Associations between serum amino acids and incident type 2 diabetes in Chinese rural adults

Background and aimsSome amino acids (AAs) may be associated with type 2 diabetes (T2DM). This study aimed to determine the associations of individual AAs with the development of T2DM in rural Chinese adults.Methods and resultsA cohort study of 1199 individuals aged 18 years or older was conducted from 2006 to 2008 in a rural community of Deqing, China, a repeated survey was done in 2015 and data linkage with the electronic health records system was performed each year for identifying new T2DM cases. A high-performance liquid chromatography approach was used to measure the baseline serum concentrations of 15 AAs. Cox proportional hazards models were used to examine the associations between AAs and the risk of incident T2DM. A total of 98 new T2DM cases were identified during the follow-up of 12 years on average. Among 15 AAs, proline was associated with an increased risk of incident T2DM after adjusted for age, sex, body mass index, fasting plasma glucose, family history of T2DM, smoking status, alcohol use, and history of hypertension, the adjusted hazard ratio for 1-standard deviation increment was 1.20 (95% confidence interval: 1.00, 1.43). The association tended to be more marked in subjects younger than 60 years and overweight/obese subjects. Among participants without hypertension, proline and phenylalanine were associated with an increased risk of incident T2DM, while aspartic acid was associated with a decreased risk.ConclusionSerum proline was associated with the risk of incident T2DM in rural Chinese adults and might be a potential predictor.     

Live-imaging of revertant and therapeutically restored dystrophin in the DmdEGFP-mdx mouse model for Duchenne muscular dystrophy

Background

Dmd^mdx, harbouring the c.2983C>T nonsense mutation in Dmd exon 23, is a mouse model for Duchenne muscular dystrophy (DMD), frequently used to test therapies aimed at dystrophin restoration. Current translational research is methodologically hampered by the lack of a reporter mouse model, which would allow direct visualization of dystrophin expression as well as longitudinal in vivo studies.

Methods

We generated a Dmd^EGFP-mdx reporter allele carrying in cis the mdx-23 mutation and a C-terminal EGFP-tag. This mouse model allows direct visualization of spontaneously and therapeutically restored dystrophin-EGFP fusion protein either after natural fibre reversion, or for example, after splice modulation using tricyclo-DNA to skip Dmd exon 23, or after gene editing using AAV-encoded CRISPR/Cas9 for Dmd exon 23 excision.

Results

Intravital microscopy in anaesthetized mice allowed live-imaging of sarcolemmal dystrophin-EGFP fusion protein of revertant fibres as well as following therapeutic restoration. Dystrophin-EGFP-fluorescence persisted ex vivo, allowing live-imaging of revertant and therapeutically restored dystrophin in isolated fibres ex vivo. Expression of the shorter dystrophin-EGFP isoforms Dp71 in the brain, Dp260 in the retina, and Dp116 in the peripheral nerve remained unabated by the mdx-23 mutation.

Conclusion

Intravital imaging of Dmd^EGFP-mdx muscle permits novel experimental approaches such as the study of revertant and therapeutically restored dystrophin in vivo and ex vivo.

     

广东省3个城市大气污染物二氧化氮对居民的死亡效应研究

目的 探讨广东省广州、佛山及珠海3个城市的大气污染二氧化氮（NO₂）对居民每日死亡效应的影响。方法 收集2013—2016年广州、佛山及珠海3个城市的每日大气污染物浓度、气象资料数据和居民的每日总死亡数据,对数据基本特征进行统计描述,并通过Spearman分析其相关关系,最后利用广义相加模型（GAM）分别对3个城市的NO₂日均浓度及每日总死亡数据进行分析。结果 2013—2016年广州、佛山及珠海市的大气污染物NO₂日均浓度分别为46.4、48.4、33.1 μg/m³,均符合国家二级标准（80 μg/m³）。广州市大气中NO₂日均浓度对当天、滞后1、2 d的每日总死亡人数、循环系统疾病死亡人数的影响有统计学意义（均P<0.05）,佛山市滞后1、2 d的NO₂日均浓度对居民每日总死亡人数及循环系统疾病每日死亡人数的影响有统计学意义（均P<0.05）,广州和佛山市均表现出滞后1 d时效应最大。滞后2 d的NO₂日均浓度对广州市居民的呼吸系统疾病每日死亡人数有影响（ER=1.38）。结论 大气污染物NO₂浓度的上升会引起居民死亡风险的增加,应引起重视。     

BOPPPS教学模型在推拿学教学中的实践和探索——以[扌衮]法实训为例

BOPPPS教学模型是以建构主义和交际法为理论依据的教学设计模型,学生积极的参与式互动和教师的及时评价反馈,促成高效的课程教学。本次研究以推拿学中的代表性手法——[扌衮]法实训教学为例,探讨BOPPPS教学模型在推拿学课程的有效构建,使学生能更好地掌握[扌衮]法的理论和实践操作,进一步优化推拿学的教学设计。     

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.     

