A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.     

Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer’s Disease

The deposition of amyloid-beta (Aβ) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer’s disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the “Molecule Activity Predictor” feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD.     

Transgenerational Effects of Di(2-Ethylhexyl) Phthalate on Anogenital Distance,Sperm Functions and DNA Methylation in Rat Offspring

Di(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in the manufacture of polyvinylchloride plastics and has been associated with concerns regarding male reproductive toxicity. In this study, we hypothesized that maternal exposure to DEHP induces transgenerational inheritance of adult-onset adverse reproductive outcomes through the male germline in the F1, F2, and F3 generations of male offspring. Pregnant rats were treated with 5 or 500 mg of DEHP/kg/day through gavage from gestation day 0 to birth. The offspring body weight, anogenital distance (AGD), anogenital index (AGI), sperm count, motility, and DNA fragmentation index (DFI) were measured for all generations. Methyl-CpG binding domain sequencing was performed to analyze sperm DNA methylation status in the F3. DEHP exposure at 500 mg/kg affected AGD, AGI, sperm count, mean DFI, and %DFI in the F1; AGD, sperm count, and mean DFI in the F2; and AGD, AGI, mean DFI, and %DFI in the F3. DEHP exposure at 5 mg/kg affected AGD, AGI, sperm count, and %DFI in the F1; sperm count in the F2; and AGD and AGI in F3. Compared with the control group, 15 and 45 differentially hypermethylated genes were identified in the groups administered 5 mg/kg and 500 mg/kg DEHP, respectively. Moreover, 130 and 6 differentially hypomethylated genes were observed in the groups administered 5 mg/kg and 500 mg/kg DEHP. Overall, these results demonstrated that prenatal exposure to DEHP caused transgenerational epigenetic effects, which may explain the observed phenotypic changes in the male reproductive system.     

Neoagarooligosaccharide Protects against Hepatic Fibrosis via Inhibition of TGF-β/Smad Signaling Pathway

Hepatic fibrosis occurs when liver tissue becomes scarred from repetitive liver injury and inflammatory responses; it can progress to cirrhosis and eventually to hepatocellular carcinoma. Previously, we reported that neoagarooligosaccharides (NAOs), produced by the hydrolysis of agar by β-agarases, have hepatoprotective effects against acetaminophen overdose-induced acute liver injury. However, the effect of NAOs on chronic liver injury, including hepatic fibrosis, has not yet been elucidated. Therefore, we examined whether NAOs protect against fibrogenesis in vitro and in vivo. NAOs ameliorated PAI-1, α-SMA, CTGF and fibronectin protein expression and decreased mRNA levels of fibrogenic genes in TGF-β-treated LX-2 cells. Furthermore, downstream of TGF-β, the Smad signaling pathway was inhibited by NAOs in LX-2 cells. Treatment with NAOs diminished the severity of hepatic injury, as evidenced by reduction in serum alanine aminotransferase and aspartate aminotransferase levels, in carbon tetrachloride (CCl₄)-induced liver fibrosis mouse models. Moreover, NAOs markedly blocked histopathological changes and collagen accumulation, as shown by H&E and Sirius red staining, respectively. Finally, NAOs antagonized the CCl₄-induced upregulation of the protein and mRNA levels of fibrogenic genes in the liver. In conclusion, our findings suggest that NAOs may be a promising candidate for the prevention and treatment of chronic liver injury via inhibition of the TGF-β/Smad signaling pathway.     

