"Genotype-first" approaches on a curious case of idiopathic progressive cognitive decline

Background In developing countries, many cases with rare neurological diseases remain undiagnosed due to limited diagnostic experience. We encountered a case in China where two siblings both began to develop idiopathic progressive cognitive decline starting from age six, and were suspected to have an undiagnosed neurological disease. Methods Initial clinical assessments included review of medical history, comprehensive physical examination, genetic testing for metabolic diseases, blood tests and brain imaging. We performed exome sequencing with Agilent SureSelect exon capture and Illumina HiSeq2000 platform, followed by variant annotation and selection of rare, shared mutations that fit a recessive model of inheritance. To assess functional impacts of candidate variants, we performed extensive biochemical tests in blood and urine, and examined their possible roles by protein structure modeling. Results Exome sequencing identified NAGLU as the most likely candidate gene with compound heterozygous mutations (chr17:40695717C > T and chr17:40693129A > G in hg19 coordinate), which were documented to be pathogenic. Sanger sequencing confirmed the recessive patterns of inheritance, leading to a genetic diagnosis of Sanfilippo syndrome (mucopolysaccharidosis IIIB). Biochemical tests confirmed the complete loss of activity of alpha-N-acetylglucosaminidase (encoded by NAGLU) in blood, as well as significantly elevated dermatan sulfate and heparan sulfate in urine. Structure modeling revealed the mechanism on how the two variants affect protein structural stability. Conclusions Successful diagnosis of a rare genetic disorder with an atypical phenotypic presentation confirmed that such “genotype-first” approaches can particularly succeed in areas of the world with insufficient medical genetics expertise and with cost-prohibitive in-depth phenotyping

Hysteresis Compensation and Sliding Mode Control with Perturbation Estimation for Piezoelectric Actuators

Based on the background of atomic force microscope (AFM) driven by piezoelectric actuators (PEAs), this paper proposes a sliding mode control coupled with an inverse Bouc–Wen (BW) hysteresis compensator to improve the positioning performance of PEAs. The intrinsic hysteresis and creep characteristics degrade the performance of the PEA and cause accuracy loss. Although creep effect can be eliminated by the closed-loop control approach, hysteresis effects need to be compensated and alleviated by hysteresis compensators. For the purpose of dealing with the estimation errors, unmodeled vibration, and disturbances, a sliding mode control with perturbation estimation (SMCPE) method is adopted to enhance the performance and robustness of the system. In order to validate the feasibility and performance of the proposed method, experimental studies are carried out, and the results show that the proposed controller performs better than a proportional-integral-derivative (PID) controller at 1 and 2 Hz, reducing error to 1.2% and 1.4%, respectively

Design, Assembly, and Simulation of Flexure-Based Modular Micro-Positioning Stages

With flexure-based micro-positioning stages (MPSs) being in high demand for high-precision applications, the performance and cost of flexure-based MPSs are two issues that urgently need to be addressed. In addition, the current MPSs are being developed toward complex spatial configurations, which further precludes monolithic fabrication. To address the aforementioned issues, modular MPSs using designed standardized modules are introduced in this paper. Firstly, the motivations are described, followed by the modular design. In addition, a new assembly concept analogy with composing compounds is proposed for guiding module assembly, including some proposed planar and spatial configurations. For validation, the static and dynamic performances of modular MPSs with respect to different modules and materials are presented as case studies. The proposed modular MPSs can provide better flexibility and functionality for further applications

Univariate Gaussian model for multimodal inseparable problems

It has been widely perceived that a univariate Gaussian model for evolutionary search can be used to solve separable problems only. This paper explores whether and how the univariate Gaussian model may also be used to solve inseparable problems. The analysis is followed up with experimental tests. The results show that the univariate Gaussian model stipulates no inclination towards separable problems. Further, it is revealed that the model is not only an efficient but also an effective method for solving multimodal inseparable problems. To verify its relative convergence speed, a restart strategy is applied to a univariate Gaussian model (the univariate marginal distribution algorithm) on inseparable problems. The results confirm that the univariate Gaussian model outperforms the five peer algorithms studied in this paper

Identification of Preisach Model Parameters Based on an Improved Particle Swarm Optimization Method for Piezoelectric Actuators in Micro-Manufacturing Stages

