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Abstract Background Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR T790M mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR T790M and their new resistance mechanisms have attracted much attention. Methods We examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan. Results We identified compound ASK120067 as a novel inhibitor of EGFR T790M , with selectivity over EGFR W T . ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR W T . Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR T790M . The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo. Conclusions Our results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.

Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in NOTCH3 gene with remarkable phenotypic heterogeneity. Cases of CADASIL associated with homozygous NOTCH3 mutations are rare and subsequently understudied. In this study, we investigate the genetic and phenotypic features within patients of CADASIL with homozygous NOTCH3 mutations. Case presentation We recruited two affected individuals with CADASIL from a mainland Chinese family. The proband (Patient 1), a 60-year-old male, presented with slow progressive gait instability, severe cognitive impairment, and emotional disorder for more than 2 years with a history of ischemic stroke and hypertension. His younger brother (Patient 2) presented with apparent gait difficulties, dysarthria as well as cognitive decline at 59 years old. Brain magnetic resonance imaging (MRI) showed diffused white matter lesions involving bilateral periventricular white matter, semioval center region, and anterior temporal lobes. Molecular genetic testing identified a homozygous variant, c.1759C > T (p.R587C), in NOTCH3 gene in both patients. Pathological analysis revealed granular osmiophilic material (GOM) deposits in small arterial walls of skin from the proband. The diagnosis of CADASIL was confirmed. Conclusions Our cases of CADASIL with homozygous mutation c.1759C > T (p.R587C) in NOTCH3 share similar manifestation to the patients with heterozygous same mutation reported previously. Other than genetic factors, vascular risk factors or environmental factors might contribute to the phenotypic variation of CADASIL.

At present, the explosive growth of software code volume and quantity makes the code review process very labor-intensive and time-consuming. An automated code review model can assist in improving the efficiency of the process. Tufano et al., designed two automated tasks to help improve the efficiency of code review based on the deep learning approach, from two different perspectives, namely, the developer submitting the code and the code reviewer. However, they only used code sequence information and did not explore the logical structure information with a richer meaning of the code. To improve the learning of code structure information, a program dependency graph serialization algorithm PDG2Seq algorithm is proposed, which converts the program dependency graph into a unique graph code sequence in a lossless manner, while retaining the program structure information and semantic information. We then designed an automated code review model based on the pre-trained model CodeBERT architecture, which strengthens the learning of code information by fusing program structure information and code sequence information, and then fine-tuned the model according to the code review activity scene to complete the automatic modification of the code. To verify the efficiency of the algorithm, the two tasks in the experiment were compared with the best Algorithm 1-encoder/2-encoder. The experimental results show that the model we proposed has a significant improvement under the BLEU, Lewinshtein distance and ROUGE-L metrics.

The improvement of our living standards puts forward higher requirements for energy storage systems, especially rechargeable batteries. Unfortunately, phenomena such as capacity failure, etc. have been major difficulties in the field of energy storage. Therefore, we need some advanced means to explore the reaction process and mechanisms of the cell. Electron paramagnetic resonance (EPR) has the advantages of a high sensitivity to electrons, lack of damage to samples, quantitative analysis, etc., which can make for a more in-depth exploration of most paramagnetic electrode materials and metal electrode materials. After a brief description of the principle of EPR, this review briefly summarizes the application of EPR to the characterization of transition metal oxide cathode and lithium metal anode electrode materials in recent years, such as showing how to study electrode materials by using EPR in situ and operando.

