Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next‐generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely ...pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty‐three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox‐Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype‐phenotype correlations would provide insights into the underlying pathogenic mechanisms.
We identified 24 causative mutations (19 novel) in a cohort of 70 EE patients and delineated new phenotype associated with CLCN4 and KCNQ2.
MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid ...leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
We report, for the first time, the long-awaited detection of diffuse gamma rays with energies between 100 TeV and 1 PeV in the Galactic disk. Particularly, all gamma rays above 398 TeV are observed ...apart from known TeV gamma-ray sources and compatible with expectations from the hadronic emission scenario in which gamma rays originate from the decay of π^{0}'s produced through the interaction of protons with the interstellar medium in the Galaxy. This is strong evidence that cosmic rays are accelerated beyond PeV energies in our Galaxy and spread over the Galactic disk.
Although the roles of the metabolic stress in organ ischemia‐reperfusion injury (IRI) have been well recognized, the question of whether and how these stress responses regulate innate immune ...activation against IR remains unclear. In a murine liver partial warm ischemia mode, we showed that prolonged ischemia triggered endoplasmic reticulum (ER) stress response, particularly, the activating transcription factor 6 (ATF6) branch, in liver Kupffer cells (KCs) and altered their responsiveness against Toll‐like receptor (TLR) stimulation. Ischemia‐primed cells increased pro‐, but decreased anti‐, inflammatory cytokine productions. Alleviation of ER stress in vivo by small chemical chaperon 4‐phenylbutyrate or ATF6 small interfering RNA (siRNA) diminished the pro‐inflammatory priming effect of ischemia in KCs, leading to the inhibition of liver immune response against IR and protection of livers from IRI. In vitro, ATF6 siRNA abrogated the ER stress‐mediated pro‐inflammatory enhancement of macrophage TLR4 response, by restricting NF‐κB and restoring Akt activations. Thus, ischemia primes liver innate immune cells by ATF6‐mediated ER stress response. The IR‐induced metabolic stress and TLR activation function in synergy to activate tissue inflammatory immune response.
This study demonstrates that ischemia promotes pro‐inflammatory innate immune activation by activating ATF6 signaling pathways in murine liver ischemia and reperfusion injury.
Ischemia and reperfusion injury (IRI) is a dynamic process that involves two distinctive yet interrelated phases of ischemic organ damage and inflammation‐mediated reperfusion injury. Although ...multiple cellular and molecular pathways contribute and regulate tissue/organ damage, integration of different players into a unified mechanism is warranted. The crosstalk between innate and adaptive immune systems plays a significant role in the pathogenesis of liver IRI. In this review, we focus on recent progress in the mechanism of liver innate immune activation by IR. Kupffer cells (KC), DCs, NK, as well as T cells initiate local inflammation response, the hallmark of IRI, by utilizing distinctive immune receptors to recognize and/or trigger various molecules, both endogenous and exogenous. The interlocked molecular signaling pathways in the context of multiple liver cell types, the IRI kinetics and positive versus negative regulatory loops in the innate immune activation process are discussed. Better appreciation of molecular interactions that mediate these intricate cascades, should allow for the development of novel therapeutic approached against IRI in liver transplant recipients.
Liver inflammation triggered by the insults of peri‐transplant ischemia and reperfusion is an innate immune‐dominated local response regulated by CD4+ T cells.
External signal steady magnetic field and electric-magnetic compound field were applied to investigate the influence of the electromagnetic field to the laser cladding NiCrBSi coatings. The ...macromorphology, phase composition and microstructure were identified by optical microscope (OM), confocal scanning laser microscope (CSLM), X-ray diffraction (XRD) and scanning electron microscope (SEM) coupled with energy dispersive spectroscopy (EDS). The experimental results demonstrated that the main phase composition of the coatings was γ-(Fe,Ni), Cr23C6, Cr7C3, CrB, Ni3B with and without electromagnetic fields. Results showed that the dilution of the coating under electric-magnetic compound field was similar (14%) to the coating without auxiliary field. While the dilution of the coating had a decrease (10.8%) under signal steady magnetic field. Results of microstructure indicated the content of CrB phase in the coating increased obviously under electromagnetic field. The average microhardness of the coating under electromagnetic field was increased compared to that of the coating without auxiliary field. Corrosion resistance was also improved under electromagnetic field auxiliary laser cladding.
