating the complex network of skin immunology response in atopic dermatitis.

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease, of which the pathogenesis is a complex interplay between genetics and environment. Although the exact mechanisms of the disease pathogenesis remain unclear, the immune dysregulation primarily involving the Th2 inflammatory pathway and accompanied with an imbalance of multiple immune cells is considered as one of the critical etiologies of AD. Tryptophan metabolism has long been firmly established as a key regulator of immune cells and then affect the occurrence and development of many immune and inflammatory diseases. But the relationship between tryptophan metabolism and the pathogenesis of AD has not been profoundly discussed throughout the literatures. Therefore, this review is conducted to discuss the relationship between tryptophan metabolism and the complex network of skin inflammatory response in AD, which is important to elucidate its complex pathophysiological mechanisms, and then lead to the development of new therapeutic strategies and drugs for the treatment of this frequently relapsing disease.

Lactobacillus rhamnosus ameliorates acne vulgaris in SD rats via changes in gut microbiota and associated tryptophan metabolism.

Background: The depletion of beneficial bacteria in the gut has been found in patients with acne vulgaris, and in previous studies, the supplement of Lactobacillus rhamnosus led to the improvement of adult acne. Nevertheless, the potential mechanism of L. rhamnosus in the amelioration of acne vulgaris has not been elucidated yet. Methods: To mimic the human intestinal environment, a pseudo-germ-free rat model was used, and then gut microbiota from healthy individuals and acne patients were transplanted into rats. The effects of L. rhamnosus and tryptophan (Trp) metabolites on a rat acne model were investigated by gavage. Then, 16S rRNA analysis and targeted measurement of metabolites were performed to discover the differences in gut microbiota and metabolites between groups. Finally, HaCaT cells pretreated with Cutibacterium acnes were employed to validate the effect and mechanism of Trp metabolites on acne. Results: L. rhamnosus significantly improved acne-like symptoms in rats by suppressing the level of inflammatory cytokines such as IL-1ß, IL-6, and TNF-α. L. rhamnosus induced an increase in the production of indole-3-acetic acid (IAA) and indole via targeted Trp metabolic analyses. Furthermore, L. rhamnosus promoted bacterial diversity and also enhanced the Firmicutes/Bacteroidota (F/B) ratio, which was positively related to both IAA and indole. Finally, the roles of IAA and indole in alleviating acne vulgaris were confirmed both in vitro and in vivo, which could be reversed by AhR inhibitors. Conclusion: Our study demonstrated that L. rhamnosus could exert its therapeutic effects on acne vulgaris by modulating the gut microbiota and regulating associated Trp metabolites.

Koumine regulates macrophage M1/M2 polarization via TSPO, alleviating sepsis-associated liver injury in mice.

BACKGROUND: Translocator protein (TSPO) is an 18-kDa transmembrane protein found primarily in the mitochondrial outer membrane, and it is implicated in inflammatory responses, such as cytokine release. Koumine (KM) is an indole alkaloid extracted from Gelsemium elegans Benth. It has been reported to be a high-affinity ligand of TSPO and to exert anti-inflammatory and immunomodulatory effects in our recent studies. However, the protective effect of KM on sepsis-associated liver injury (SALI) and its mechanisms are unknown. PURPOSE: To explore the role of TSPO in SALI and then further explore the protective effect and mechanism of KM on SALI. METHODS: The effect of KM on the survival rate of septic mice was confirmed in mouse models of caecal ligation and puncture (CLP)-induced and lipopolysaccharide (LPS)-induced sepsis. The protective effect of KM on CLP-induced SALI was comprehensively evaluated by observing the morphology of the mouse liver and measuring liver injury markers. The serum cytokine content was detected in mice by flow cytometry. Macrophage polarization in the liver was examined using western blotting. TSPO knockout mice were used to explore the role of TSPO in sepsis liver injury and verify the protective effect of KM on sepsis liver injury through TSPO. RESULTS: KM significantly improved the survival rate of both LPS- and CLP-induced sepsis in mice. KM has a significant liver protective effect on CLP-induced sepsis in mice. KM treatment ameliorated liver ischaemia, improved liver pathological injuries, and decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and proinflammatory cytokines in serum. Western blotting results showed that KM inhibited M1 polarization of macrophages and promoted M2 polarization. In TSPO knockout mice, we found that TSPO knockout can improve the survival rate of septic mice, ameliorate liver ischaemia, improve liver pathological injuries, and decrease the levels of ALT, AST, and LDH. In addition, TSPO knockout inhibits the M1 polarization of macrophages in the liver of septic mice and promotes M2 polarization and the serum levels of proinflammatory cytokines. Interestingly, in TSPO knockout septic mice, these protective effects of KM were no longer effective. CONCLUSIONS: We report for the first time that TSPO plays a critical role in sepsis-associated liver injury by regulating the polarization of liver macrophages and reducing the inflammatory response. KM, a TSPO ligand, is a potentially desirable candidate for the treatment of SALI that may regulate macrophage M1/M2 polarization through TSPO in the liver.