Emerging evidence suggests that astrocyte loss is one of the most important pathological features in the hippocampus of patients with major depressive disorder (MDD) and depressive mice. Pyroptosis is a recently discovered form of programmed cell death depending on Caspase–gasdermin D (Casp-GSDMD), which is involved in multiple neuropsychiatric diseases. However, the involvement of pyroptosis in the onset of MDD and glial pathological injury remains obscure. Here, we observed that depressive mice showed astrocytic pyroptosis, which was responsible for astrocyte loss, and selective serotonin reuptake inhibitor (SSRI) treatment could attenuate the pyroptosis induced by the chronic mild stress (CMS) model. Genetic KO of GSDMD, Casp-1, and astrocytic NOD-like receptor protein 3 (NLRP3) inflammasome in mice alleviated depression-like behaviors and inhibited the pyroptosis-associated protein expression. In contrast, overexpression of astrocytic GSDMD–N-terminal domain (GSDMD-N) in the hippocampus could abolish the improvement of behavioral alterations in GSDMD-deficient mice. This work illustrates that targeting the NLRP3/Casp-1/GSDMD–mediated pyroptosis may provide potential therapeutic benefits to stress-related astrocyte loss in the pathogenesis of depression.

As a basic mechanical property of rocks, brittleness is closely related to the drillability, wellbore stability, and rockburst characteristics of reservoir rocks. Accurate evaluation of rock brittleness is of great significance for guiding oil and gas production and reservoir reconstruction. This paper systematically introduced the commonly used brittleness evaluation methods based on the stress–strain curve and analyzed their theoretical background and mathematical models. Combined with practical engineering application, the characterization effect of commonly used brittleness indexes in various rock samples is verified and optimized, and it is obtained that the brittleness index (B17 in this paper), based on the stress–strain curve and considering energy conversion, has the best characterization result for rock brittleness, which has good differentiation for different rock samples. At the same time, considering that the stress–strain curve under high confining pressure may result in a significant yield plateau phenomenon before and after the peak strength, the endpoint of the plastic yield plateau is used to replace the peak point as the starting point for the drop of bearing capacity. The revised brittleness index is consistent with the changing trend of the original curve, which verifies the reliability of the model. Finally, the method for characterizing the brittleness of Class II curves is supplemented, and the combined brittleness index of rock is established, which verifies the rationality and correctness of the index and provide a more general evaluation method for rock brittleness in engineering.

Much research on adversarial attacks has proved that deep neural networks have certain security vulnerabilities. Among potential attacks, black-box adversarial attacks are considered the most realistic based on the the natural hidden nature of deep neural networks. Such attacks have become a critical academic emphasis in the current security field. However, current black-box attack methods still have shortcomings, resulting in incomplete utilization of query information. Our research, based on the newly proposed Simulator Attack, proves the correctness and usability of feature layer information in a simulator model obtained by meta-learning for the first time. Then, we propose an optimized Simulator Attack+ based on this discovery. Our optimization methods used in Simulator Attack+ include: (1) a feature attentional boosting module that uses the feature layer information of the simulator to enhance the attack and accelerate the generation of adversarial examples; (2) a linear self-adaptive simulator-predict interval mechanism that allows the simulator model to be fully fine-tuned in the early stage of the attack and dynamically adjusts the interval for querying the black-box model; and (3) an unsupervised clustering module to provide a warm-start for targeted attacks. Results from experiments on the CIFAR-10 and CIFAR-100 datasets clearly show that Simulator Attack+ can further reduce the number of consuming queries to improve query efficiency while maintaining the attack.

Objective Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer (NSCLC). However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3Kα-selective inhibition against KRAS-mutated NSCLC remains largely unknown.Methods Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo.Results CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation.Conclusions Simultaneous inhibition of PI3Kα and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3Kα inhibitor and a CDK4/6 inhibitor for the treatment of KRAS-mutated NSCLC.

A novel AlGaInAs/InP electro-absorption modulated laser (EML) with a simple fabrication process is proposed, in which the electro-absorption modulator (EAM) has a 10 nm blueshift induced by quantum well intermixing (QWI) and is monolithically integrated with a sidewall grating distributed-feedback (DFB) laser working at 1.55 μm wavelength. The extent of the QWI process is characterized by a diffusion length. The quantum confined Stark effect (QCSE) is simulated in terms of extinction ratio (ER) and chirp for bias electric fields from 0 kV/cm to 200 kV/cm and for different amounts of intermixing. The results indicate that for a 150 µm-long EAM with a 10 nm blueshift induced by QWI, an ER of 40 dB is obtained at 2.5 V reverse bias with no penalty in chirp compared to an as-grown quantum well (QW) and the insertion loss at 0 V bias is 0.11 dB for 1.55 µm operation wavelength. The simulated –3 dB bandwidth of the electrical to optical power response is 22 GHz.

