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Background: Superior semicircular canal dehiscence (SSCD) is gradually recognized by otologists in recent years. The patients with SSCD have a syndrome comprising a series of vestibular symptoms and hearing function disorders which can be cured by the operation. In this study, we evaluated the characteristics of patients with SSCD and determined the effectiveness of treating this syndrome by resurfacing the canal via the transmastoid approach using a dumpling structure. Methods: Patients with SSCD, confirmed by high-resolution computed tomography and hospitalized at Beijing Tongren Hospital between November 2009 and October 2012, were included in the study. All of the patients underwent the unilateral transmastoid approach for resurfacing the canal, and received regular follow-up after surgery. Data from preoperative medical records and postoperative follow-up were comparatively analyzed to evaluate the effect of surgery. Results: In total, 10 patients and 13 ears (three left ears, four right ears, three bilateral ears) were evaluated in the study, which included 7 men and 3 women. Different symptoms and distinctive manifestations of vestibular evoked myogenic potential were found in these patients. After surgery, 4 patients had complete resolution, 5 had partial resolution, and 1 patient, with bilateral SSCD, had aggravation. None of the patients suffered from serious complications such as sensorineural hearing loss, facial paralysis, cerebrospinal fluid leakage, or intracranial hypertension. Conclusions: In patients with unilateral SSCD, resurfacing the canal via the transmastoid approach using a dumpling structure is an effective and safe technique. However, more consideration is needed for patients with bilateral SSCD.

Polysaccharide extracted from the Maitake mushroom (MP) is considered as a potential anticancer agent. The present study was performed to investigate the cytotoxic effects of MP and vitamin C (VC) alone and in combination on the viability of human neuroglioma M059 K cells in vitro. A combination of MP (1.0 mg/mL) and VC (0.4 mmol/L) led to a 53.10% reduction in cell viability and this treatment induced cell cycle arrest at the G2/M phase, and apoptosis occurred in 38.54% of the cells. Results of Hoechst 33258 staining and Western blot showed apoptotic cells appeared and changes in the expression of apoptosis-related proteins (upregulation of Bax and caspase-3, downregulation of Bcl-2, and activation of poly-(ADP-ribose)-polymerase). Moreover, the activities of caspase-3, caspase-8, and caspase-9 were enhanced in M059 K cells. The inhibiting effect of combined treatment with MP and VC on M059 K cells indicates the mechanism of anticancer activity involved induction of cell apoptosis.

As a major diarrheagenic human pathogen, enterohemorrhagic Escherichia coli (EHEC) produce attaching and effacing (A/E) lesions, characterized by the formation of actin pedestals, on mammalian cells. A bacterial T3SS effector NleL from EHEC O157:H7 was recently shown to be a HECT-like E3 ligase in vitro, but its biological functions and host targets remain elusive. Here, we report that NleL is required to effectively promote EHEC-induced A/E lesions and bacterial infection. Furthermore, human c-Jun NH2-terminal kinases (JNKs) were identified as primary substrates of NleL. NleL-induced JNK ubiquitylation, particularly mono-ubiquitylation at the Lys 68 residue of JNK, impairs JNK's interaction with an upstream kinase MKK7, thus disrupting JNK phosphorylation and activation. This subsequently suppresses the transcriptional activity of activator protein-1 (AP-1), which modulates the formation of the EHEC-induced actin pedestals. Moreover, JNK knockdown or inhibition in host cells complements NleL deficiency in EHEC infection. Thus, we demonstrate that the effector protein NleL enhances the ability of EHEC to infect host cells by targeting host JNK, and elucidate an inhibitory role of ubiquitylation in regulating JNK phosphorylation.

The global warming and shortage of energy are two critical problems for human social development. CO2 mitigation and replacing conventional diesel with biodiesel are effective routes to reduce these problems. Production of microalgal lipids as biodiesel feedstock by a freshwater microalga, Chlorella vulgaris, with the ability to fixate CO2 is studied in this work. The results show that nitrogen deficiency, CO2 volume fraction and photoperiod are the key factors responsible for the lipid accumulation in C. vulgaris. With 5 % CO2, 0.75 g/L of NaNO3 and 18:6 h of light/dark cycle, the lipid content and overall lipid productivity reached 14.5 % and 33.2 mg/(L·day), respectively. Furthermore, we proposed a technique to enhance the microalgal lipid productivity by activating acetyl-CoA carboxylase (ACCase) with an enzyme activator. Citric acid and Mg2+ were found to be efficient enzyme activators of ACCase. With the addition of 150 mg/L of citric acid or 1.5 mmol/L of MgCl2, the lipid productivity reached 39.1 and 38.0 mg/(L·day), respectively, which was almost twofold of the control. This work shows that it is practicable to produce lipids by freshwater microalgae that can fixate CO2, and provides a potential route to solving the global warming and energy shortage problems.

The connection mode of the direct current (DC) power distribution system and the alternating current (AC) system is the foundation of system design, and it is also one of key technologies of the DC power distribution network. Based on the topology structure, grounding method, main equipment parameters, load parameters and system control protection strategy of the DC power distribution system, this paper establishes the system simulation model in the case of configuring the connection transformer and not configuring the connection transformer. Simulation results show that, when no connecting transformer is installed, the interaction between AC and DC systems will be great when faults occur, and the cost of converter valves and DC reactors will be increased. When connecting transformers are installed, the interaction between AC and DC systems can be effectively isolated, and the operation reliability of the system will be greatly improved while the cost is saved. Therefore, it is recommended to configure an independent connection transformer in the DC distribution system.

