Histone Deacetylase 4 Inhibition Reduces Rotenone-Induced Alpha-Synuclein Accumulation via Autophagy in SH-SY5Y Cells.

(1) Background: Parkinson's disease (PD) is the most common movement disorder. Imbalanced protein homeostasis and α-syn aggregation are involved in PD pathogenesis. Autophagy is related to the occurrence and development of PD and can be regulated by histone deacetylases (HDACs). Various inhibitors of HDACs exert neuroprotective effects within in vitro and in vivo models of PD. HDAC4, a class Ⅱ HDAC, colocalizes with α-synuclein and ubiquitin in Lewy bodies and also accumulates in the nuclei of dopaminergic neurons in PD models. (2) Methods: In the present study, the gene expression profile of HDACs from two previously reported datasets in the GEO database was analyzed, and the RNA levels of HDAC4 in brain tissues were compared between PD patients and healthy controls. In vitro, SH-SY5Y cells transfected with HDAC4 shRNA or pretreated with mc1568 were treated with 1 µM of rotenone for 24 h. Then, the levels of α-syn, LC3, and p62 were detected using Western blot analysis and immunofluorescent staining, and cell viabilities were detected using Cell Counting Kit-8 (CCK-8). (3) Results: HDAC4 was highly expressed in PD substantia nigra and locus coeruleus. Mc1568, an inhibitor of HDAC4, decreased α-synuclein levels in rotenone-treated SH-SY5Y cells in a concentration-dependent manner and activated autophagy, which was impaired by rotenone. The knockdown of HDAC4 reversed rotenone-induced α-syn accumulation in SH-SY5Y cells and protected the neurons by enhancing autophagy. (4) Conclusions: HDAC4 is a potential therapeutic target for PD. The inhibition of HDAC4 by mc1568 or a gene block can reduce α-syn levels by regulating the autophagy process in PD. Mc1568 is a promising therapeutic agent for PD and other disorders related to α-syn accumulation.

Effect of integrin α7 on cell proliferation, invasion, apoptosis and the PI3K/AKT pathway, and its association with clinicopathological features in endometrial cancer.

Targeting integrin α7 (ITGA7) suppresses malignant progression of several types of cancer, including tongue squamous cell carcinoma, hepatocellular carcinoma and non-small cell lung cancer, while the effect of its knockdown on cell function and its association with clinicopathological features in endometrial cancer (EC) is unclear. The present study aimed to investigate this issue. ITGA7 was knocked down by short-interfering (si)RNA in Ishikawa and RL95-2 cells followed by western blotting and reverse transcription-quantitative PCR assays. Subsequently, cell proliferation, apoptosis, invasion and expression levels of PI3K, phosphorylated (p-) PI3K, AKT and p-AKT were determined using Cell Counting Kit-8, TUNEL, Transwell assays and western blotting. Moreover, ITGA7 in tumor and adjacent tissues from 50 patients with endometrial cancer was detected using immunohistochemical assay. ITGA7 expression was increased in EC cell lines (HEC-1A, RL95-2, Ishikawa and KLE) compared with telomerase-immortalized human endometrial stromal cells (THESCs). In both Ishikawa and RL95-2 cells, three ITGA7 siRNAs all demonstrated good efficiency on ITGA7 knockdown, amongst which the one with the highest efficiency was selected for the following experiments. ITGA7 knockdown reduced cell proliferation and invasion, while inducing apoptosis; moreover, it suppressed p-PI3K/PI3K and p-AKT/AKT ratios. In patients with EC, ITGA7 expression was increased in tumor tissues compared with adjacent tissues, and its lower tumor expression was associated with myometrial invasion (<1/2), non-lymphovascular invasion and decreased FIGO stage. In conclusion, ITGA7 knockdown repressed proliferation, invasion and the PI3K/AKT pathway while inducing apoptosis in EC cell lines, and its insufficiency was associated with less advanced tumor features in EC patients. These results indicated that ITGA7 may be a potential target for the treatment of EC.

Experimental study on FBG sensing technology-based stress monitoring at the corners of reinforced soil retaining walls.