Wood formation is a complicated process under the control of a large set of transcription factors. NAC transcription factors are considered “master switches” in this process. However, few NAC members have been cloned and characterized in Eucalyptus, which is one of the most economically important woody plants. Here, we reported an NAC transcription factor from Eucalyptus grandis, EgNAC141, which has no Arabidopsis orthologs associated with xylogenesis-related processes. EgNAC141 was predominantly expressed in lignin-rich tissues, such as the stem and xylem. Overexpression of EgNAC141 in Arabidopsis resulted in stronger lignification, larger xylem, and higher lignin content. The expression of lignin biosynthetic genes in transgenic plants was significantly higher compared with wild-type plants. The transient expression of EgNAC141 activated the expression of Arabidopsis lignin biosynthetic genes in a dual-luciferase assay. Overall, these results showed that EgNAC141 is a positive regulator of lignin biosynthesis and may help us understand the regulatory mechanism of wood formation.

Oocyte maturation and fertilization are fundamental processes for successful human reproduction, and abnormalities in these processes will cause infertility. Recently, we identified biallelic mutations in CDC20 that are responsible for human oocyte maturation arrest, fertilization failure, and early embryonic development arrest. In this study, we screened for further CDC20 mutations in a new cohort of patients with abnormalities in oocyte maturation, fertilization, and early embryonic development. Through whole-exome sequencing, we identified the four novel mutations c.887G > A (p. Arg296Gln), c.964C > T (p.Arg322∗), c.1155G > C (p.Trp385Cys), and c.330 + 1G > A (p. Glu111Ilefs∗36) and one previously reported mutation c.965G > A (p.Arg322Gln) in CDC20 in four infertile individuals from three independent families. The patients had different phenotypes of oocyte maturation arrest and fertilization failure resulting from the different mutations. This study confirms our previous research and expands the spectrum of known mutations in CDC20, providing new evidence supporting the function of CDC20 in the genetic etiology of female infertility characterized by oocyte maturation arrest and fertilization failure.

Up to 30% of breast cancer mortality is caused by cancer relapse despite primary clinical treatments due to distant metastases. Further research focusing on breast cancer mechanisms are needed for deeper understanding of disease prognosis. 3-bromopyruvate (3-BP), a glycolysis inhibitor, has been studied as one of the antitumor agents in recent years. In this report, we want to investigate the form of cell death induced by 3-BP and demonstrate the inhibitory effect of 3-BP on breast cancer cell proliferation and its mechanism in vivo and in vitro. We found that 3-BP could inhibit MDA-MB-231 and MCF-7 breast cancer cell proliferation, through energy metabolism inhibition. Further, necroptosis characters in MDA-MB-231 cells after 3-BP treatment were observed, which could be negatively regulated through Ppm1b by dephosphorylation of RIP3. In addition, 3-BP treatment in an MDA-MB-231 cell-transplanted mouse model showed a significant antitumor effect, which correlated with necroptosis-related protein Ppm1b. The findings demonstrate the potential for 3-BP in the treatment of breast cancer, providing impetus for further clinical studies.

Magnetic multilayer with large perpendicular magnetic anisotropy (PMA) has attracted sustained interest owing to its importance to fundamental physics and applications. In this work, the high quality of Pt/Co/Pt heterostructures with large PMA was successfully achieved to exhibit a large anomalous Hall effect (AHE) with squared Hall loops. By calculating the proportional relationship between the longitudinal resistivity (ρxx) and the abnormal Hall coefficient (Rs), it is confirmed that the basic mechanism of AHE comes from the external skew scattering (SS) and side jump (SJ), while SS contribution, related to asymmetric scattering from impurities, is dominant in the AHE. Furthermore, the obvious magneto-optical Kerr effect (MOKE) was also observed using the polar MOKE microscopy. The obviously circular magnetic domain can form and propagate in response to the applied out-of-plane magnetic field, resulting in the magnetization reversal of the entire film. This work offers important information in terms of both AHE and MOKE in the ultrathin ferromagnetic films with perpendicular anisotropy, establishing the application foundation for the nonvolatile memories and spintronics.