Design and fabrication of lutetium aluminum silicate glass and nanostructured glass for radiation detection

Flexible scintillating fiber plays an important role in X-ray radiation monitoring and high-resolution medical imaging, while construction of scintillating fiber derived from the commercial material system meet with limited success. Here, we report the design and successful fabrication of the Ce-activated lutetium aluminum silicate glass, nanostructured glass, and fiber, and explore their scintillating properties. The scintillating glass with optimized composition and optical properties is determined. The crystallization behavior of lutetium aluminum silicate glass is studied and the nanostructured glass embedded with orthorhombic Lu₂Si₂O₇ phase is successfully constructed for the first time. Importantly, the crystalline layer thickness of the nanostructured glass can be finely tuned and ~172.89% enhancement in the scintillating performance can be achieved. Furthermore, the fiber with large sized core is fabricated and its radiation response properties are tested. The results show that it exhibits high sensitivity and its scintillating emission is lineally dependent on the X-ray power, indicating the potential application for radiation detection.     

Dense and core-rim structured B4C-TiB2 ceramics with Mo-Co-WC additive

B₄C-TiB₂ ceramics (TiB₂ ranging 5~70 vol%) with Mo-Co-WC as the sintering additive were prepared by spark plasma sintering. In comparison with B₄C-TiB₂ without additive, the enhanced densification was evident in the sintered specimen with Mo-Co-WC additive. Core-rim structured grain was observed around TiB₂ grains. The interface of the rim between TiB₂ and B₄C phases demonstrated different feature: the inner borderline of the rim exhibited a smooth feature, whereas a sharp curved grain boundary was observed between the rim and the B₄C grain. The formation mechanism is discussed: the epitaxial growth of (Ti,Mo,W)B₂ rim around the TiB₂ core may occur as a result of the solid solution and dissolution-precipitation between TiB₂ phase and the sintering additive. It was revealed that the fracture toughness increased as the content of TiB₂ content increased, alongside the decreased hardness. B₄C-30 vol% TiB₂ specimen demonstrated the optimal combination of mechanical properties, reaching Vickers hardness of 24.3 GPa and fracture toughness of 3.33 MPa·m^1/2.     

Good dielectric performance and broadband dielectric polarization in Ag,Nb co-doped TiO2

Due to the demand of miniaturization and integration for ceramic capacitors in electronic components market, TiO₂-based ceramics with colossal permittivity has become a research hotspot in recent years. In this work, we report that Ag⁺/Nb⁵⁺ co-doped (Ag_1/4Nb_3/4)_xTi_1−xO₂ (ANTOx) ceramics with colossal permittivity over a wide frequency and temperature range were successfully prepared by a traditional solid–state method. Notably, compositions of ANTO0.005 and ANTO0.01 respectively exhibit both low dielectric loss (0.040 and 0.050 at 1 kHz), high dielectric permittivity (9.2 × 10³ and 1.6 × 10⁴ at 1 kHz), and good thermal stability, which satisfy the requirements for the temperature range of application of X9R and X8R ceramic capacitors, respectively. The origin of the dielectric behavior was attributed to five dielectric relaxation phenomena, i.e., localized carriers' hopping, electron–pinned defect–dipoles, interfacial polarization, and oxygen vacancies ionization and diffusion, as suggested by dielectric temperature spectra and valence state analysis via XPS; wherein, electron-pinned defect–dipoles and internal barrier layer capacitance are believed to be the main causes for the giant dielectric permittivity in ANTOx ceramics.     

基于全U网络的混凝土路面裂缝检测算法

针对现有的混凝土裂缝检测算法在各种复杂环境中检测精度不够、鲁棒性不强的问题,根据深度学习理论和U-net模型,提出一种全U型网络的裂缝检测算法。首先,依照原U-net模型路线构建网络;然后,在每个池化层后都进行一次上采样,恢复其在池化层之前的特征图规格,并将其与池化之前的卷积层进行融合,将融合之后的特征图作为新的融合层与原U-net网络上采样之后的网络层进行融合;最后,为了验证算法的有效性,在测试集中进行实验。结果表明,所提算法的平均精确率可达到83.48%,召回率为85.08%,F1为84.11%,相较于原U-net分别提升了1.48%,4.68%和3.29%,在复杂环境中也能提取完整裂缝,保证了裂缝检测的鲁棒性。