As a unique type of flexible slope fill-retaining structure, reinforced soil-retaining walls have the advantages of convenient construction, broad application conditions, good seismic performance, and high economic benefits. In general, reinforced soil-retaining walls appear at corners due to the restriction in topographic conditions during engineering construction. However, their special structures and stress conditions are usually ignored, thus triggering panel bulging, cracking, and collapse. In this study, an experimental method based on fiber Bragg grating (FBG) sensing technology was proposed for a physical model of reinforced soil-retaining walls. Then, a uniformly distributed load experiment was performed on this model by combining the measurement advantages of intelligent wire-type soil pressure sensors and the flexible characteristics of geotechnical reinforcement materials. The deformation development of this reinforced soil-retaining wall was monitored. Results revealed that before and after the loading of the reinforced soil-retaining wall, the deformation was mainly concentrated above the retaining wall, and the deformation scale at the corners was larger than that in the bilateral linear parts. After loading, the largest force deformation area on the retaining wall was transferred from the corners to the load area. The maximum strain was right beneath the load above the retaining wall, and the peak value at the other layers gradually approached the retaining wall. The experimental results prove that FBG sensing technology is feasible and effective for the whole-process monitoring of reinforced soil-retaining walls and is thus worthy of popularization and application.

Metabolomic, proteomic and lactylated proteomic analyses indicate lactate plays important roles in maintaining energy and C:N homeostasis in Phaeodactylum tricornutum.

BACKGROUND: Phaeodactylum tricornutum accumulates lipids while the growth also increases under high CO2, shedding light on its potential application in the reduction of CO2 emissions and at the same time acquiring biodiesel raw materials. However, the sensing and transducing of high C:N signals and the related response mechanism(s) remained unknown. RESULTS: In this study, a multiple omics analysis was performed with P. tricornutum under low nitrogen (LN) and high CO2 (HC) conditions. The results indicated that 2-oxoglutarate was significantly increased under both LN and HC. Meanwhile, proteins involved in carbon concentration mechanism decreased, indicated that 2-oxoglutarate might regulate C:N balance through suppressing carbon fixation. Lactate, which acts in energy metabolism, signal transduction and 'LactoylLys' modification on proteins, was the most upregulated metabolite under both LN and HC conditions. Meanwhile, proteins involved in carbon, nitrogen and energy metabolisms were significantly regulated. Western blotting analysis suggested that non-histone L-lactylation modification was enhanced under LN and HC. Moreover, lactylated proteins were enriched in photosynthesis, central carbon metabolism, nitrogen metabolism, fatty acid synthesis and oxidative phosphorylation. CONCLUSION: It is suggested that lactate might play important roles in energy homeostatic maintenance and C:N balance regulation in P. tricornutum through protein lactylation modification.

Exosomes from patients with Parkinson's disease are pathological in mice.

Cell-to-cell transport of risk molecules is a highly anticipated pathogenic mechanism in the initiation and progression of various neurodegenerative diseases. Extracellular exosome-mediated neuron to neuron transport of α-synuclein (α-syn) is increasingly recognized as a potential etiologic mechanism in Parkinson's disease (PD). Exosomal inflammation has also been increasingly implicated in PD pathogenesis and could trigger, facilitate, or aggravate disease development. However, these mechanisms have not been verified systematically, especially in vivo. Since serum contains abundant exosomes, the correlation between serum exosomes and PD pathogenesis remains unknown. Here, we show that exosomes from PD patient serum contain more α-syn and inflammatory factors such as IL-1ß and TNF-α than neurological normal controls, eventually cause α-syn, ubiquitin, and P62 aggregation in recipient cells. More importantly, the intravenous or intrastriatal treatment of mice with exosomes from PD patient serum could evoke protein aggregation, trigger dopamine neuron degeneration, induce microglial activation, and cause apomorphine-coaxed rotation and movement defects. All these findings imply the exosome pathway as a new pathogenesis mechanism for PD, and therefore may present new targets for therapeutics. KEY MESSAGES: We have presented the evidence for a relationship between PD (Parkinson's disease) patients' serum exosomes and pathogenesis. PD patients' serum-derived exosomes could induce α-syn, ubiquitin and P62 aggregation in recipient cells. Intravenous or intrastriatal treatments of mice with PD exosomes were able to recapitulate the molecular, cellular and behavioral phenotypes of PD.

Graphene and SESAM mode-locked Yb:CNGS lasers with self-frequency doubling properties.