A DC circuit breaker is piece of core equipment for DC grid construction and can achieve fast isolation of DC faults in the grid. In this paper, based on the fault characteristics and protection requirements of an AC/DC hybrid distribution network, the technical parameters and topology structure of an inductance and capacitance (LC) resonant commutation-type mechanical DC breaker are proposed. Furthermore, an engineering prototype of the mechanical DC circuit breaker is developed, then a small current breaking test and a large current breaking test are carried out. The test results show that a 10 kA fault current can be interrupted within 10 ms by the engineering prototype. Finally, the engineering prototype of the mechanical DC circuit breaker is installed in the AC/DC hybrid distribution network project, and a current breaking test is carried out. The test results show that the mechanical DC circuit breaker has good running conditions, and the function and performance meet the engineering design and operation requirements.

As a new torsional vibration absorber, the dual mass flywheel (DMF) contains a symmetric structure in which the damping element is a pair of springs symmetrically distributed along the circumference direction. Through reasonable matching parameters, the DMF functions in isolating torsional vibrations caused by the engine from the transmission system. Our work aims to solve the accuracy of matching models between the DMF and power transmission system. The critical structural parameters of each order modal are treated consecutively by two methods: Absolute sensitivity (e.g., under the idle condition and driving condition), and relative sensitivity. The operation achieves a separation of the parameters and diagnosis of the relationship between these parameters and the natural frequency in the system. In addition, the natural frequency range is determined based upon the area of the resonance speed. As a result, the matching model is established based on the sensitivity analysis method and the natural frequency range, which means the moment of inertia distribution (its coefficient should be used as one structural parameter in relative sensitivity analysis) and the torsional stiffness in multiple stages can be observed under the combined values. The effectiveness of the matching model is verified by experiments of a real vehicle test under the idling condition and driving condition. It is concluded that the analysis study can be applied to solve the parameters matching accuracy among certain multi-degree-of-freedom dynamic models.

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A novel strain, Microbacterium sp., which can be used as a catalyst in the asymmetric reduction of simple aromatic ketones to produce chiral aromatic alcohols, was isolated from soil by microbial screening. Using acetophenone as a model substrate for asymmetric reduction, 82 % reaction yield with more than 99 % enantiomeric excess of (R)-1-phenylethanol were achieved under the optimal conditions. Furthermore, the key reductase responsible for the asymmetric reduction was purified from the newly isolated Microbacterium sp. through (NH4)2SO4 fractional precipitation, anion exchange chromatography and gel filtration chromatography. The purified reductase is a NADH-dependent aromatic ketone reductase. Gel filtration chromatography and SDS-PAGE results reveal that it is a homodimer with two 28-kDa subunits. The enzymatic properties of the reductase indicate that it is a highly efficient catalyst for the asymmetric reduction of simple aromatic ketone.

Lightning and lightning induced effects have significant influence on many aspects affecting the public, which makes the research of lightning and lightning protection very important. However, due to the strong randomness and complex discharge mechanisms of lightning, the understanding of lightning is still far from satisfactory. On the basis of the International Conference on Lightning Protection 2014, this study gives a review of recent progress on lightning and lightning protection research covering the following aspects: lightning locating and observation, lightning physics, lightning electromagnetic transients, and lightning protection for various systems. The goals of this study are to give readers an overall introduction to the recent progress in lightning and lightning protection research, and to motivate them to conduct further studies to address the unsolved problems in lightning-related research.

To evaluate clinical characteristics and present surgical outcomes of PT caused by sigmoid sinus wall dehiscence (SSWD).This study retrospectively reviewed 34 patients with PT who were diagnosed with SSWD in our institution between December 2008 and July 2013. Among them, 27 patients underwent sigmoid sinus wall reconstruction (surgery group) and 7 patients refused surgery (non-surgery group). Preoperative data were obtained from the patients' medical records. All patients were followed up regularly for at least 25 months. Preoperative and postoperative computed tomography angiography (CTA) images were compared. Student's t-tests were used to compare age, body mass index (BMI) and preoperative Tinnitus Handicap Inventory (THI) scores between the surgery and the non-surgery groups and to compare pre- and follow-up THI scores.There was no significant difference in age, body mass index, or preoperative THI scores between groups. Following surgery, 14 patients had complete resolution, 5 had partial resolution, 7 experienced no change and PT was aggravated in 1 patient. The difference between preoperative and postoperative THI scores was significant. No severe complications were found postoperatively. Comparison of the preoperative and postoperative CTA images revealed that remnant unrepaired dehiscences were the cause of unsatisfactory outcomes following surgery. In the non-surgery group, PT remained largely unchanged.Sigmoid sinus wall reconstruction is an effective and safe treatment for PT caused by SSWD. It is imperative that all regions of the dehiscence are sufficiently exposed and resurfaced during surgery.

Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies have shown that neurological changes are important findings in vascular pulsatile tinnitus (PT) patients. Here, we utilized rs-fMRI to measure the amplitude of low-frequency fluctuations (ALFF) in forty patients with unilateral PT and forty age-, gender-, and education-matched normal control subjects. Two different frequency bands (slow-4, 0.027–0.073 Hz, and slow-5, 0.010–0.027 Hz, which are more sensitive to subcortical and cortical neurological signal changes, resp.) were analyzed to examine the intrinsic brain activity in detail. Compared to controls, PT patients had increased ALFF values mainly in the PCu, bilateral IPL (inferior parietal lobule), left IFG (inferior frontal gyrus), and right IFG/anterior insula and decreased ALFF values in the multiple occipital areas including bilateral middle-inferior occipital lobe. For the differences of the two frequency bands, widespread ALFF differences were observed. The ALFF abnormalities in aMPFC/ACC, PCu, right IPL, and some regions of occipital and parietal cortices were greater in the slow-5 band compared to the slow-4 band. Additionally, the THI score of PT patients was positively correlated with changes in slow-5 and slow-4 band in PCu. Pulsatile tinnitus is a disease affecting the neurological activities of multiple brain regions. Slow-5 band is more sensitive in detecting the alternations. Our results also indicated the importance of pathophysiological investigations in patients with pulsatile tinnitus in the future.

The measurement of intense E-fields is a fundamental need in various research areas. Integrated optical E-field sensors (IOESs) have important advantages and are potentially suitable for intense E-field detection. This paper comprehensively reviews the development and applications of several types of IOESs over the last 30 years, including the Mach-Zehnder interferometer (MZI), coupler interferometer (CI) and common path interferometer (CPI). The features of the different types of IOESs are compared, showing that the MZI has higher sensitivity, the CI has a controllable optical bias, and the CPI has better temperature stability. More specifically, the improvement work of applying IOESs to intense E-field measurement is illustrated. Finally, typical uses of IOESs in the measurement of intense E-fields are demonstrated, including application areas such as E-fields with different frequency ranges in high-voltage engineering, simulated nuclear electromagnetic pulse in high-power electromagnetic pulses, and ion-accelerating field in high-energy physics.

A novel serine protease inhibitor (serpin) gene designated as Spi1C was cloned via the sequenced-based screening of a metagenomic library from uncultured marine microorganisms. The gene had an open reading frame of 642 base pairs, and encoded a 214-amino acid polypeptide with a predicted molecular mass of about 28.7 kDa. The deduced amino acid sequence comparison and phylogenetic analysis indicated that Spi1C and some partial proteinase inhibitor I4 serpins were closely related. Functional characterization demonstrated that the recombinant Spi1C protein could inhibit a series of serine proteases. The Spi1C protein exhibited inhibitory activity against α-chymotrypsin and trypsin with Ki values of around 1.79 × 10−8 and 1.52 × 10−8 M, respectively. No inhibition activity was exhibited against elastase. Using H-D-Phe-Pip-Arg-pNA as the chromogenic substrate, the optimum pH and temperature of the inhibition activity against trypsin were 7.0–8.0 and 25 °C, respectively. The identification of a novel serpin gene underscores the potential of marine metagenome screening for novel biomolecules.

A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide association study restricted this NCL locus to a 1.3 Mb region of canine chromosome 2 which contains canine ATP13A2. NCL-affected dogs were homozygous for a single-base deletion in ATP13A2, predicted to produce a frameshift and premature termination codon. Homozygous truncating mutations in human ATP13A2 have been shown by others to cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease. These findings suggest that KRS is also an NCL, although analysis of KRS brain tissue will be needed to confirm this prediction. Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with ATP13A2 mutations; however, other clinical features differ between the species. For example, Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. To see if ATP13A2 mutations could be responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced ATP13A2 from 28 Kufs disease patients. None of these patients had ATP13A2 sequence variants likely to be causal for their disease, suggesting that mutations in this gene are not common causes of Kufs disease.

The position synchronous control of multi-axis gantry-type feed stage is crucial in precision machine tools. Industrial position control which aims to widen the bandwidth and improve disturbance rejection of single axis is not enough to achieve precise synchronization in a dual-driving feed stage. The characteristics diversity, transmission-mechanism deformation, and mechanical coupling effect between dual axes will degrade the control accuracy. Hence, the novel two-degree-of-freedom (2-DOF) dynamic model-based terminal sliding mode control (TSMC) with disturbance and state observer is proposed in this paper for the synchronous control of a 2-DOF dual-driving feed stage. The 2-DOF dynamic model, based on Lagrange equation, is established along with the parameters identification method. The predictive natural frequencies and vibration modes frequencies by the proposed dynamic model are compared by a modal experiment. Then, the 2-DOF dynamic model-based TSMC is provided to satisfy the tracking and synchronization control. In order to reduce the chattering and to increase the robustness against the mechanical coupling, the disturbance and state observer is designed. Moreover, Lyapunov stability criterion is used to analyze the stability of the proposed control scheme. Finally, an industrial application of 2-DOF dual-driving feed stage is utilized to validate the effectiveness of the proposed control scheme. The proposed 2-DOF dynamic model-based TSMC with observer has been effectively demonstrated to improve synchronous performance and tracking accuracy.