Aiming at the problem of door opening caused by the unlocking of the side door latch system under the action of inertial force when the car is in a side impact, this paper takes a light truck door latch as the research object, and proposes an inertia load resistance analysis method combining theoretical calculation and simulation analysis. Through the theoretical calculation of inertia load resistance of the door latch, the force of each part and the rotation of the pawl are analyzed. We perform inertia load resistance simulation analysis on the latch to verify the reliability of the theoretical calculation results. If the theoretical calculation result is that the latch will be unlocked under the inertia load of 60 g (588 m/s2), we compare the force of each part in the theoretical calculation process with the normal opening condition of the latch to provide a basis for the optimization of the latch structure. Finally, theoretical calculations and a simulation analysis are carried out on the optimized results again, and a latch structure that meets the requirements of the inertia load resistance is obtained. Since the results obtained from the inertia load resistance simulation analysis are basically consistent with the theoretical calculation results of the inertia load resistance and the inertia load resistance simulation requires a lot of computing time, after the verification of the inertia load resistance simulation analysis, firstly, the inertia load resistance simulation step can be omitted in the subsequent structural optimization process.

We herein describe the preoperative and postoperative clinical data of a patient with a rare case of vulvar malignant melanoma and discuss her clinical characteristics and prognosis. After surgical resection and immunotherapy, the patient’s illness continued to worsen. She then received local vulvar radiotherapy. However, further treatment was discontinued because of intolerable complications of radiotherapy, and the patient died about 18 months postoperatively. Management of vulvar malignant melanoma is challenging. No unified, effective, and standardized diagnostic and treatment plan has been established for this disease. Surgery remains the primary treatment modality for locally resectable vulvar malignant melanoma. Radiation therapy and chemotherapy do not benefit survival. Encouragingly, however, immunotherapy and targeted therapy have shown clinical efficacy in metastatic vulvar malignant melanoma.

Autophagy is an efficient degradation system for maintaining cellular homeostasis when plants are under environmental stress. ATG9 is the only integral membrane protein within the core ATG machinery that provides a membrane source for autophagosome formation. In this study, we isolated an ATG9 homologs gene in apple, MdATG9, from Malus domestica. The analysis of its sequence, subcellular localization, promoter cis-elements, and expression patterns revealed the potential function of MdATG9 in response to abiotic stressors. Overexpression of MdATG9 in apple callus conferred enhanced tolerance to nitrogen depletion stress. During the treatment, other important MdATGs were expressed at higher levels in transgenic callus than in the wild type. Furthermore, more free amino acids and increased sucrose levels were found in MdATG9-overexpression apple callus compared with the wild type in response to nitrogen starvation, and the expression levels of MdNRT1.1, MdNRT2.5, MdNIA1, and MdNIA2 were all increased higher in transgenic lines. These data suggest that, as an important autophagy gene, MdATG9 plays an important role in the maintenance of amino acids and sugars in response to nutrient starvation in apple.

There have been numerous reports regarding the occurrence of keratitis in patients with soft contact lenses, but few reports in patients with rigid gas permeable contact lenses. To the best of our knowledge, the occurrence of infection associated with three species of pathogens has never been reported. Here, we describe a patient who exhibited refractory painless keratitis caused by three pathogens ( Staphylococcus epidermidis , Acanthamoeba , and herpes simplex virus) and summarize similar reports published at multiple centers worldwide, with the aim of providing guidance for clinicians who might encounter mixed-type corneal infections. We describe the results of many ophthalmologic and laboratory investigations, which guided our treatment selection. We achieved good treatment efficacy, such that the patient exhibited a corrected visual acuity of 20/20 in the affected eye after a series of treatments, including curettage of ulcer lesions. Corneal infections caused by multiple pathogens are challenging in clinical practice. This summary of our experience in patient diagnosis and treatment can help clinicians to achieve a favorable prognosis in treatment of future patients.