The Preisach model is a typical scalar mathematical model used to describe the hysteresis phenomena, and it attracts considerable attention. However, parameter identification for the Preisach model remains a challenging issue. In this paper, an improved particle swarm optimization (IPSO) method is proposed to identify Preisach model parameters. Firstly, the Preisach model is established by introducing a Gaussian−Gaussian distribution function to replace density function. Secondly, the IPSO algorithm is adopted to Fimplement the parameter identification. Finally, the model parameter identification results are compared with the hysteresis loop of the piezoelectric actuator. Compared with the traditional Particle Swarm Optimization (PSO) algorithm, the IPSO algorithm demonstrates faster convergence, less calculation time and higher calculation accuracy. This proposed method provides an efficient approach to model and identify the Preisach hysteresis of piezoelectric actuators

Psychiatric Symptoms and Frequency of Eating out among Commuters in Beijing: A Bidirectional Association?

Background: Mental illness places as a distant first in global burdens, exceeding both cardiovascular and circulatory diseases, in terms of the years lived with the disability. The emergence of the new and burgeoning area of “Nutrition Psychiatry” offers promise in improving mental health with diet. Mental health and well-being are critical to commuters but rarely recieve the attention they need. This study aimed to examine the bidirectional relationship between the frequency of eating out and depression, anxiety, and stress symptoms in a sample of Beijing commuters. Methods: A total of 3337 commuters (mean (SD) age, 38.78 (10.41); 74.74% males) from the cohort study CHCN-BTH were included. The psychiatric symptoms were evaluated using a 21-item self-reported depression–anxiety–stress scale (DASS-21). A Cochran–Armitage trend chi-square test, restricted cubic spline, multiple logistic regression, multinomial logit models, and E-values were performed to estimate the associations between eating out and psychiatric symptoms in both directions. Results: A daily rate of eating out more than 50% had a higher risk for depression (OR, 95% CI: 1.68, 1.184–2.393), anxiety (1.73, 1.259–2.369), and stress (1.99, 1.191–3.329) than the individuals eating at home. A higher frequency of eating out for lunch was significantly associated with an increased risk of depression (1.78, 1.28–2.46), anxiety (1.67, 1.26–2.23), and stress (2.05, 1.31–3.22). Similar results were found when eating out for dinner with increased risks for depression 2.20 (1.59, 3.06), anxiety 1.91 (1.42, 2.59), and stress 2.61 (1.68, 4.05). There is limited evidence supporting the effects of psychiatric symptoms on the frequency of eating out in the reverse analyses. Conclusions: The frequency of eating out is positively associated with an increased risk of psychiatric symptoms, especially when eating out for lunch and dinner. People eating at home have the lowest risk of suffering psychiatric symptoms, followed by those eating in the workplace canteen. Eating at home should be considered for future recommendations for the prevention of psychiatric symptoms

SNPs in lncRNA KCNQ1OT1 Modulate Its Expression and Confer Susceptibility to Salt Sensitivity of Blood Pressure in a Chinese Han Population

Long noncoding RNA (lncRNA) plays an important role in cardiovascular diseases, but the involvement of lncRNA in salt sensitivity of blood pressure (SSBP) is not well-known. We aimed to explore the association of sixteen single-nucleotide polymorphisms (SNPs) in five lncRNA genes (KCNQOT1, lnc-AGAP1-8:1, lnc-IGSF3-1:1, etc.) with their expression and susceptibility to SSBP. A two-stage association study was conducted among 2057 individuals. Quantified expression of the lncRNA was detected using real-time PCR. Genotyping was accomplished using the MassARRAY System. The expression quantitative tra2it loci test and the generalized linear model were utilized to explore the function of SNPs. One-sample Mendelian randomization was used to study the causal relationship between KCNQOT1 and SSBP. Significant effects were observed in KCNQ1OT1 expressions on the SSBP phenotype (p < 0.05). Rs10832417 and rs3782064 in KCNQ1OT1 may influence the secondary structure, miRNA binding, and expression of KCNQ1OT1. Rs10832417 and rs3782064 in KCNQ1OT1 were identified to be associated with one SSBP phenotype after multiple testing corrections and may be mediated by KCNQ1OT1. One-sample Mendelian randomization analyses showed a causal association between KCNQ1OT1 and SSBP. Our findings suggest that rs10832417 and rs3782064 might be associated with a lower risk of SSBP through influencing the KCNQ1OT1 secondary structure and miRNA binding, resulting in changes in KCNQ1OT1 expression

Combined effects of ambient air pollution and PM2.5 components on renal function and the potential mediation effects of metabolic risk factors in China