This paper investigates softening phenomena within the post-dynamic recrystallization (PDRX) process in 300M high-strength steel specimens with different initial dynamically recrystallized volume fractions. Isothermal, interrupted compression experiments were performed on a Gleeble-3500 at a temperature of 1273 K and strain rate of 0.01 s−1. To acquire different initial volume fractions of dynamically recrystallized (DRX) grains, deformation was interrupted at two strain levels and immediately followed by isothermal annealing treatments. The softening behaviors respectively caused by the static recrystallization (SRX) and metadynamic recrystallization (MDRX) were qualitatively characterized by variations in the mechanical properties of the deformed and recrystallized grains. On the basis of the Taylor dislocation model, the evolution of geometric necessary dislocations (GNDs) and statistically stored dislocations (SSDs) densities were also discussed to qualitatively clarify the nature of different softening behaviors. Results indicate that the SRX occurred alone in samples without initial DRX grains, after an incubation time of approximately 50 s, while MDRX initially appeared within 1 s and completed at about 8 s in samples with a high initial volume fraction of DRX grains. The microhardness, indentation hardness, and Young’s modulus in the deformed and recrystallized grains decreased gradually with an increase of MDRX and SRX volume fractions. The sink-in and pile-up phenomena were enhanced by the SRX and MDRX softening processes, respectively. The SSDs density decreased more noticeably during the MDRX process than that during the SRX, which indicates that the MDRX process contributed to a more significant softening effect within the microstructural evolution regimes.

Thus far, despite the development of electric field sensors (EFSs) such as field mills, optoelectronic EFSs and microelectromechanical system (MEMS)-based EFSs, no sensor can accurately measure an electric field in space due to the existence of space charge and the influence of charge attachment. To measure a spatial synthetic electric field in an ion flow field, a double potential independent differential EFS based on MEMS is proposed. Compared with other EFSs, this method has the advantages of independent potential (without grounding) and the ability to support the measurement of the synthetic ion flow electric field in space. First, to analyse the charge distribution after the sensor is involved exposed to an electric field, a simulation model was constructed. Then, given the redistribution of the spatial electric field in space and the influence of the surface charge on the sensor, the quantitative relationship between the electric field to be measured and that measured by the proposed sensor was obtained. To improve the performance of the EFS, a set of synthetic field strength sensor calibration systems that consider spatial ion flow injection was established. Furthermore, the parameter λ, which is related to the relative position of the differential chips, was determined. Finally, a series of comparative experiments indicated that the differential EFS highlighted in the present study exhibits good linearity and accuracy.

Reliability is one of the critical issues for a modular multilevel converter (MMC) since it consists of a large number of series-connected power electronics submodules (SMs). In this paper, a complete control strategy including fault detection, localization, and tolerant operation is proposed for the MMC under an insulated gate bipolar transistor (IGBT) open circuit fault. According to the output characteristics of the SM with the open-circuit fault of IGBT, a fault detection method based on the circulating current and output current observation is used. In order to further precisely locate the position of the faulty SM, a fault localization method based on the SM capacitor voltage observation is developed. After the faulty SM is isolated, the continuous operation of the converter is ensured by adopting the fault-tolerant strategy based on the use of redundant modules. To verify the proposed fault detection, fault localization, and fault-tolerant operation strategies, a 900 kVA MMC system under the conditions of an IGBT open circuit is developed in the Matlab/Simulink platform. The capabilities of rapid detection, precise positioning, and fault-tolerant operation of the investigated detection and control algorithms are also demonstrated.

Spiroheterocycles are regarded as a privileged framework because of their wide distribution in various natural products and synthetic molecules and promising bioactivities. This review focuses on the recent advances in the synthesis of spiroheterocycles by using the strategy of N-heterocyclic carbene (NHC) organocatalysis, and is organized based on the stereoselectivity and the reactive intermediates. According to the stereochemistry, this review was divided into two main parts, covering racemic and enantioselective versions. In each part, we firstly describe the synthetic transformations using nucleophilic Breslow intermediates, and then discuss the reactions that employ electrophilic acylazolium or radical cation intermediates. With those distinct catalytic activation modes of NHC organocatlysis, we expect this synthetic protocol will possibly produce new molecules with structural novelty and complexity, which may warrant further research in the field of drug discovery.

Ionic liquids (ILs) are considered as another ’green solvent’, after the supercritical carbon dioxide. They are a promising reaction medium for biocatalysis process. The tolerance of active cells in hydrophobic imidazolium-based ILs (1-R-3-methylimidazolium hexafluorophosphate, [RMim][PF6]) has been studied in this work. Calcium-alginate-entrapped baker’s yeast has been chosen as the model of living cells. The results show that this kind of ILs possess a certain degree of biocompatibility. The tolerance of yeast cells to the ILs decreases with the increase of the R chain length of these ILs. The experiment indicated that 1-butyl-3-methylimidazolium hexafluorophosphate ([BMim][PF6]) possessed excellent biocompatibility compared to the other imidazolium-based ILs. The moisture content in the ILs was the key factor that affected the tolerance. The activity retention of yeast cells pretreated with [BMim][PF6] saturated with water and aqueous [BMim][PF6] biphasic system was about 70 %, but it was only 50 % with the anhydrous [BMim][PF6]. Although the yeast cells were pretreated with [BMim][PF6] for 24 h, the activity retention was up to 45 %. The yeast cells had around 50 % activity after being pretreated 4 times with [BMim][PF6]. This shows that the water immiscible ILs possess good biocompatibility, and they are suitable for application as the reaction medium catalyzed by living cells.