Abstract Background Limb-girdle muscular dystrophy (LGMD) is a commonly diagnosed hereditary muscular disorder, characterized by the progressive weakness of the limb-girdle muscles. Although the condition has been well-characterized, clinical and genetic heterogeneity can be observed in patients with LGMD. Here, we aimed to describe the clinical manifestations and genetic variability among a cohort of patients with LGMD in South China. Results We analyzed the clinical information, muscle magnetic resonance imaging (MRI) findings, and genetic results obtained from 30 patients (24 families) with clinically suspected LGMD. In 24 probands, 38 variants were found in total, of which 18 were shown to be novel. Among the 30 patients, the most common subtypes were dysferlinopathy in eight (26.67%), sarcoglycanopathies in eight [26.67%; LGMD 2C in three (10.00%), LGMD 2D in three (10.00%), and LGMD 2F in two (6.67%)], LGMD 2A in seven (23.33%), followed by LGMD 1B in three (10.00%), LGMD 2I in three (10.00%), and early onset recessive Emery-Dreifuss-like phenotype without cardiomyopathy in one (3.33%). Furthermore, we also observed novel clinical presentations for LGMD 1B, 2F, and 2I patients with hypermobility of the joints in the upper limbs, a LGMD 2F patient with delayed language development, and other manifestations. Moreover, distinct distributions of fatty infiltration in patients with LGMD 2A, dysferlinopathy, and the early onset recessive Emery-Dreifuss-like phenotype without cardiomyopathy were also observed based on muscle MRI results. Conclusions In this study, we expanded the clinical spectrum and genetic variability found in patients with LGMD, which provided additional insights into genotype and phenotype correlations in this disease.

The biotrickling filter (BTF) treatment is an effective way of dealing with air pollution caused by volatile organic compounds (VOCs). However, this approach is typically used for single VOCs treatment but not for the mixtures of VOC and volatile organic sulfur compounds (VOSCs), even if they are often encountered in industrial applications. Therefore, we investigated the performance of BTF for single and ternary mixture gas of dimethyl sulfide (DMS), propanethiol, and toluene, respectively. Results showed that the co-treatment enhanced the removal efficiency of toluene, but not of dimethyl sulfide or propanethiol. Maximum removal rates (rmax) of DMS, propanethiol and toluene were calculated to be 256.41 g·m−3·h−1, 204.08 g·m−3·h−1 and 90.91 g·m−3·h−1, respectively. For a gas mixture of these three constituents, rmax was measured to be 114.94 g·m−3·h−1, 104.17 g·m−3·h−1 and 99.01 g·m−3·h−1, separately. Illumina MiSeq sequencing analysis further indicated that Proteobacteria and Bacteroidetes were the major bacterial groups in BTF packing materials. A shift of bacterial community structure was observed during the biodegradation process.

The formation process of Particulate Matter (PM) during sludge pyrolysis at different temperatures (300–700 °C) and the ecological risks of heavy metals were studied. The results showed that the particulate matter is mainly condensed on the quartz film in a carbon-based organic matter when the pyrolysis temperature was between 200–500 °C in a volatilization process. Inorganic particles was found in the particulate matter when the temperature was raised to 500–700 °C in a decomposition stage. Heavy metals were enriched in particulate matter with increase in pyrolysis temperature. When the temperature reached 700 °C, the concentration of Pb and Cd in the particulate matter significantly increased. The ecological risk assessment showed that heavy metals in the sewage sludge had considerable ecological toxicity. When the pyrolysis temperature reached 700 °C, the ecological toxicity of those heavy metals enriched in the particulate matter decreased considerably.

