Mutations in C1orf194, encoding a calcium regulator, cause dominant Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy exhibiting great clinical and genetic heterogeneity. Here, the identification of two heterozygous missense mutations in the C1orf194 gene at 1p21.2-p13.2 with Charcot-Marie-Tooth disease are reported. Specifically, the p.I122N mutation was the cause of an intermediate form of Charcot-Marie-Tooth disease, and the p.K28I missense mutation predominately led to the demyelinating form. Functional studies demonstrated that the p.K28I variant significantly reduced expression of the protein, but the p.I122N variant increased. In addition, the p.I122N mutant protein exhibited the aggregation in neuroblastoma cell lines and the patient's peroneal nerve. Either gain-of-function or partial loss-of-function mutations to C1ORF194 can specify different causal mechanisms responsible for Charcot-Marie-Tooth disease with a wide range of clinical severity. Moreover, a knock-in mouse model confirmed that the C1orf194 missense mutation p.I121N led to impairments in motor and neuromuscular functions, and aberrant myelination and axonal phenotypes. The loss of normal C1ORF194 protein altered intracellular Ca2+ homeostasis and upregulated Ca2+ handling regulatory proteins. These findings describe a novel protein with vital functions in peripheral nervous systems and broaden the causes of Charcot-Marie-Tooth disease, which open new avenues for the diagnosis and treatment of related neuropathies.

Resonant-enhanced full-color emission of quantum-dot-based micro LED display technology.

Colloidal quantum dots which can emit red, green, and blue colors are incorporated with a micro-LED array to demonstrate a feasible choice for future display technology. The pitch of the micro-LED array is 40 µm, which is sufficient for high-resolution screen applications. The method that was used to spray the quantum dots in such tight space is called Aerosol Jet technology which uses atomizer and gas flow control to obtain uniform and controlled narrow spots. The ultra-violet LEDs are used in the array to excite the red, green and blue quantum dots on the top surface. To increase the utilization of the UV photons, a layer of distributed Bragg reflector was laid down on the device to reflect most of the leaked UV photons back to the quantum dot layers. With this mechanism, the enhanced luminous flux is 194% (blue), 173% (green) and 183% (red) more than that of the samples without the reflector. The luminous efficacy of radiation (LER) was measured under various currents and a value of 165 lm/Watt was recorded.

Improvement of light quality by DBR structure in white LED.

This study demonstrates the application of DBR structure into the remote phosphor structure to improve the angular correlated color temperature (CCT) deviation in white light-emitting diodes (WLEDs). In the experiment, the LED device with DBR structure yielded a higher luminous efficiency than a conventional structure. The CCT deviation can be improved from 1758K to 280K in a range of -70 to 70 degree and the luminous flux increases more than 10% due to the enhancement of the light extraction of the blue light. Moreover, the reflectance of the different DBR structures is analyzed with different angles to reveal the reasons of such improvements. As the result, this LED device with DBR structure shows the great potential to use as the next generation lighting source.

[Effects of Bu Zhong Yi Qi decoction on CIH-induced interstitial lung fibrosis in mice].

OBJECTIVE: To investigate the effects of chronic intermittent hypoxia (CIH) on the expression of transforming growth factor-ß (TGF-ß), P-samd3, serum laminin (LN) and hyaluronidase (HA) in mouse lung tissues and the protective effects of Bu Zhong Yi Qi decoction on lung interstitial deposition damage in CIH mice. METHODS: Fifty SPF-grade C57BL mice were randomly divided into five groups (n=10): blank control group, CIH model group, and CIH+ low, medium and high doses of Bu Zhong Yi Qi decoction group. Mice were placed under normoxia or CIH conditions, respectively. The Chinese medicine group was given the corresponding doses of drugs. HE staining was performed to assess pathological changes and Masson staining was performed to assess collagen deposition. Western blot was performed to detect the expressions of channel proteins such as TGF-ß1, P-smad3 and down stream α-SMA and Collagen I. ELISA was performed to detect the serum levels of TGF-ß1, LN and HA. RESULTS: HE staining showed alveolar collapse, septal thickening and epithelial cell necrosis in CIH mice, Masson showed massive collagen fiber proliferation and deposition in lung interstitium, while the above changes in lung tissues were significantly improved in the CIH + Bu Zhong Yi Qi decoction groups compared with the CIH group. TGF-ß1, P-smad3 and Collagen I, Collagen Ⅲ, and α-SMA expression levels were increased compared with the blank control group (P＜0.05), and the expressions of TGF-ß1 and LN in serum were upregulated (P＜0.05). The expressions of TGF-ß1, P-smad3, Collagen I protein and SMA-α in the lung tissues of the CIH+ Bu Zhong Yi Qi decoction groups were downregulated significantly compared with those of the CIH group (P＜0.05), and the improvement of multiple indexes in the CIH+high-dose CIH intervention group was better than those of the low-dose group (P＜0.05). CONCLUSION: Bu Zhong Yi Qi decoction can inhibit alveolar structural changes and excessive collagen deposition in the interstitium of CIH mice, and then improve lung function in CIH mice. The mechanism may be related to the down-regulation of protein expression related to TGF-ß/smads signaling pathway by Bu Zhong Yi Qi decoction.