Real-time PCR is becoming a preferred method for quantification of minute amounts of nucleic acids. To achieve the full potential of this technique, accurate and convenient models for post-PCR data analysis are required. In this study, three different models were chosen to quantify the definitive copy numbers of Cucumber mosaic virus (CMV) genomic RNAs using raw fluorescence data of real-time PCR, and equations were proposed to compare their expression levels in virions or in planta. The results, as confirmed by standard curve and Northern blotting methods, show that the expression levels of different genes can be compared more accurately and more efficiently by these equations, especially using theoretical fluorescence (F0) and calibration factors (CF), determined by linear regression PCR (LinRegPCR). Thus, these equations, combined with data analysis by the LinRegPCR method, can greatly enhance the high-throughput quantification ability of real-time PCR, and permit accurate, reliable, and facile investigation of the changes in CMV RNAs accumulation.

Asymmetric reduction of the prochiral aromatic ketone catalyzed by yeast cells is one of the most promising routes to produce its corresponding enantiopure aromatic alcohol, but the space-time yield does not meet people’s expectations. Therefore, the toxicity of aromatic ketone and aromatic alcohol to the yeast cell is investigated in this work. It has been found that the aromatic compounds are poisonous to the yeast cell. The activity of yeast cell decreases steeply when the concentration of acetophenone (ACP) is higher than 30.0 mmol/L. Asymmetric reduction of acetophenone to chiral S-α-phenylethyl alcohol (PEA) catalyzed by the yeast cell was chosen as the model reaction to study in detail the promotion effect of the introduction of the resin adsorption on the asymmetric reduction reaction. The resin acts as the substrate reservoir and product extraction agent in situ. It has been shown that this reaction could be remarkably improved with this technique when the appropriate kind of resin is applied. The enantioselectivity and yield are acceptable even though the initial ACP concentration reaches 72.2 mmol/L.

Cyclin Y-like 1 (Ccnyl1) is a newly-identified member of the cyclin family and is highly similar in protein sequences to Cyclin Y (Ccny). However, the function of Ccnyl1 is poorly characterized in any organism. Here we found that Ccnyl1 was most abundantly expressed in the testis of mice and was about seven times higher than the level of Ccny. Male Ccnyl1-/- mice were infertile, whereas both male and female Ccny-/- mice displayed normal fertility. These results suggest that Ccnyl1, but not Ccny, is indispensable for male fertility. Spermatozoa obtained from Ccnyl1-/- mice displayed significantly impaired motility, and represented a thinned annulus region and/or a bent head. We found that the protein, but not the mRNA, level of cyclin-dependent kinase 16 (CDK16) was decreased in the testis of Ccnyl1-/- mice. Further study demonstrated that CCNYL1 interacted with CDK16 and this interaction mutually increased the stability of these two proteins. Moreover, the interaction increased the kinase activity of CDK16. In addition, we observed an alteration of phosphorylation levels of CDK16 in the presence of CCNYL1. We identified the phosphorylation sites of CDK16 by mass spectrometry and revealed that several phosphorylation modifications on the N-terminal region of CDK16 were indispensable for the CCNYL1 binding and the modulation of CDK16 kinase activity. Our results therefore reveal a previously unrecognized role of CCNYL1 in regulating spermatogenesis through the interaction and modulation of CDK16.

The hysteresis, stick–slip, and rotational speed-dependent characteristics in a basic dual mass flywheel are obtained from a static and a dynamic experiments. Based on the experimental results, a nonlinear model of the transferred torque in this dual mass flywheel is developed, with the overlying form of nonlinear elastic torque and frictional torque. The nonlinearities of stiffness are investigated, deriving a nonlinear model to describe the rotational speed-dependent stiffness. In addition, Bouc–Wen model is used to model the hysteretic frictional torque. Thus, the nonlinear 2-degree-of-freedom system of this dual mass flywheel is set up. Then, the Levenberg–Marquardt method is adopted for the parameter estimation of the frictional torque. Finally, taking the nonlinear stiffness in this model into account, the parameters of Bouc–Wen model are estimated based on the dynamic test data.

Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is commonly managed with antithyroid drugs (ATDs). However, previous studies about the effects of ATDs on congenital anomalies are controversial. Therefore, the present meta-analysis was performed to explore the risk of congenital anomalies in children exposed to ATDs in-utero.Embase, Pubmed, Web of Knowledge, and BIOSIS Citation Index were searched to find out studies about congenital anomalies in children exposed to ATDs in-utero reported up to May 2014. The references cited by the retrieved articles were also searched. The relative risks (RRs) and confidence intervals (CIs) for the individual studies were pooled by fixed effects models, and heterogeneity was analyzed by chi-square and I2 tests.Eight studies met the inclusion criteria. Exposure to propylthiouracil (PTU), methimazole/carbimazole (MMI/CMZ), and PTU & MMI/CMZ was investigated in 7, 7 and 2 studies, respectively. The pooled RR was 1.20 (95%CI: 1.02-1.42), 1.64 (95%CI: 1.39-1.92), and 1.83 (95%CI: 1.30-2.56) for congenital anomalies after exposure to PTU, MMI/CMZ, and PTU & MMI/CMZ, respectively.The meta-analysis suggests that exposure to ATDs in-utero increases the risk of congenital anomalies. The use of ATDs in pregnancy should be limited when possible. Further research is needed to delineate the exact teratogenic risk for particular congenital anomaly.