Summary: Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients. : In this article, Cheng and colleagues isolated primitive neural stem cells from a patient presenting a c.1444-2A>C mutation in TSC2. These iPSC-derived neural cells recapitulated the pathophysiology of TSC2-deficient patients and could be used for screening appropriate drugs for personalized therapies. Keywords: induced pluripotent stem cells, mTOR, neural differentiation, neurological abnormalities, primitive neural stem cells, tuberous sclerosis complex

ABSTRACT PURPOSE: To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. METHODS: Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. RESULTS: 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. CONCLUSION: 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

A nonlinear dynamic modeling method for a spacecraft body composed of a laminated composite beam undergoing large rotation is proposed in this paper. To study the characteristics of a laminated composite beam attached to a spacecraft body for the dynamic systems, the deformation description of a laminated beam is established with the consideration of laying angles and laying layers, and the displacement-strain relations is acquired based on the global-local higher-order shear deformation theory. Accordingly, a nonlinear dynamic model of the spacecraft body composed of a laminated composite beam is deduced using Hamilton variational principle. And the complete coupling terms for the laminated material properties are considered unlike any other singular or unidirectional materials. Then, the dynamic behavior of the spacecraft system is analyzed by comparison of an orthogonal-symmetric, singular, and unidirectional laminated beam. The results show that the laminated composite structures have significant influences on the dynamics properties of spacecraft compared with conventional equivalent singular or unidirectional materials. Hence, the nonlinear model is well suitable for approaching the problem of coupling relationship between geometric nonlinearity and large rotation motions. These conclusions will have significant theory and engineering practice values for coupling dynamics properties of laminated beams.

Here, we investigated correlations between serum creatinine (SCRN) levels and clinical phenotypes of dystrophinopathy in young patients. Sixty-eight patients with dystrophinopathy at the Neuromuscular Clinic, The First Affiliated Hospital, Sun Yat-sen University, were selected for this study. The diagnosis of dystrophinopathy was based on clinical manifestation, biochemical changes, and molecular analysis. Some patients underwent muscle biopsies; SCRN levels were tested when patients were ≤3 years old, and reading frame changes were analyzed. Each patient was followed up, and motor function and clinical phenotype were assessed when the same patients were ≥4 years old. Our findings indicated that in young patients, lower SCRN levels were associated with increased disease severity (p

Mutations of WD40-repeat protein 62 (WDR62) have been identified recently to cause human MCPH (autosomal-recessive primary microcephaly), a neurodevelopmental disorder characterized by decreased brain size. However, the underlying mechanism is unclear. Here, we investigate the function of WDR62 in brain development and the pathological role of WDR62 mutations. We find that WDR62 knockdown leads to premature differentiation of neural progenitor cells (NPCs). The defect can be rescued by wild-type human WDR62, but not by the five MCPH-associated WDR62 mutants. We demonstrate that WDR62 acts upstream of JNK signaling in the control of neurogenesis. Depletion of JNK1 and WDR62 incurs very similar defects including abnormal spindle formation and mitotic division of NPCs as well as premature NPC differentiation during cortical development. Thus, our findings indicate that WDR62 is required for proper neurogenesis via JNK1 and provide an insight into the molecular mechanisms underlying MCPH pathogenesis.

Carotenoids and folate are two mandatory supplying micronutrients for children or pregnant women. Inadequate intake of these two nutrients was relevant to a higher mortality of both children and pregnancies. This study is intended to investigate the thermal impact on the changes of carotenoids and folate in sweet potato roots (SPRs). Carotenoids were identified by high performance liquid chromatography (HPLC) while the folate was estimated using a microbial assay. An obvious decline was observed in total carotenoids after heating. Nevertheless, the content of provitamin compound β-carotene exhibited incredible stability during steaming and α-carotene multiplied in certain varieties, evidencing that SPRs could be an efficient way for addressing Vitamin A deficiency (VAD). As for the total folate contents, two varieties were found no significant loss after thermal process while the others showed a significant decrease. The results indicated that steaming process led to generally loss of both carotenoids and folate while the α-carotene and β-carotene were well preserved. The information provided by this study might help with enhancing the food quality in processing industry and the understanding in the nutrition changes during steaming.