Mesenchymal stem cell-derived exosomes: therapeutic opportunities and challenges for spinal cord injury.

Spinal cord injury (SCI) often leads to serious motor and sensory dysfunction of the limbs below the injured segment. SCI not only results in physical and psychological harm to patients but can also cause a huge economic burden on their families and society. As there is no effective treatment method, the prevention, treatment, and rehabilitation of patients with SCI have become urgent problems to be solved. In recent years, mesenchymal stem cells (MSCs) have attracted more attention in the treatment of SCI. Although MSC therapy can reduce injured volume and promote axonal regeneration, its application is limited by tumorigenicity, a low survival rate, and immune rejection. Accumulating literature shows that exosomes have great potential in the treatment of SCI. In this review, we summarize the existing MSC-derived exosome studies on SCI and discuss the advantages and challenges of treating SCI based on exosomes derived from MSCs.

A rapid juvenile murine model of nonalcoholic steatohepatitis (NASH): Chronic intermittent hypoxia exacerbates Western diet-induced NASH.

AIMS: Many dietary NASH models require a long duration to establish (4-6 months). Chronic intermittent hypoxia (CIH), a cardinal hallmark of obstructive sleep apnea (OSA), may accelerate the progression of pediatric nonalcoholic fatty liver disease (NAFLD). However, diet-induced obese (DIO) mice exposed to CIH have not been perceived as a fast or reliable tool in NASH research. This study was designed to establish a rapid juvenile murine NASH model, and determine whether the combination of CIH and a western-style diet (hypercaloric fatty diet plus high fructose) can fully display key pathologic features of NASH. METHODS: C57BL/6 N mice (3 weeks old) fed a control diet or western diet (WD) were exposed to CIH (9% nadir of inspired oxygen levels) or room air for 6 and 12 weeks. KEY FINDINGS: The Control/CIH group mainly exhibited hyperinsulinemia and insulin resistance (IR). In contrast, mice fed a WD developed weight gain after 3 weeks, microvesicular steatosis in 6 weeks, and indices of metabolic disorders at 12 weeks. Furthermore, CIH exposure accelerated WD- induced macromicrovesicular steatosis (liver triglycerides and de novo lipogenesis), liver injury (ballooned hepatocytes and liver enzymes), lobular/portal inflammation (inflammatory cytokines and macrophage recruitment), and fibrogenesis (hydroxyproline content and TGF-ß protein). Notably, only the WD/CIH group exhibited elevated hepatic MDA content, protein levels of NOX4, α-SMA and collagen I, as well as reduced Nrf2 and HO-1 protein expression. SIGNIFICANCE: WD/CIH treatment rapidly mimics the histological characteristics of pediatric NASH with metabolic dysfunction and fibrosis, representing an appropriate experimental model for NASH research.

[Effect of xiaotan huayu liqiao traditional Chinese medicine compound on myocardial fibrosis in rats with chronic intermittent hypoxia and its mechanism].