We report on mode-locking of an Yb:Ca3NbGa3Si2O14 laser, which is pumped by a fiber-coupled single-mode laser diode. The shortest pulse duration obtained with a semiconductor saturable absorber mirror is 52 fs, with 75 mW of average output power. Sub-60 fs operation tunable between 1055 and 1074 nm is achieved by employing semiconductor absorbers with different characteristics. We also demonstrate passive mode-locking results with transmissive graphene saturable absorber, reaching an 85 fs pulse duration with 23 mW output power. Moreover, we present the non-phase-matched self-frequency doubling properties of this non-centrosymmetric crystal in the femtosecond regime.

Passive Q switching of Yb:CNGS lasers by Cr4+:YAG and V3+:YAG saturable absorbers.

Trigonal langasite-type ordered silicate crystal Yb:Ca3NbGa3Si2O14 (Yb:CNGS) is a promising material for efficient ∼1 µm lasers. We report on the first passively Q-switched Yb:CNGS laser using Cr4+:YAG and V3+:YAG saturable absorbers (SAs) with a 976 nm volume-Bragg-grating-stabilized diode as a pump source. The laser crystal was a c cut 3 at.% Yb:CNGS grown by the Czochralski method. It was placed in a compact microchip-type laser cavity. With a Cr4+:YAG SA, very stable 62.2 µJ/4.4 ns pulses were achieved at a repetition rate of 22.5 kHz. The average output power was 1.40 W at 1015.3 nm, corresponding to a Q switching conversion efficiency of 90%. With the V3+:YAG SA, the pulse characteristics were 13.3 µJ/11.1 ns at a higher repetition rate of 68.4 kHz. The performance of the Yb:CNGS/Cr4+:YAG was numerically modeled showing a good agreement with the experiment.

Weight Loss and Malnutrition in Patients with Parkinson's Disease: Current Knowledge and Future Prospects.

Parkinson's Disease (PD) is currently considered a systemic neurodegenerative disease manifested with not only motor but also non-motor symptoms. In particular, weight loss and malnutrition, a set of frequently neglected non-motor symptoms, are indeed negatively associated with the life quality of PD patients. Moreover, comorbidity of weight loss and malnutrition may impact disease progression, giving rise to dyskinesia, cognitive decline and orthostatic hypotension, and even resulting in disability and mortality. Nevertheless, the underlying mechanism of weight loss and malnutrition in PD remains obscure and possibly involving multitudinous, exogenous or endogenous, factors. What is more, there still does not exist any weight loss and malnutrition appraision standards and management strategies. Given this, here in this review, we elaborate the weight loss and malnutrition study status in PD and summarize potential determinants and mechanisms as well. In conclusion, we present current knowledge and future prospects of weight loss and malnutrition in the context of PD, aiming to appeal clinicians and researchers to pay a closer attention to this phenomena and enable better management and therapeutic strategies in future clinical practice.

Diode-pumped passively Q-switched self-frequency-doubled Nd:CNGS laser.

With Cr4+:YAG as a saturable absorber, a passively Q-switched self-frequency-doubled (SFD) laser based on a trigonal Nd:Ca3NbGa3Si2O14 (Nd:CNGS) silicate crystal was demonstrated for the first time. The maximum average output power at 532 nm was 16.2 mW, and the corresponding pulse repetition frequency, single pulse energy, pulse duration and peak power were 2.25 kHz, 7.2 µJ, 13.7 ns, 0.53 kW, respectively. We also present a rate-equation model of such a passively Q-switched SFD laser showing a good agreement with the experiment. Nd:CNGS is a promising pulse SFD material for miniature all-solid-state visible light sources.

Protein-Restricted Diets for Ameliorating Motor Fluctuations in Parkinson's Disease.

Levodopa is considered to be the most effective symptomatic drug for Parkinson's disease (PD). As the disease progresses, however, the patients are likely to experience a reduced response to levodopa and develop motor fluctuations (i.e., end-of-dose wearing off and unpredictable "on-off"). Protein-rich diets and elevated plasma concentrations of large neutral amino acids have been proved to impair the therapeutic effect of levodopa by reducing its absorption and influx into the brain. On the other hand, the protein-restricted diets including low-protein diet (LPD), protein-redistribution diet (PRD) and PRD with use of low-protein products can all improve the efficacy of levodopa in patients with motor fluctuations. However, it should be noted that protein-restricted diets may also contribute to several side effects, including dyskinesia, weight loss, and malnutrition (e.g., protein and calcium insufficiency). Together, protein-restricted diets are an effective approach to improve motor fluctuations in PD patients, while long-term adherence to these diets requires monitoring for side effects.

Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management.

Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs) in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non-pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and α2δ agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered.

The implication of neuronimmunoendocrine (NIE) modulatory network in the pathophysiologic process of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder implicitly marked by the substantia nigra dopaminergic neuron degeneration and explicitly characterized by the motor and non-motor symptom complexes. Apart from the nigrostriatal dopamine depletion, the immune and endocrine study findings are also frequently reported, which, in fact, have helped to broaden the symptom spectrum and better explain the pathogenesis and progression of PD. Nevertheless, based on the neural, immune, and endocrine findings presented above, it is still difficult to fully recapitulate the pathophysiologic process of PD. Therefore, here, in this review, we have proposed the neuroimmunoendocrine (NIE) modulatory network in PD, aiming to achieve a more comprehensive interpretation of the pathogenesis and progression of this disease. As a matter of fact, in addition to the classical motor symptoms, NIE modulatory network can also underlie the non-motor symptoms such as gastrointestinal, neuropsychiatric, circadian rhythm, and sleep disorders in PD. Moreover, the dopamine (DA)-melatonin imbalance in the retino-diencephalic/mesencephalic-pineal axis also provides an alternative explanation for the motor complications in the process of DA replacement therapy. In conclusion, the NIE network can be expected to deepen our understanding and facilitate the multi-dimensional management and therapy of PD in future clinical practice.

Novel VPS13A Gene Mutations Identified in Patients Diagnosed with Chorea-acanthocytosis (ChAc): Case Presentation and Literature Review.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive inherited syndrome characterized by hyperkinetic movements, seizures, cognitive impairment, neuropsychiatric symptoms, elevated serum biochemical indicators and acanthocytes detection in peripheral blood smear. Vacuolar protein sorting 13A (VPS13A) gene mutations have been proven to be genetically responsible for the pathogenesis of ChAc. Herein, based on the typical clinical symptoms and neuroimaging features, we present two suspected ChAc cases which are further genetically confirmed by four novel VPS13A gene mutations. Nevertheless, the sharp contrast between the population base and published ChAc reports implies that ChAc is considerably underdiagnosed in China. Therefore, we conclude several suggestive features and propose a diagnostic path of ChAc from a clinical, genetic and neuroimaging perspective, aiming to facilitate the diagnosis and management of ChAc in China.

RBD and Neurodegenerative Diseases.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disorder characterized by enacting one's dreams during the REM sleep, with most of the dreams being violent or aggressive, so that patients often come to see the doctor complaining hurting themselves or bed partners during sleep. Prevalence of RBD, based on population, is 0.38-2.01 %, but much higher in patients with neurodegenerative diseases, especially synucleinopathies. RBD may herald the emergence of synucleinopathies by decades, such that it may be used as an effective early marker of neurodegenerative diseases. Pharmaceutical treatment of RBD includes clonazepam, melatonin, pramipexole, and some newly reported medications. In this review, we summarized the clinical and PSG features of RBD, the pathophysiology and the therapy of it, focusing on the correlation between neurodegenerative diseases and RBD, in order to emphasize the significance of RBD as an early marker of neurodegenerative diseases.

759 fs pulse generation with Nd3+-doped CNGS ordered crystal based on a semiconductor saturable absorber mirror.

A diode-pumped passively continuous wave mode-locked laser at 1064.2 nm based on an ordered Nd:CNGS crystal has been experimentally investigated (for the first time, to our knowledge). Stable mode-locked pulses with a duration of 759 fs were produced at a repetition rate of 43.2 MHz. It is the shortest pulse generation of mode-locked lasers based on Nd3+-doped ordered crystal, as far as we know. A maximum average mode-locked output power of 133 mW was obtained at the absorbed pumped power of 6.7 W, and corresponding single-pulse energy and peak power were determined to be 3.1 nJ and 4.1 kW, respectively. The results indicate that the Nd:CNGS as an ordered crystal is indeed a potential candidate as a femtosecond laser gain medium.

Low-temperature selective catalytic reduction of NO on CeO2-CuO/Al2O3 catalysts prepared by different methods.