The feasibility of near-infrared spectroscopy (NIR) to detect chlorogenic acid, luteoloside and 3,5-O-dicaffeoylquinic acid in Chrysanthemum was investigated. An NIR spectroradiometer was applied for data acquisition. The reference values of chlorogenic acid, luteoloside, and 3,5-O-dicaffeoylquinic acid of the samples were determined by high-performance liquid chromatography (HPLC) and were used for model calibration. The results of six preprocessing methods were compared. To reduce input variables and collinearity problems, three methods for variable selection were compared, including successive projections algorithm (SPA), genetic algorithm-partial least squares regression (GA-PLS), and competitive adaptive reweighted sampling (CARS). The selected variables were employed as the inputs of partial least square (PLS), back propagation-artificial neural networks (BP-ANN), and extreme learning machine (ELM) models. The best performance was achieved by BP-ANN models based on variables selected by CARS for all three chemical constituents. The values of rp2 (correlation coefficient of prediction) were 0.924, 0.927, 0.933, the values of RMSEP were 0.033, 0.018, 0.064 and the values of RPD were 3.667, 3.667, 2.891 for chlorogenic acid, luteoloside, and 3,5-O-dicaffeoylquinic acid, respectively. The results indicated that NIR spectroscopy combined with variables selection and multivariate calibration methods could be considered as a useful tool for rapid determination of chlorogenic acid, luteoloside, and 3,5-O-dicaffeoylquinic acid in Chrysanthemum.

The formation of proximal cytoplasmic dilation in the leading process (PCDLP) of migratory neocortical neurons is crucial for somal translocation and neuronal migration, processes that require the elaborate coordination of F-actin dynamics, centrosomal movement, and nucleokinesis. However, the underlying molecular mechanisms remain poorly understood. Here, we show that the Rac1-interacting scaffold protein POSH is essential for neuronal migration in vivo. We demonstrate that POSH is concentrated in the PCDLP and that knockdown of POSH impairs PCDLP formation, centrosome translocation, and nucleokinesis. Furthermore, POSH colocalizes with F-actin and the activated form of Rac1. Knockdown of POSH impairs F-actin assembly and delocalizes activated Rac1. Interference of Rac1 activity also disrupts F-actin assembly and PCDLP formation and perturbs neuronal migration. Thus, we have uncovered a mechanism by which POSH regulates the localization of activated Rac1 and F-actin assembly to control PCDLP formation and subsequent somal translocation of migratory neurons.

BACKGROUND: Major depressive disorder (MDD) is an important and highly prevalent mental disorder characterized by anhedonia and a lack of interest in everyday activities. Additionally, patients with MDD appear to have deficits in various cognitive abilities. Although a number of studies investigating the central auditory processing of low-level sound features in patients with MDD have demonstrated that this population exhibits impairments in automatic processing, the influence of emotional voice processing has yet to be addressed. To explore the automatic processing of emotional prosodies in patients with MDD, we analyzed the ability to detect automatic changes using event-related potentials (ERPs). METHOD: This study included 18 patients with MDD and 22 age- and sex-matched healthy controls. Subjects were instructed to watch a silent movie but to ignore the afferent acoustic emotional prosodies presented to both ears while continuous electroencephalographic activity was synchronously recorded. Prosodies included meaningless syllables, such as "dada" spoken with happy, angry, sad, or neutral tones. The mean amplitudes of the ERPs elicited by emotional stimuli and the peak latency of the emotional differential waveforms were analyzed. RESULTS: The sad MMN was absent in patients with MDD, whereas the happy and angry MMN components were similar across groups. The abnormal sad emotional MMN component was not significantly correlated with the HRSD-17 and HAMA scores, respectively. CONCLUSION: The data indicate that patients with MDD are impaired in their ability to automatically process sad prosody, whereas their ability to process happy and angry prosodies remains normal. The dysfunctional sad emotion-related MMN in patients with MDD were not correlated with depression symptoms. The blunted MMN of sad prosodies could be considered a trait of MDD.