Suppression of obesity by melatonin through increasing energy expenditure and accelerating lipolysis in mice fed a high-fat diet.

BACKGROUNDS/OBJECTIVES: Melatonin promotes brown adipose tissue (BAT) activity, leading to body mass reduction and energy expenditure. However, the mechanisms governing these beneficial effects are not well-established. This study aimed to assess the effects of (1) melatonin on BAT and energy metabolism, and (2) fibroblast growth factor 21 (FGF21) in BAT-mediated thermogenesis. METHODS: Male C57BL/6 J mice received a high-fat diet (HFD) or normal chow, accompanied by intraperitoneal injection of 20 mg/kg melatonin for 12 weeks. FGF21-/- mice consumed an HFD with or without melatonin for 8 weeks. RESULTS: Melatonin attenuated weight gain, insulin resistance, adipocyte hypertrophy, inflammation, and hepatic steatosis induced by the HFD and increased energy expenditure. Furthermore, melatonin improved cold tolerance by increasing BAT uncoupling protein 1 (UCP1) expression and producing heat. Notably, melatonin resulted in a shift in energy metabolism favouring the utilization of fat, and it increased FGF21 in circulating and metabolic tissues and skeletal muscle phosphorylation of AMP-activated protein kinase. However, melatonin did not protect against obesity, insulin resistance, and energy expenditure in HFD-fed FGF21-/- mice. CONCLUSIONS: Melatonin suppressed obesity and insulin resistance resulting from the HFD by enhancing BAT activity and energy expenditure, and these effects were dependent on FGF21.

Preparation, Shelf, and Eating Quality of Ready-to-Eat "Guichang" Kiwifruit: Regulation by Ethylene and 1-MCP.

The acceptance of kiwifruit by consumers is significantly affected by its slow ripening and susceptibility to deterioration. Ready-to-eat "Guichang" kiwifruit and its preparation technology were studied by the regulation of ethylene and 1-MCP. Harvested kiwifruits were treated with 100-2000 µl L-1ethylene for 36 h (20°C) and then treatment with 0-0.5 µl L-1 1-MCP. The results showed that the preservation effect of 0.5 µl L-1 1-MCP is inefficient when the soluble solid content of kiwifruit exceeded 15%. The ethylene-treated fruits reached an "edible window" after 24 h, but a higher concentration of ethylene would not further improve ripening efficiency, while the optimal ethylene concentration was 250 µl L-1. Moreover, after 250 µl L-1 ethylene treatment, 0.5 µl L-1 1-MCP would effectively prolong the "edible window" of fruits by approximately 19 days. The volatile component variety and ester content of 0.5 µl L-1 1-MCP-treated fruits were not different from those of the CK group. Principal component analysis and hierarchical cluster analysis indicated that the eating quality of fruits treated with 0.5 µl L-1 1-MCP was similar to that of fruits treated with ethylene. Consequently, ready-to-eat "Guichang" kiwifruit preparation includes ripening with 250 µl L-1 (20°C, 36 h) ethylene without exceeding the 1-MCP threshold and then treated with 0.5 µl L-1 1-MCP (20°C, 24 h). This study highlights the first development of a facile and low-cost preparation technology for ready-to-eat "Guichang" kiwifruit, which could reduce the time for harvested kiwifruit to reach the "edible window" and prolong the "edible window" of edible kiwifruit.

Bioethanol Conversion into Propylene over Various Zeolite Catalysts: Reaction Optimization and Catalyst Deactivation.

Catalytic conversions of bioethanol to propylene were investigated over different zeolite catalysts. H-ZSM-5 (SiO2/Al2O3 = 80) was found to be the most effective for propylene production. Furthermore, H-ZSM-5 (SiO2/Al2O3 = 80) was investigated under different variables of catalytic reaction (calcination temperature, feed composition, reaction temperature, and time on stream) for the conversion of ethanol to propylene. The H-ZSM-5(80) catalysts calcined at 600 °C showed the highest propylene yield. The moderate acidic site on ZSM-5 is required for the production of propylene. The activity on ZSM-5 is independent of the ethanol feed composition. H-ZSM-5 catalyst deactivation was observed, owing to dealumination. The highest propylene yield was 23.4% obtained over HZSM-5(80). Propylene, butene, and ≥C5 olefins were formed by parallel reaction from ethylene. Olefins were converted to each paraffin by sequential hydrogenation reaction. HZSM-5(80) catalyst is a promising catalyst not only for ethanol but also for the conversion of bioethanol to light olefins.

Deuterium-Reinforced Polyunsaturated Fatty Acids Prevent Diet-Induced Nonalcoholic Steatohepatitis by Reducing Oxidative Stress.