•Electromagnetic field can change the dilution rate of the coating.•The steady magnetic field can suppress the diffusion of element.•Electromagnetic field can improve the microhardness and corrosion resistance of coating.•Electromagnetic field does not affect the type of coating phase.
Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 ...mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production and ATP generation. Knockdown of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV-transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism.
Electrically tunable dielectric materials have potential applications as various microwave devices, such as tunable oscillators, phase shifters and varactors. High dielectric tunability, low ...dielectric loss tangent and appropriate level of dielectric constant, are basic requirements for such applications. Ferroelectric materials are the most promising candidates. In general, strontium titanate (SrTiO3 or ST) is used for devices operating at low temperatures, while the devices based on barium strontium titanate (Ba1a degree x Sr x TiO3 or BST) are operated at room temperatures. The modifications of parent ferroelectrics, such as Sr1a degree x Pb x TiO3, BaZr x Ti1a degree x O3 and BaTi1a degree x Sn x O3 etc., have also been widely investigated. In addition, there have been reports on electrically tunable dielectric materials, based on non-ferroelectric compounds, such as microwave dielectrics and carbon nanotube (CNT) composites. Specifically for ferroelectric materials, a critical issue is the reduction of the dielectric losses, because their dielectric loss tangents are relatively high for practical device applications. Recently, many efforts have been made in order to reduce the dielectric losses of BST based ferroelectrics. An efficient way is to dope oxides that have low dielectric losses, such as MgO, ZrO2 and Al2O3, TiO2, LaAlO3, and Bi1.5ZnNb1.5O7 etc., into the ferroelectric materials. In addition to the reduction in dielectric loss tangents, the introduction of oxides would also be able to modify the dielectric constant to be suitable for practical design of various devices. Meanwhile, dielectric and electrical properties of thin films can be improved by chemical doping, substrate adaptation, orientation and anisotropy optimization. This review provides an overall summary on the recent progress in developing electrically tunable dielectric materials, based on ferroelectrics and non-ferroelectrics, with a specific attention to the strategies employed to improve the performances of ferroelectric materials for microwave device applications.
•Fatigue short crack propagation behavior of SLM Inconel 718 alloy is studied by in situ SEM.•Fatigue crack growth deceleration is related to the blocking effects of grain boundaries.•Fatigue crack ...growth along the build-up plane is fastest.•Fatigue crack growth rates are higher at 650 °C than 25 °C regardless of orientation.
The influence of orientation and temperature on fatigue short crack propagation behavior of Inconel 718 alloy was studied at both 25 °C and 650 °C by in-situ fatigue testing under scanning electron microscope. The fatigue crack growth rates (FCGR) showed evident dependence on orientation at both temperatures, following: XZ < X < Z. The FCGR difference of XZ and Z orientation became less pronounced at 650 °C. Fatigue cracks exhibited commonly transgranular fracture at both temperatures, with enhanced FCGR at 650 °C. Microstructurally short crack propagation showed evident fluctuations, which were closely related to the blocking effects of grain boundaries.
•Electromagnetic field does not change the phase composition of the coating.•Electromagnetic field can change the temperature gradient.•Electromagnetic field can improve the microstructure of the ...coating.•Electromagnetic field can reduce the cracks and improve the microhardness of the coating.
Laser cladding Ni-base coatings were prepared on pure iron assisted by an electromagnetic compound field. The microstructure, phase composition, crack and microhardness of the cladding coatings were investigated. Results indicated that laser cladding Ni-base coatings with and without the electromagnetic field was composed of γ-(Fe, Ni), CrB, Cr7C3, Ni3B and Ni2B. The electromagnetic compound field could promote the transformation of γ-(Fe, Ni) to equiaxed crystals. The volume fraction of hard phase CrB can be increased by electromagnetic field. Mechanical scouring effect of electromagnetic stirring makes hard phase Cr7C3 form an independent rod structure. The number of cracks in coatings is decreased under the electromagnetic field. The average microhardness of cladding coatings increased to 923.7 HV0.2. Under the combined action of the electromagnetic stirring and current thermal effect, the temperature gradient in the molten pool had an optimum value. That is, the value of AC current was 1200 A and magnetic flux intensity was 0.2 T.
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