BACKGROUND: Vitamin D plays an important role in pulmonary resistance and immunity, and its deficiency has been linked to various respiratory infections. Little is known about the effect of vitamin D deficiency on host pulmonary defense to Aspergillus fumigatus (A. fumigatus). METHODS: Mice raised on vitamin D sufficient or deficient diets were infected intratracheally with A. fumigatus conidia. Mortality, fungal growth, weight loss and lung histology were monitored. Alveolar macrophages (AMs) were stimulated with A. fumigatus conidia in vitro. The kinetics of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), chemokines (CXCL1, CCL3), and pattern recognition receptors (Toll-like receptor [TLR] 2, TLR 4 and dectin-1) expression in the lungs and AMs were measured. RESULTS: Upon A. fumigatus infection, vitamin D deficient mice showed higher mortality, greater fungal load, and more weight loss than its sufficient counterparts. Vitamin D deficient mice demonstrated aggravated and prolonged histological evidence of lung inflammation as well as enhanced BAL cell counts, dominated by neutrophils after A. fumigatus inoculation. Increased basal levels of pro-inflammatory cytokines in the lungs and AMs from naïve vitamin D deficient mice were observed. Upon A. fumigatus exposure, vitamin D deficiency led to enhanced and sustained expression of TNF-α, IL-1β, IL-6, CXCL1 and CCL3 both in vivo and in vitro. Up-regulation of TLR2, TLR4 and dectin-1was observed in the lungs and AMs from vitamin D deficient mice both at baseline and after A. fumigatus exposure. CONCLUSIONS: Vitamin D deficiency causes defective pulmonary resistance to A. fumigatus in mice, possibly by the enhanced basal expression of pattern recognition receptors and pro-inflammatory cytokines, which induced excessive inflammatory response in response to A. fumigatus challenge.

Stem cell therapy has a potential for regenerating damaged myocardium. However, a key obstacle to cell therapy's success is the loss of engrafted cells due to apoptosis or necrosis in the ischemic myocardium. While many strategies have been developed to improve engrafted cell survival, tools to evaluate cell efficacy within the body are limited. Traditional genetic labeling tools, such as GFP-like fluorescent proteins (eGFP, DsRed, mCherry), have limited penetration depths in vivo due to tissue scattering and absorption. To circumvent these limitations, a near-infrared fluorescent mutant of the DrBphP bacteriophytochrome from Deinococcus radiodurans, IFP1.4, was developed for in vivo imaging, but it has yet to be used for in vivo stem/progenitor cell tracking. In this study, we incorporated IFP1.4 into mouse cardiac progenitor cells (CPCs) by a lentiviral vector. Live IFP1.4-labeled CPCs were imaged by their near-infrared fluorescence (NIRF) using an Odyssey scanner following overnight incubation with biliverdin. A significant linear correlation was observed between the amount of cells and NIRF signal intensity in in vitro studies. Lentiviral mediated IFP1.4 gene labeling is stable, and does not impact the apoptosis and cardiac differentiation of CPC. To assess efficacy of our model for engrafted cells in vivo, IFP1.4-labeled CPCs were intramyocardially injected into infarcted hearts. NIRF signals were collected at 1-day, 7-days, and 14-days post-injection using the Kodak in vivo multispectral imaging system. Strong NIRF signals from engrafted cells were imaged 1 day after injection. At 1 week after injection, 70% of the NIRF signal was lost when compared to the intensity of the day 1 signal. The data collected 2 weeks following transplantation showed an 88% decrease when compared to day 1. Our studies have shown that IFP1.4 gene labeling can be used to track the viability of transplanted cells in vivo.

Protein is important to the human body, and different sources of protein may have different effects on the risk of breast cancer. Thus, we conducted a meta-analysis to investigate the association between different dietary protein sources and breast cancer risk. PubMed and several databases were searched until December 2015. Relevant articles were retrieved according to specific searching criteria. Forty-six prospective studies were included. The summary relative risk (RR) for highest versus lowest intake was 1.07 (95% confidence interval (CI) 1.01–1.14, I2 = 34.6%) for processed meat, 0.92 (95% CI 0.84–1.00, I2 = 0%) for soy food, 0.93 (95% CI 0.85–1.00, I2 = 40.1%) for skim milk, and 0.90 (95% CI 0.82–1.00, I2 = 0%) for yogurt. Similar conclusions were obtained in dose-response association for each serving increase: total red meat (RR: 1.07; 95% CI 1.01–1.14, I2 = 7.1%), fresh red meat (RR: 1.13; 95% CI 1.01–1.26, I2 = 56.4%), processed meat (RR: 1.09; 95% CI 1.02–1.17, I2 = 11.8%), soy food (RR: 0.91; 95% CI 0.84–1.00, I2 = 0%), and skim milk (RR: 0.96; 95% CI 0.92–1.00, I2 = 11.9%). There was a null association between poultry, fish, egg, nuts, total milk, and whole milk intake and breast cancer risk. Higher total red meat, fresh red meat, and processed meat intake may be risk factors for breast cancer, whereas higher soy food and skim milk intake may reduce the risk of breast cancer.

While splicing differences between tissues, sexes and species are well documented, little is known about the extent and the nature of splicing changes that take place during human or mammalian development and aging. Here, using high‐throughput transcriptome sequencing, we have characterized splicing changes that take place during whole human lifespan in two brain regions: prefrontal cortex and cerebellum. Identified changes were confirmed using independent human and rhesus macaque RNA‐seq data sets, exon arrays and PCR, and were detected at the protein level using mass spectrometry. Splicing changes across lifespan were abundant in both of the brain regions studied, affecting more than a third of the genes expressed in the human brain. Approximately 15% of these changes differed between the two brain regions. Across lifespan, splicing changes followed discrete patterns that could be linked to neural functions, and associated with the expression profiles of the corresponding splicing factors. More than 60% of all splicing changes represented a single splicing pattern reflecting preferential inclusion of gene segments potentially targeting transcripts for nonsense‐mediated decay in infants and elderly.