Objective: To explore the role of transforming growth factor-ß (TGF-ß) signaling pathway in xiaotan huayu liqiao traditional Chinese medicine compound (XC)'s anti-myocardial fibrosis in chronic intermittent hypoxia (CIH) rats. Methods: Forty SD rats were randomly divided into normoxia group, oxygen + traditional Chinese medicine compound group ( TCMC), Chronic intermittent hypoxia model group (CIH), TCMC + CIH, 10 in each group. CIH cabin was built by filling with nitrogen and oxygen. Firstly, the volume fraction of oxygen in the cabin reduced from 21% to 9% in 90 s by filling the cabin with nitrogen. And then it gradually rose to 21% by reoxygenating in 90s, as a cycle. CIH and TCMC+CIH group rats were placed in the CIH device, while normoxia and TCMC group rats were placed in the normal oxygen chamber. In addition, rats in TCMC +CIH group and TCMC group were treated with XC crude drug (24 g/kg) daily by gavage, while rats in CIH group and normoxia group were given equal volume normal saline. Using sirius red staining, the collagen in myocardial interstitium was visualized. The protein expressions of collagen I, collagen III and fibronectin were detected by Western blot, p-Smad3, p-Smad2 and TGF-ß protein in the TGF-ß/Smads signaling pathway were also analyzed by Western blot. The mRNA expressions of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinase -2(TIMP-2) were measured by real-time quantitative polymerase chain reaction (PCR). Results: Compared with the rats exposed to normoxia, the CIH rats showed obvious collagen deposition, protein expressions of collagen I, collagen III and fibronectin were significantly increased in the myocardial tissue (P＜0.01). The protein expression levels of TGF-ß, p-smad2 and p-smad3 in the myocardial tissue of the CIH rats were also significantly increased (P＜0.01). The up-regulation of TIMP-2 mRNA in the myocardial tissues resulted in the decrease of MMP-2 mRNA(P＜0.01). XC reduced myocardial fibrosis of CIH rats and inhibited the expressions of collagen I and collagen III and fibronectin protein (P＜0.05,P＜0.01,P＜0.05, respectively). The further mechanism study showed that XC inhibited the expression of TGF-ß (P＜0.01), which down-regulated the expressions of p-smad2, p-smad3 and TIMP-2 (P＜0.05). Conclusion: XC could reduce the expression of TGF-ß and smad2/3 phosphorylation, down-regulate the expression of TIMP-2, which would inhibit the formation of myocardial fibrosis in CIH rats, and improve the myocardial function of CIH rats.

Valley Polarization and Valleyresistance in a Monolayer Transition Metal Dichalcogenide Superlattice.

A significant, fundamental challenge in the field of valleytronics is how to generate and regulate valley-polarized currents in practical ways. Here, we discover a new mechanism for producing valley polarization in a monolayer transition metal dichalcogenide superlattice, in which valley-resolved gaps are formed at the supercell Brillouin zone boundaries and centers due to intervalley scattering. When the incident energy of the electron lies in the gaps, the available states are valley polarized, thus providing a valley-polarized current from the superlattice. We show that the direction and strength of the valley polarization may be further tuned by varying the potential applied to the superlattice. The transmission can have a net valley polarization of 55% for a four-period heterostructure. Moreover, two such valley filters in series may function as an electrostatically controlled giant valleyresistance device, representing a zero-magnetic field counterpart to the familiar giant magnetoresistance device.

Hydrogen and Oxygen Mixture to Improve Cardiac Dysfunction and Myocardial Pathological Changes Induced by Intermittent Hypoxia in Rats.

Obstructive sleep apnea (OSA) can cause intermittent changes in blood oxygen saturation, resulting in the generation of many reactive oxygen species (ROS). To discover new antioxidants and clarify the endoplasmic reticulum (ER) stress involved in cardiac injury in OSA, we established a chronic intermittent hypoxia (CIH) rat model with a fraction of inspired O2 (FiO2) ranging from 21% to 9%, 20 times/h for 8 h/day, and the rats were treated with H2-O2 mixture (67% hydrogen and 33% oxygen) for 2 h/day for 35 days. Our results showed that H2-O2 mixture remarkably improved cardiac dysfunction and myocardial fibrosis. We found that H2-O2 mixture inhalation declined ER stress-induced apoptosis via three major response pathways: PERK-eIF2α-ATF4, IRE 1-XBP1, and ATF 6. Furthermore, we revealed that H2-O2 mixture blocked c-Jun N-terminal kinase- (JNK-) MAPK activation, increased the ratio of Bcl-2/Bax, and inhibited caspase 3 cleavage to protect against CIH-induced cardiac apoptosis. In addition, H2-O2 mixture considerably decreased ROS levels via upregulating superoxide dismutase (SOD) and glutathione (GSH) as well as downregulating NADPH oxidase (NOX 2) expression in the hearts of CIH rats. All the results demonstrated that H2-O2 mixture significantly reduced ER stress and apoptosis and that H2 might be an efficient antioxidant against the oxidative stress injury induced by CIH.

Protective role of Gentianella acuta on isoprenaline induced myocardial fibrosis in rats via inhibition of NF-κB pathway.