CeO2-CuO/Al2O3 catalysts were prepared by three different methods and their activities for selective catalytic reduction (SCR) of NO with NH3 were investigated. As can be seen from the experimental results, the catalyst prepared by the single-step sol-gel (SG) method showed the best SCR activity and resistance to SO2 and H2O. In order to investigate the relationship between the preparation method and the performance of SCR catalysts, the catalysts were characterized by using Brunauer-Emmett-Teller, X-ray diffraction, temperature programmed reduction with hydrogen, temperature programmed desorption with ammonia, X-ray photoelectron spectroscopy, Fourier transform infrared and thermo-gravimetric analysis techniques. It was found that the excellent performance of CeO2-CuO/Al2O3 catalyst prepared by the single-step SG method should be resulted from its large surface area, low crystallinity, high oxygen storage capacity, high NH3 adsorption capacity, high concentration of surface chemisorbed oxygen, weak sulphation process and weak water absorption.

Hot-injection synthesis of highly luminescent and monodisperse CdS nanocrystals using thioacetamide and cadmium source with proper reactivity.

Thioacetamide (TAA) has served as an excellent sulfur source to react with cadmium stearate to controllably produce highly luminescent and monodisperse CdS nanocrystals through the hot-injection method in dodecylamine solvent. The kinetics and thermodynamics of nucleation/growth of CdS nanocrystals, as well as their optical properties are controlled by changing synthesis conditions such as reaction time, injection/growth temperatures, TAA concentration and cadmium source with different reactivity. Temperature-dependent release of reactive sulfur species from TAA, together with proper reactivity of cadmium source, facilitates the better separation of nucleation and growth stage, the formation of highly monodisperse CdS nanocrystals with tunable size and further self-assembly into ordered superlattices. When cadmium carboxylates such as cadmium stearate and cadmium oleate are used as cadmium sources, surface trap emission of CdS nanocrystals can be gradually removed to obtain bright pure-blue emission with increasing reaction time. The highest quantum efficiency of up to 33.6% is achieved when using cadmium stearate as cadmium source at the injection/growth temperatures of 230/210 degrees C for 90min.

[Transformation of attached cells derived from fetal umbilical cord blood induced by conditional medium of hepatoma cells].

BACKGROUND & OBJECTIVE: Stem cells derived from fetal umbilical cord blood are of undifferentiated at early stage. They are sensitive to stimulations from the environment, and may be transformed under the effects of carcinogenic factors. This study was to explore the sensitivity of stem cells derived from fetal umbilical cord blood to carcinogenic factors. METHODS: Mononuclear cells were isolated from fetal umbilical cord blood, and the attached cells were cultured in the medium containing 10% conditional medium of HepG2 hepatoma cells. A new cell line was gained, termed H-UCB. The biological features of H-UCB cells were detected by electron microscopy, karyotype analysis, cell cytometry, Western blot, and colony formation assay. RESULTS: H-UCB cells proliferated faster after passage 3. The cells were fibroblast-like and hepatocyte-like, with the ratio of nucleus to cytoplasm increased. Under electron microscope, many microvilli on the surface and numbers of vacuoles in the cytoplasm of the cells were observed, the nuclei were large and irregular, endocytosis phenomena were noticed. Karyotype analysis indicated that the cells were heteroploid, and the number of chromosomes was between 50 and 70. Flow cytometry data indicated that the proliferation period was 22.9 h, and the karyotype was between diploid and tetraploid. Western blot showed that c-Myc protein and proliferating cell nuclear antigen (PCNA) were overexpressed in H-UCB cells. According to flow cytometry, the positive rates of surface markers of H-UCB cells were 79.0% for CD105, 1.2% for CD34, and 12.2% for CD106; those of control HepG2 cells were 15.0% for CO105, 9.8% for CD34, and 1.4% for CD106. The colony formation rate of H-UCB cells in soft agar was (13.2+/-2.6)%. CONCLUSION: H-UCB cells are derived from endothelial cells, and are transformed as malignant cells with tumor cell characteristics.

Formation of spindlelike aggregates and flowerlike arrays of polystyrene-b-poly(acrylic acid) micelles.

In this letter we describe a simple physical method for the ordered aggregation of scattered single spherical polystyrene-b-poly(acrylic acid) (PS-b-PAA) micelles. First, narrow dispersed spindlelike aggregates, about 60 nm in diameter and 1.5 microm in length, are obtained from the aggregation of single spherical PS-b-PAA micelles at 0 degrees C on a glass slide. Then, the yielding spindlelike units can further aggregate into long-ranged, close-packed, flowerlike arrays after a given amount of freeze-thaw cycles. The formation of the interesting arrays is ascribed to the templated aggregation of micelles on the water polycrystal at the freezing point.