Type 2 diabetes and its chronic complications have become a worldwide epidemic nowadays. However, its molecular mechanism is still unknown. We have previously identified a novel variant rs12742393 of NOS1AP for type 2 diabetes susceptibility in the Chinese population. In this study, we analyzed the total serum profiling among three genotypes of rs12742393 to discover potential crosstalk under the variant and the disease through proteomic analyses for the first time. We used OFFGEL peptide fractionation, LC-MS/MS analysis, and label-free quantification to profile the fasting human serum samples of the genotypes in rs12742393 (n=4, for CC, AC, and AA, resp.). Four proteins were identified, including apoA4, alpha1-ACT, HABP2, and keratin 10, with blood levels changed significantly between CC and AA homozygotes of rs12742393. Compared with AA group, the levels of apoA4 increased (P=0.000265), whereas the concentration of alpha1-ACT, HABP2, and keratin 10 decreased in CC group (P=0.011116, 0.021175, and 0.015661, resp.). Then we selected additional fasting serum samples for ELISA and western blot validation. However, no significant differences were identified by neither ELISA nor western blot (P>0.05). The protein profiling changes between the genotypes of rs12742393 indicated that this SNP might play a role in the development of type 2 diabetes.

Growing evidence from epidemiological studies indicates the association between rheumatoid arthritis (RA) and measles. However, the exact mechanism for this association is still unclear now. We consider that the strong association between both diseases may be caused by shared genetic pathways. We performed a pathway analysis of large-scale RA genome-wide association studies (GWAS) dataset with 5,539 cases and 20,169 controls of European descent. Meanwhile, we evaluated our findings using previously identified RA loci, protein-protein interaction network and previous results from pathway analysis of RA and other autoimmune diseases GWAS. We confirmed four pathways including Cytokine-cytokine receptor interaction, Jak-STAT signaling, T cell receptor signaling and Cell adhesion molecules. Meanwhile, we highlighted for the first time the involvement of Measles and Intestinal immune network for IgA production pathways in RA. Our results may explain the strong association between RA and measles, which may be caused by the shared genetic pathway. We believe that our results will be helpful for future genetic studies in RA pathogenesis and may significantly assist in the development of therapeutic strategies.

Screening and obtaining a novel high activity cellulase and its producing microbe strain is the most important and essential way to improve the utilization of crop straw. In this paper, we devoted our efforts to isolating a novel microbe strain which could produce high activity cellulase. A novel strain Trichoderma virens ZY-01 was isolated from a cropland where straw is rich and decomposed, by using the soil dilution plate method with cellulose and Congo red. The strain has been licensed with a patent numbered ZL 201210295819.6. The cellulase activity in the cultivation broth could reach up to 7.4 IU/mL at a non-optimized fermentation condition with the newly isolated T. virens ZY-01. The cellulase was separated and purified from the T. virens culture broth through (NH4)2SO4 fractional precipitation, anion-exchange chromatography and gel filtration chromatography. With the separation process, the CMC specific activity increased from 0.88 IU/mg to 31.5 IU/mg with 35.8 purification fold and 47.04% yield. Furthermore, the enzymatic properties of the cellulase were investigated. The optimum temperature and pH is 50 °C and pH 5.0 and it has good thermal stability. Zn2+, Ca2+ and Mn2+ could remarkably promote the enzyme activity. Conversely, Cu2+ and Co2+ could inhibit the enzymatic activity. This work provides a new highly efficient T. virens strain for cellulase production and shows good prospects in practical application.

Lung cancer is the leading cause of cancer deaths worldwide. Clinically, the treatment of non-small cell lung cancer (NSCLC) can be improved by the early detection and risk screening among population. To meet this need, here we describe the application of extensive peptide level fractionation coupled with label free quantitative proteomics for the discovery of potential serum biomarkers for lung cancer, and the usage of Tissue microarray analysis (TMA) and Multiple reaction monitoring (MRM) assays for the following up validations in the verification phase. Using these state-of-art, currently available clinical proteomic approaches, in the discovery phase we confidently identified 647 serum proteins, and 101 proteins showed a statistically significant association with NSCLC in our 18 discovery samples. This serum proteomic dataset allowed us to discern the differential patterns and abnormal biological processes in the lung cancer blood. Of these proteins, Alpha-1B-glycoprotein (A1BG) and Leucine-rich alpha-2-glycoprotein (LRG1), two plasma glycoproteins with previously unknown function were selected as examples for which TMA and MRM verification were performed in a large sample set consisting about 100 patients. We revealed that A1BG and LRG1 were overexpressed in both the blood level and tumor sections, which can be referred to separate lung cancer patients from healthy cases.

