Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer’s disease (AD). An RNA interference screen using APP-CTF ...99-residue CTF (C99)- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.
Whole-exome sequencing (WES) has become an invaluable tool for genetic diagnosis in paediatrics. However, it has not been widely adopted in the prenatal setting. This study evaluated the use of WES ...in prenatal genetic diagnosis in fetuses with structural congenital anomalies (SCAs) detected on prenatal ultrasound.
Thirty-three families with fetal SCAs on prenatal ultrasonography and normal chromosomal microarray results were recruited. Genomic DNA was extracted from various fetal samples including amniotic fluid, chorionic villi, and placental tissue. Parental DNA was extracted from peripheral blood when available. We used WES to sequence the coding regions of parental-fetal trios and to identify the causal variants based on the ultrasonographic features of the fetus.
Pathogenic mutations were identified in three families (n = 3/33, 9.1%), including mutations in DNAH11, RAF1 and CHD7, which were associated with primary ciliary dyskinesia, Noonan syndrome, and CHARGE syndrome, respectively. In addition, variants of unknown significance (VUSs) were detected in six families (18.2%), in which genetic changes only partly explained prenatal features.
WES identified pathogenic mutations in 9.1% of fetuses with SCAs and normal chromosomal microarray results. Databases for fetal genotype-phenotype correlations and standardized guidelines for variant interpretation in prenatal diagnosis need to be established to facilitate the use of WES for routine testing in prenatal diagnosis.
To promote the adhesion strength between diamond-like carbon (DLC) films and nitrile butadiene rubber (NBR) substrates, titanium-doped carbon (Ti-C) films prepared by dual-target magnetron sputtering ...under varied substrate bias voltages were used as an interlayer on the rough NBR. The surface topography and structure of Ti-C films were investigated by atomic force microscopy (AFM) and Raman spectra. Raman analysis indicates that the increase of substrate bias voltage leads to an increase of the number or the size of sp2 clusters in the Ti-C interlayer. The adhesion strength and tribological properties of DLC films coated on NBR substrate were scrutinized by a scratch tester and a ball-on-disk tribometer, respectively. It was found that DLC film with a Ti-C interlayer at a certain bias voltage exhibited superior wear resistance with a low coefficient of friction (CoF) during the sliding of 6000 laps. No clear damages in the coatings were observed from the wear tracks. Besides, the scratch test also revealed a reliable adhesion when the interlayer was prepared at −150 V, as confirmed by a scratch crack width of ~50 μm as compared to that of the pure DLC film increasing to ~ 120 μm. Therefore, a Ti-C interlayer could significantly enhance the adhesion and wear resistance of DLC thin films deposited on NBR.
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•A Ti-C interlayer on rubber promotes the adhesion of diamond-like carbon film.•The tribology property of diamond-like carbon film is tailored by the Ti-C interlayer.•The wear resistance of diamond-like carbon film on rubber is tuned by bias voltage.
Background and Purpose
Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinaemia‐associated vascular diseases. ...Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on l‐homocysteine‐induced vascular inflammation.
Experimental Approach
A high methionine diet‐induced hyperhomocysteinaemic mouse model was used to assess cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with l‐homocysteine and the cathepsin L/V inhibitor SID to assess the pro‐inflammatory effects of cathepsin V. Transfection and antisense techniques were utilized to investigate the effects of cathepsin V on the dual‐specificity protein phosphatases (DUSPs) and MAPK pathways.
Key Results
Cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinaemic mice; l‐homocysteine promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V and reversed the up‐regulation of inflammatory cytokines (IL‐6, IL‐8 and TNF‐α), adhesion and chemotaxis of leukocytes and vascular inflammation induced by l‐homocysteine in vivo and in vitro. Increased cathepsin V promoted the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL‐6, IL‐8 and TNF‐α.