Poor immune response to coronavirus disease vaccines in decompensated cirrhosis patients and liver transplant recipients

Background and aimsRecent studies have reported poor humoral immune response to mRNA vaccines in patients with chronic liver disease (CLD). However, the immunogenicity of ChAdOx1 (vector-based) and BBV152 (inactivated virus) vaccines in patients with CLD and liver transplant recipients (LTRs) is unknown. Therefore, we aimed to assess the immunogenicity of ChAdOx1 and BBV152 vaccines in patients with CLD (including cirrhosis patients) and LTRs.MethodsIn this single-center prospective study, consecutive completely vaccinated (ChAdOx1 or BBV152) non-cirrhosis CLD patients, those with cirrhosis, and LTRs were compared with matched healthy controls for anti-spike antibody and cellular response.ResultsSixty healthy individuals, 50 NCCLD patients, 63 compensated and 50 decompensated cirrhosis, and 17 LTRs were included. The proportion of non-responders was similar among the healthy control (8 %), non-cirrhosis CLD (16 %), and compensated cirrhosis groups (17.5 %;p = 0.3). However, a higher proportion of patients with decompensated cirrhosis (34 %) and LTRs (59 %) were non-responders than the healthy controls (p = 0.001). Cluster of differentiation (CD) 4-effector cells were lower in patients with non-cirrhosis CLD and compensated cirrhosis. CD4-naïve, CD4-effector, B, and B-memory cells were lower in the decompensated cirrhosis group. Although the central memory cells were higher in the decompensated cirrhosis group, they could not differentiate into effector cells. CD4- and CD8-naïve cells were higher in the marrow in the LTRs, while the CD4-effector memory cells and CD4- and CD8-effector cells were lower in the LTRs. Furthermore, B cells were more deficient in the LTRs, suggesting poor antibody response.ConclusionPatients with decompensated cirrhosis and LTRs demonstrated suboptimal humoral and cellular immune responses against recombinant and inactivated COVID-19 vaccines.     

A statistical assembled deformable model (SAMTUS) for vasculature reconstruction

Although many deformable models have been proposed in medical applications for segmenting isolated structures in the human anatomy, not much of such work had been done on tubular structures such as the vasculature. In this paper, we propose a statistical assembled model for tubular structures (SAMTUS) to segment entire tubular structure from three-dimensional (3D) volumetric data. To our knowledge, there is no literature about the statistical deformable model for entire tubular structures. Specifically, the statistical tubular model is composed of a statistical axis model (SAM) and a statistical surface model (SSM). Both of them are assembled from a set of branch segments through the control points. Instead of searching for fuzzy correspondence along tubular axes or surfaces, we build point matching between feature points along tubular segments, and train SAM and SSM independently to characterize, respectively, the axial and the cross-sectional variation of the entire structure. In this way, more accurate point correspondence can be established, and a larger number of deformation modes can be captured. Our SAMTUS-based segmentation process consists of three stages: initialization, model fitting and final refinement. The experimental results demonstrate that the algorithm obtains good quantifications on the morphology and volume of the vasculature of the zebrafish which is being used increasingly as a specimen for drug screening and genomic research.     

Association of tobacco dependence and quit attempt duration with Rasch-modeled withdrawal sensitivity using retrospective measures

Aim   To examine whether Rasch modeling would yield a unidimensional withdrawal sensitivity measure correlating with factors associated with successful smoking cessation.
Design   The psychometric Rasch modeling approach was applied to estimate an underlying latent construct (withdrawal sensitivity) in retrospective responses from 1644 smokers who reported quitting for 3 or more months at least once.
Setting   Web-based, passcode-controlled self-administered computerized questionnaire.
Participants   Randomly selected convenience sample of 1644 adult members of an e-mail invitation-only web panel drawn from consumer databases.
Measurements   Lifetime Tobacco Use Questionnaire, assessing tobacco use across the life-span, including demographics and respondent ratings of the severity of withdrawal symptoms experienced in respondents' first and most recent quit attempts lasting 3 or more months.
Findings   Rasch-modeled withdrawal sensitivity was generally unidimensional and was associated with longer periods of smoking cessation. One latent variable accounted for 74% of the variability in symptom scores. Rasch modeling with a single latent factor fitted withdrawal symptoms well, except for increased appetite, for which the fit was marginal. Demographic variables of education, gender and ethnicity were not related to changes in sensitivity. Correlates of greater withdrawal sensitivity in cessation attempts of at least 3 months included younger age at first quit attempt and indicators of tobacco dependence.
Conclusion   The relationship between tobacco dependence symptoms and Rasch-model withdrawal sensitivity defines further the relationship between sensitivity and dependence. The findings demonstrate the utility of modeling to create an individual-specific sensitivity measure as a tool for exploring the relationships among sensitivity, dependence and cessation.     

Special Feature: Complex Systems: From Chemistry to Systems Biology Special Feature: Complexity in bacterial cell–cell communication: Quorum signal integration and subpopulation signaling in the Bacillus subtilis phosphorelay

A common form of quorum sensing in Gram-positive bacteria is mediated by peptides that act as phosphatase regulators (Phr) of receptor aspartyl phosphatases (Raps). In Bacillus subtilis, several Phr signals are integrated in sporulation phosphorelay signal transduction. We theoretically demonstrate that the phosphorelay can act as a computational machine performing a sensitive division operation of kinase-encoded signals by quorum-modulated Rap signals, indicative of cells computing a “food per cell” estimate to decide whether to enter sporulation. We predict expression from the rapA-phrA operon to bifurcate as relative environmental signals change in a developing population. We experimentally observe that the rapA-phrA operon is heterogeneously induced in sporulating microcolonies. Uninduced cells sporulate rather synchronously early on, whereas the RapA/PhrA subpopulation sporulates less synchronously throughout later stationary phase. Moreover, we show that cells sustain PhrA expression during periods of active growth. Together with the model, these findings suggest that the phosphorelay may normalize environmental signals by the size of the (sub)population actively competing for nutrients (as signaled by PhrA). Generalizing this concept, the various Phrs could facilitate subpopulation communication in dense isogenic communities to control the physiological strategies followed by differentiated subpopulations by interpreting (environmental) signals based on the spatiotemporal community structure.