Among other factors, changes in gene expression on the human evolutionary lineage have been suggested to play an important role in the establishment of human-specific phenotypes. However, the molecular mechanisms underlying these expression changes are largely unknown. Here, we have explored the role of microRNA (miRNA) in the regulation of gene expression divergence among adult humans, chimpanzees, and rhesus macaques, in two brain regions: prefrontal cortex and cerebellum. Using a combination of high-throughput sequencing, miRNA microarrays, and Q-PCR, we have shown that up to 11% of the 325 expressed miRNA diverged significantly between humans and chimpanzees and up to 31% between humans and macaques. Measuring mRNA and protein expression in human and chimpanzee brains, we found a significant inverse relationship between the miRNA and the target genes expression divergence, explaining 2%-4% of mRNA and 4%-6% of protein expression differences. Notably, miRNA showing human-specific expression localize in neurons and target genes that are involved in neural functions. Enrichment in neural functions, as well as miRNA-driven regulation on the human evolutionary lineage, was further confirmed by experimental validation of predicted miRNA targets in two neuroblastoma cell lines. Finally, we identified a signature of positive selection in the upstream region of one of the five miRNA with human-specific expression, miR-34c-5p. This suggests that miR-34c-5p expression change took place after the split of the human and the Neanderthal lineages and had adaptive significance. Taken together these results indicate that changes in miRNA expression might have contributed to evolution of human cognitive functions.

Large efforts have been taken to search for genes responsible for type 2 diabetes (T2D), but have resulted in only about 20 in humans due to its complexity and heterogeneity. The GK rat, a spontanous T2D model, offers us a superior opportunity to search for more diabetic genes. Utilizing array comparative genome hybridization (aCGH) technology, we identifed 137 non-redundant copy number variation (CNV) regions from the GK rats when using normal Wistar rats as control. These CNV regions (CNVRs) covered approximately 36 Mb nucleotides, accounting for about 1% of the whole genome. By integrating information from gene annotations and disease knowledge, we investigated the CNVRs comprehensively for mining new T2D genes. As a result, we prioritized 16 putative protein-coding genes and two microRNA genes (rno-mir-30b and rno-mir-30d) as good candidates. The catalogue of CNVRs between GK and Wistar rats identified in this work served as a repository for mining genes that might play roles in the pathogenesis of T2D. Moreover, our efforts in utilizing bioinformatics methods to prioritize good candidate genes provided a more specific set of putative candidates. These findings would contribute to the research into the genetic basis of T2D, and thus shed light on its pathogenesis.

BACKGROUND:Leptin is an adipocyte-derived hormone that plays a critical role in energy homeostasis and lipid metabolism. Overnutrition-associated obesity is known to be accompanied by hyperleptinemia. However, the physiological actions of leptin in the metabolic responses to high-fat diet (HFD) intake remain to be completely elucidated. Here we characterized the metabolic features of mice fed high-fat diets and investigated the impact of leptin upon the lipogenic program which was found to be suppressed by HFD feeding through a proteomics approach. RESULTS:When maintained on two types of high-fat diets for up to 16 weeks, mice with a higher fat intake exhibited increased body fat accumulation at a greater pace, developing more severely impaired glucose tolerance. Notably, HFD feeding at 4 weeks elicited the onset of marked hyperleptinemia, prior to the occurrence of apparent insulin resistance and hyperinsulinemia. Proteomic analysis revealed dramatically decreased expression of lipogenic enzymes in the white adipose tissue (WAT) from HFD-fed mice, including ATP-citrate lyase (ACL) and fatty acid synthase (FAS). The expression of ACL and FAS in the liver was similarly suppressed in response to HFD feeding. By contrast, HFD-induced downregulation of hepatic ACL and FAS was significantly attenuated in leptin receptor-deficient db/db mice. Furthermore, in the liver and WAT of wild type animals, intraperitoneal leptin administration was able to directly suppress the expression of these two lipogenic enzymes, accompanied by reduced triglyceride levels both in the liver and serum. CONCLUSIONS:These results suggest that leptin contributes to the metabolic responses in adaptation to overnutrition through suppressing the expression of lipogenic enzymes, and that the lipogenic pathway represents a key targeted peripheral component in exerting leptin's liporegulatory actions.

BACKGROUND: Recent advances in proteomics have shed light to discover serum proteins or peptides as biomarkers for tracking the progression of diabetes as well as understanding molecular mechanisms of the disease. RESULTS: In this work, human serum of non-diabetic and diabetic cohorts was analyzed by proteomic approach. To analyze total 1377 high-confident serum-proteins, we developed a computing strategy called localized statistics of protein abundance distribution (LSPAD) to calculate a significant bias of a particular protein-abundance between these two cohorts. As a result, 68 proteins were found significantly over-represented in the diabetic serum (p

Even though mRNA expression levels are commonly used as a proxy for estimating functional differences that occur at the protein level, the relation between mRNA and protein expression is not well established. Further, no study to date has tested whether the evolutionary differences in mRNA expression observed between species reflect those observed in protein expression. Since a large proportion of mRNA expression differences observed between mammalian species appears to have no functional consequences for the phenotype, it is conceivable that many or most mRNA expression differences are not reflected at the protein level. If this is true, then differences in protein expression may largely reflect functional adaptations observed in species phenotypes. In this paper, we present the first direct comparison of mRNA and protein expression differences seen between humans and chimpanzees. We reproducibly find a significant positive correlation between mRNA expression and protein expression differences. This correlation is comparable in magnitude to that found between mRNA and protein expression changes at different developmental stages or in different physiological conditions within one species. Noticeably, this correlation is mainly due to genes with large expression differences between species. Our study opens the door to a new level of understanding of regulatory evolution and poses many new questions that remain to be answered.