Conclusions and Implications
This study has identified a novel mechanism, which shows that l‐homocysteine‐induced upregulation of cathepsin V mediates vascular endothelial inflammation under high homocysteine condition partly via ERK1/2/STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperaemia‐associated vascular diseases.
Linked Articles
This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc
The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of ...PER2 enhanced invasion and activated expression of epithelial-mesenchymal transition (EMT) genes including TWIST1 , SLUG, and SNAIL . This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2.
ABSTRACT
We present our piggyback search for fast radio bursts using the Nanshan 26 m Radio Telescope and the Kunming 40 m Radio Telescope. The observations are performed in the L band from 1380 to ...1700 MHz at Nanshan and the Sband from 2170 to 2310 MHz at Kunming. We built the roach2-based FFT spectrometer and developed the real-time transient search software. We introduce a new radio interference mitigation technique named zero-DM matched filter and give the formula of the signal-to-noise ratio loss in the transient search. Though we have no positive detection of bursts in about 1600 and 2400 h data at Nanshan and Kunming, respectively, an intriguing peryton was detected at Nanshan, from which hundreds of bursts were recorded. Perytons are terrestrial radio signals that mimic celestial fast radio bursts. They were first reported at Parkes and identified as microwave oven interferences later. The bursts detected at Nanshan show similar frequency swept emission and have double-peaked profiles. They appeared in different sky regions in about tens of minutes observations and the dispersion measure index is not exactly 2, which indicates the terrestrial origin. The peryton differs drastically from the known perytons detected at Parkes, because it appeared in a precise period of p = 1.712 87 ± 0.000 04 s. Its origin remains unknown.
Respiratory syncytial virus (RSV) is one of the most common respiratory viruses. It not only affects young children but also the elderly and immunocompromised patients. After the emergence of ...SARS-CoV-2 and the corona virus disease 2019 (COVID-19) era, a dramatic reduction in RSV activity was found, which coincided with the implementation of public health and social measures (PHSMs). However, the correlation is more complicated than we initially thought. After PHSMs were gradually lifted, a seasonality shift and a delayed RSV outbreak with greater number of infected patients were found in numerous countries, such as Israel, Australia, South Africa, New Zealand, France, United States, and Japan. Several hypotheses and possible reasons explaining the interaction between SARS-CoV-2 and RSV were mentioned. Since RSV vaccinations are still under investigation, administration of palivizumab should be considered in high-risk patients. In the post-COVID-19 era, greater attention should be paid to a further resurgence of RSV. In this narrative review, we conducted a thorough review of the current knowledge on the epidemiology of RSV during the COVID-19 era, the out-of-season outbreak of RSV, and the data on co-infection with RSV and SARS-CoV-2.
We performed the angle dependent magnetoresistance (MR), Hall effect measurements, the temperature dependent magneto-thermoelectric power (TEP) S(T) measurements, and the first-principles ...calculations to study the electronic properties of orthorhombic phase MoTe2(Td−MoTe2), which was proposed to be electronically two dimensional (2D). There are some interesting findings about Td−MoTe2. (1) A scaling approach ɛθ=(sin2θ+γ−2cos2θ)1/2 is applied, where θ is the magnetic field angle with respect to the c axis of the crystal and γ is the mass anisotropy. Unexpectedly, the electronically three-dimensional (3D) character with γ as low as 1.9 is observed in Td−MoTe2. (2) The possible Lifshitz transition and the following electronic structure change can be verified around T∼150K and T∼60K, which is supported by the evidence of the slope changing of the temperature dependence of TEP, the carrier density extracted from Hall resistivity, and the onset temperature of γ obtained from the MR measurements. The extremely large MR effect in Td−MoTe2 could originate from the combination of the electron-hole compensation and a particular orbital texture on the electron pocket, which is supported by the calculations of electronic structure. Our results may provide a general scaling relation for the anisotropic MR and help to recognize the origins of the MR effect in other systems, such as the Weyl semimetals and the Dirac ones.
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