Gentianella acuta (Michx.) Hulten (G. acuta) has been widely used in Mongolian medicines for the treatment of cardiovascular diseases in Ewenki and Oroqen, Inner Mongolia autonomous region, China. The aim of this study was to investigate the effects and related mechanism of G. acuta on isoproterenol (ISO)-induced oxidative stress, fibrosis, and myocardial damage in rats. Male Sprague Dawley rats were randomly divided into the normal control group, ISO induced group and ISO+G. acuta treatment group. Rats were administered with ISO subcutaneously (5 mg/kg/day) for 7 days, and were orally administered simultaneously with aqueous extracts of G. acuta for 21 days. This investigation showed G. acuta treatment ameliorated cardiac structural disorder, excessive collagenous fiber accumulation and cardiac malfunction. Compared with the ISO induced model group, G. acuta treatment increased superoxide dismutase (SOD) activities and glutathione (GSH) level, prevented the rise of malondialdehyde (MDA), and decreased hydroxyproline contents in the heart tissues. Moreover, G. acuta reduced the expression of transforming growth factor ß1 (TGF-ß1) and connective tissue growth factor (CTGF), and inhibited the expression and activation of NF-κB-P65 in myocardial tissues. These results suggested that G. acuta protects against ISO-induced cardiac malfunction probably by preventing oxidative stress, and fibrosis, and the mechanism might be through inhibiting NF-κB pathway.

Fasudil improves endothelial dysfunction in rats exposed to chronic intermittent hypoxia through RhoA/ROCK/NFATc3 pathway.

Endothelial dysfunction is one of the main pathological changes in Obstructive sleep apnoea (OSA). The Rho kinase (ROCK) pathway is associated with endothelial dysfunction. However, the interaction between ROCK and nuclear factor of activated T cells isoform c3 (NFATc3) in the development of this pathological response under chronic intermittent hypoxia (CIH) is unclear. To simulate the OSA model, we established a moderate CIH rat model by administering the fraction of inspired O2 (FiO2) from 21% to 9%, 20 times/h, 8 h/day for 3 weeks. Fasudil (ROCK inhibitor, 8 mg/kg/d, i.p.) was administrated in the rats exposed to CIH for 3 weeks. Our results demonstrated that CIH caused significantly endothelial dysfunction, accompanying with increased ET-1 level, decreased eNOS expression and NO production, which reduced ACh-induced vascular relaxation responses. Moreover, RhoA/ROCK-2/NFATc3 expressions were up-regulated. Fasudil significantly improved CIH induced endothelial dysfunction. Data suggested that the ROCK activation is necessary for endothelial dysfunction during CIH.

[Early cardiac injury in patients with obstructive sleep apnea].

OBJECTIVE: To evaluate the early cardiac injury caused by obstructive sleep apnea (OSA) before the development of cardiovascular symptoms of OSA. METHODS: Ninety-two patients without any known cardiovascular disorders who underwent polysomnography (PSG) were enrolled in the study. Subjects were divided into mild, moderate, and severe OSA groups by their apnea hypopnea index (AHI), and 25 healthy individuals were identified as controls. After PSG examination, fasting blood samples for the evaluation of N-terminal pro-brain natriuretic peptide (NT-proBNP) and heart-type fatty acid binding protein (h-FABP) were collected in the morning, and left ventricular(LV) functions were assessed by using echocardiographic methods. Thirty moderate and severe OSA patients were treated with continuous positive airway pressure respectively (CPAP). RESULTS: The levels of h-FABP and NT-proBNP were obviously higher in all OSA groups than those in the control group (P<0.01), and were positively correlated with AHI (P<0.01). The Em/Am values of all OSA groups and E/A values of the moderate and severe OSA groups were significantly reduced (P<0.01). The difference in Em/Am values among the groups was statistically significant (P<0.01). Compared with those before treatment, h-FABP and NT-BNP levels in serum of OSA patients after CPAP treatment were significantly reduced (P<0.01), and Em/Am and E/A values were significantly increased (P<0.01). CONCLUSIONS: Left ventricular diastolic dysfunction and early myocardial microtrauma are major manifestations of early heart damage in patients with OSA. CPAP therapy could significantly improve early cardiac damage in OSA patients.

Correction: A high quality liquid-type quantum dot white light-emitting diode.

Correction for 'A high quality liquid-type quantum dot white light-emitting diode' by Chin-Wei Sher et al., Nanoscale, 2016, 8, 1117-1122.

Repression of DOK7 mediated by DNMT3A promotes the proliferation and invasion of KYSE410 and TE-12 ESCC cells.

Increasing evidence shows that aberrant epigenetic regulation of tumor suppressor genes is a contributing factor to their altered expression in esophageal squamous cell carcinoma (ESCC). In the current study, we investigate the role of DOK7 in ESCC cells. We found that enforced expression of DOK7 inhibited the proliferation and invasion of ESCC cells. We also found that treatment of ESCC cells with the DNA methylation inhibitor, 5-aza-2-deoxycytidine (5-azadC), induced the demethylation of DOK7 in promoter and DOK7 expression. Moreover, silencing DNMT3A decreased methylation of DOK7 and increased DOK7 expression, followed by repressing the proliferation and invasion of ESCC cells. Collectively, our data indicated that silencing DNMT3A inhibits proliferation and invasion in ESCC cells by inducing demethylation of DOK7.

Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Previous meta-analyses of pulmonary arterial hypertension (PAH)-specific therapy for PAH pooled PAH-specific combination therapy and monotherapy. This flaw may threaten the authenticity of their findings. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials that evaluated any PAH-specific medications in the treatment of PAH. We calculated ORs with 95% CIs for dichotomous data and standardized mean differences for continuous data. RESULTS: In total, 35 randomized controlled trials involving 6,702 patients were included. In monotherapy vs placebo/conventional therapy, significance was obtained in mortality reduction (OR, 0.50 [95% CI, 0.33 to 0.76]; P = .001), 6-min walk test (mean difference, 31.10 m [95% CI, 25.40 to 36.80]; P < .00001), New York Heart Association/World Health Organization functional class (OR, 2.48 [95% CI, 1.51 to 4.07]; P = .0003), and hemodynamic status based on mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and incidence of withdrawal due to adverse effects. In combination therapy vs monotherapy, significance was reached for the 6-min walk test (mean difference, 19.96 m [95% CI, 15.35 to 24.57]; P < .00001), functional class (OR, 1.65 [95% CI, 1.20 to 2.28]; P = .002), hemodynamic status, and incidence of withdrawal due to adverse effects (OR, 2.01 [95% CI, 1.54 to 2.61]; P < .00001) but not for mortality reduction (OR, 0.98 [95% CI, 0.57 to 1.68]; P = .94). CONCLUSIONS: Our meta-analysis revealed that PAH-specific monotherapy could improve mortality, exercise capacity, functional class, and hemodynamic status compared with placebo or conventional therapy. However, combination therapy could further improve exercise capacity, functional class, and hemodynamic status compared with monotherapy, but it had no proven effect on mortality. Combination therapy had a much higher incidence of withdrawal due to adverse effects than monotherapy.

Pulsed-laser micropatterned quantum-dot array for white light source.

In this study, a novel photoluminescent quantum dots device with laser-processed microscale patterns has been demonstrated to be used as a white light emitting source. The pulsed laser ablation technique was employed to directly fabricate microscale square holes with nano-ripple structures onto the sapphire substrate of a flip-chip blue light-emitting diode, confining sprayed quantum dots into well-defined areas and eliminating the coffee ring effect. The electroluminescence characterizations showed that the white light emission from the developed photoluminescent quantum-dot light-emitting diode exhibits stable emission at different driving currents. With a flexibility of controlling the quantum dots proportions in the patterned square holes, our developed white-light emitting source not only can be employed in the display applications with color triangle enlarged by 47% compared with the NTSC standard, but also provide the great potential in future lighting industry with the correlated color temperature continuously changed in a wide range.

A high quality liquid-type quantum dot white light-emitting diode.

This study demonstrates a novel package design to store colloidal quantum dots in liquid format and integrate them with a standard LED. The high efficiency and high quality color performance at a neutral white correlated color temperature is demonstrated. The experimental results indicate that the liquid-type quantum dot white light-emitting diode (LQD WLED) is highly efficient and reliable. The luminous efficiency and color rendering index (CRI) of the LQD WLED can reach 271 lm Wop(-1) and 95, respectively. Moreover, a glass box is employed to prevent humidity and oxygen erosion. With this encapsulation design, our quantum dot box can survive over 1000 hours of storage time.

[Correlation between expression of matrix metalloproteinase-2 and angiogenesis in esophageal carcinoma].

OBJECTIVE: To study expression of MMP-2 in relation to microvessel density (MVD) in esophageal carcinoma. METHODS: Forty-eight specimens of esophageal carcinoma (Ec) and 17 specimens of grade II + III epithelial dysplasia (Dy) close to the tumor and 12 specimens of normal tissue (Nt) along the incisional margin were examined by S-P immunohistochemical staining with anti-MMP-2 monoclonal antibody. An anti-CD34 monoclonal antibody was used to show MVD. RESULTS: MMP-2 expression in Ec was remarkably higher than that in Dy, which was higher than that in Nt. MMP-2 expression in Ec and Dy was significantly correlated with MVD in the tumor and nearby tissue. MMP-2 expression and MVD in Ec significantly associated with lymph node metastasis. CONCLUSION: Expression of MMP-2 plays an important role in angiogenesis and lymph node metastasis of esophageal cancer.