Background and Objectives: Oxidative stress is implicated in the progression of nonalcoholic steatohepatitis (NASH) through the triggering of inflammation. Deuterium-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to the reactive oxygen species (ROS)-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-) PUFAs. Here, we aimed to investigate the impacts of D-PUFAs on oxidative stress and its protective effect on NASH. Materials and Methods: C57BL/6 mice were randomly divided into three groups and were fed a normal chow diet, a methionine-choline-deficient (MCD) diet, and an MCD with 0.6% D-PUFAs for 5 weeks. The phenotypes of NASH in mice were determined. The levels of oxidative stress were examined both in vivo and in vitro. Results: The treatment with D-PUFAs attenuated the ROS production and enhanced the cell viability in tert-butyl hydroperoxide (TBHP)-loaded hepatocytes. Concurrently, D-PUFAs decreased the TBHP-induced oxidative stress in Raw 264.7 macrophages. Accordingly, D-PUFAs increased the cell viability and attenuated the lipopolysaccharide-stimulated proinflammatory cytokine expression of macrophages. In vivo, the administration of D-PUFAs reduced the phenotypes of NASH in MCD-fed mice. Specifically, D-PUFAs decreased the liver transaminase activity and attenuated the steatosis, inflammation, and fibrosis in the livers of NASH mice. Conclusion: D-PUFAs may be potential therapeutic agents to prevent NASH by broadly reducing oxidative stress.

Simultaneous quantification of SMN1 and SMN2 copy numbers by MALDI-TOF mass spectrometry for spinal muscular atrophy genetic testing.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by defects in the survival motor neuron 1 (SMN1) gene. Homozygous deletion of the SMN1 gene accounts for 95% of all affected SMA patients. A highly homologous gene survival motor neuron 2 (SMN2) compensates weakly with the loss of SMN1 and its copy number correlates with disease severity. METHODS: We report here the MS-CNV method combining competitive PCR and MALDI-TOF mass spectrometry for simultaneous quantification of SMN1, SMN2 and NAIP dosages. For both SMN1 and SMN2, the exon 7 and exon 8 were analyzed. MS-CNV was validated with parallel analysis by a commercial MLPA assay in two independent cohorts. RESULTS: In the first cohort of 79 blood samples containing 3 SMA patients and 5 carriers, MS-CNV results were highly concordant with MLPA analysis for the copy numbers of SMN1, SMN2 and NAIP. In the second independent and blinded cohort of 62 blood samples containing 21 SMA patients and 14 carriers, MS-CNV results were also highly concordant with MLPA. Both MS-CNV and MLPA quantified SMN1 dosages without ambiguity. CONCLUSIONS: MS-CNV can be used for carrier screening and genetic diagnosis of SMA, providing dosages information for both SMN1 and SMN2 given its accuracy and high sample processing throughput by mass spectrometric analysis.

Moisture adsorption-desorption full cycle power generation.

Environment-adaptive power generation can play an important role in next-generation energy conversion. Herein, we propose a moisture adsorption-desorption power generator (MADG) based on porous ionizable assembly, which spontaneously adsorbs moisture at high RH and desorbs moisture at low RH, thus leading to cyclic electric output. A MADG unit can generate a high voltage of ~0.5 V and a current of 100 µA at 100% relative humidity (RH), delivers an electric output (~0.5 V and ~50 µA) at 15 ± 5% RH, and offers a maximum output power density approaching to 120 mW m-2. Such MADG devices could conduct enough power to illuminate a road lamp in outdoor application and directly drive electrochemical process. This work affords a closed-loop pathway for versatile moisture-based energy conversion.

2-Deoxy-D-glucose increases the sensitivity of glioblastoma cells to BCNU through the regulation of glycolysis, ROS and ERS pathways: In vitro and in vivo validation.

Chloroethylnitrosoureas (CENUs) exert antitumor activity via producing dG-dC interstrand crosslinks (ICLs). However, tumor resistance make it necessary to find novel strategies to improve the therapeutic effect of CENUs. 2-Deoxy-D-glucose (2-DG) is a well-known glycolytic inhibitor, which can reprogram tumor energy metabolism closely related to tumor resistance. Here, we investigated the chemosensitization effect of 2-DG on l,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against glioblastoma cells and the underlying mechanisms. We found that 2-DG significantly increased the inhibitory effects of BCNU on tumor cells compared with BCNU alone, while 2-DG showed no obvious enhancing effect on the BCNU-induced cytotoxicity for normal HaCaT and HA1800 cells. Proliferation, migration and invasion determinations presented the same trend as survival on tumor cells. 2-DG plus BCNU increased the energy deficiency through a more effective inhibition of glycolytic pathway. Notably, the combination of 2-DG and BCNU aggravated oxidative stress in glioblastoma cells, along with a significant decrease in glutathione (GSH) levels, and an increase in intracellular reactive oxygen species (ROS). Subsequently, we demonstrated that the combination treatment led to increased apoptosis via activating mitochondria and endoplasmic reticulum stress (ERS) related apoptosis pathways. Finally, we found that the dG-dC level was significantly increased after 2-DG pretreatment compared to BCNU alone by HPLC-ESI-MS/MS analysis. Finally, in vivo, 2-DG plus BCNU significantly suppressed tumor growth with lower side effects compared with BCNU alone in tumor-bearing mice. In summary, we proposed that 2-DG may have potential to increase the sensitivity of glioblastoma cells to BCNU by regulating glycolysis, ROS and ERS pathways in clinical setting.