Growing evidence links long-term air pollution exposure with renal function. However, little research has been conducted on the combined effects of air pollutant mixture on renal function and multiple mediation effects of metabolic risk factors. This study enrolled 8996 adults without chronic kidney disease (CKD) at baseline from the CHCN-BTH cohort study. Three-year exposure to air pollutants [particulate matter ≤ 2.5 µm (PM2.5), PM10, PM1, ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO)] and PM2.5 components [black carbon (BC), ammonium (NH4+), nitrate (NO3-), sulfate (SO42-) and organic matter (OM)] were assessed using well-validated machine learning methods. Linear mixed models were applied to investigate the associations between air pollutants and estimated glomerular filtration rate (eGFR). Quantile G-computation was used to assess the combined effects of pollutant mixtures. Causal mediation analysis and Bayesian mediation analysis were employed to estimate the mediation effects of metabolic risk factors. An interquartile range increases in BC (−0.256, 95 %CI: −0.331, −0.180) and OM (−0.603, 95 %CI: −0.810, −0.397) were significantly associated with eGFR decline; while O3 (1.151, 95 %CI: 0.813, 1.489), PM10 (0.721, 95 %CI: 0.309, 1.133), NH4+ (0.990, 95 %CI: 0.638, 1.342), and NO3- (0.610, 95 %CI: 0.405, 0.815) were associated with higher eGFR. The combined effect of the PM2.5 component mixture was found to be associated with lower eGFR (−1.147, 95 % CI: −1.456, −0.839), with OM contributing 72.4 % of the negative effect. Univariate mediation analyses showed that high-density lipoprotein (HDL) mediated 7.1 %, 6.9 %, and 6.1 % effects of O3, BC, and OM, respectively. However, these mediation effects were not significant in Bayesian mediation analysis. These findings suggest the effect of the PM2.5 component mixture on eGFR decline and the strong contribution of OM. Metabolic risk factors may not mediate the effects of air pollutants. Further study is warranted to clarify the potential mechanisms involved

Higher Potassium Intake and Lower Sodium Intake May Help in Reducing CVD Risk by Lowering Salt Sensitivity of Blood Pressure in the Han Chinese Population

Sodium (Na) reduction with a parallel supplemental potassium (K) intake can prevent cardiovascular diseases (CVDs). The relationship of the urinary Na/K ratio and salt sensitivity of blood pressure (SSBP) with CVDs is not clearly explained. We assumed that the SSBP mediates the relationship between the Na/K ratio and CVDs. In total, 2055 subjects who had 24 h urine collected and SSBP determined were included in this study. CVD risk was estimated using the China-PAR equation. MediationMultivariate logistic regression was used to explore the associations between the Na/K ratio or SSBP with CVD risk. Mediation analysis using a logistic regression model was performed. Both the urinary Na/K ratio and SSBP were related to the estimated CVD risk (p < 0.05). The mediation analysis found that SSBP mediated approximately 12% of the association between Na/K ratio and CVD risk. Our findings indicate that higher K intake and lower Na intake may help in preventing CVD risk by reducing SSBP risk in individuals with normotension or stage-one hypertension

A comparative study on welding characteristics and mechanical properties of Ti–6Al–4V laser welded joints under the sub-atmospheric pressure and beam oscillation

Sub-atmospheric pressure environment and oscillation laser are both excellent ways to improve welded joint quality. However, the differences in their effects and mechanisms are unclear. Therefore, the differences between sub-atmospheric pressure and oscillating laser in weld formation, porosity suppression and grain size refinement were analyzed in this study. The results revealed that penetration depth of welded joint was increased to 6.09 mm under sub-atmospheric pressure environment while it was decreased to 3.3 mm under oscillation laser. Furthermore, reducing fluctuating vapor pressure and suppressing vortex formation were the main means to improve the keyhole stability and promote the escape of bubbles in a sub-atmospheric pressure environment. The improvement of the oscillating laser in these two aspects was attributed to enlarging keyhole area, shortening escape path and oscillation keyhole absorption. Additionally, the average grain size in the upper weld was reduced from 134.6 μm to 118.6 μm and 114.1 μm under the sub-atmospheric pressure environment and laser oscillation, respectively. The reduction of the temperature gradient led to former grain refinement while the increase of heterogeneous nucleation rate was responsible for latter grain refinement. Correspondingly, the mechanical properties of welded joints were improved. The study offered valuable insights for the application of laser welding with oscillation laser and sub-atmospheric pressure in industrial production