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MICAL proteins represent a unique family of actin regulators crucial for synapse development, membrane trafficking, and cytokinesis. Unlike classical actin regulators, MICALs catalyze the oxidation of specific residues within actin filaments to induce robust filament disassembly. The potent activity of MICALs requires tight control to prevent extensive damage to actin cytoskeleton. However, the molecular mechanism governing MICALs' activity regulation remains elusive. Here, we report the cryo-EM structure of MICAL1 in the autoinhibited state, unveiling a head-to-tail interaction that allosterically blocks enzymatic activity. The structure also reveals the assembly of C-terminal domains via a tripartite interdomain interaction, stabilizing the inhibitory conformation of the RBD. Our structural, biochemical, and cellular analyses elucidate a multi-step mechanism to relieve MICAL1 autoinhibition in response to the dual-binding of two Rab effectors, revealing its intricate activity regulation mechanisms. Furthermore, our mutagenesis study of MICAL3 suggests the conserved autoinhibition and relief mechanisms among MICALs. This study reports the cryo-EM structure of full-length MICAL1 in its autoinhibited conformation, unveiling the molecular mechanisms of tail-mediated inhibition and Rab-binding-mediated relief that regulate MICAL's activity in F-actin disassembly. [ABSTRACT FROM AUTHOR]

Myosin VI is the only molecular motor that moves towards the minus end along actin filaments. Numerous cellular processes require myosin VI and tight regulations of the motor's activity. Defects in myosin VI activity are known to cause genetic diseases such as deafness and cardiomyopathy. However, the molecular mechanisms underlying the activity regulation of myosin VI remain elusive. Here, we determined the high-resolution cryo-electron microscopic structure of myosin VI in its autoinhibited state. Our structure reveals that autoinhibited myosin VI adopts a compact, monomeric conformation via extensive interactions between the head and tail domains, orchestrated by an elongated single-α-helix region resembling a "spine". This autoinhibited structure effectively blocks cargo binding sites and represses the motor's ATPase activity. Certain cargo adaptors such as GIPC can release multiple inhibitory interactions and promote motor activity, pointing to a cargo-mediated activation of the processive motor. Moreover, our structural findings allow rationalization of disease-associated mutations in myosin VI. Beyond the activity regulation mechanisms of myosin VI, our study also sheds lights on how activities of other myosin motors such as myosin VII and X might be regulated. This study reveals the high-resolution cryo-EM structure of autoinhibited myosin VI, offering insights into cargo-mediated activation of this unique myosin motor and advancing our understanding of motor activity control in the myosin superfamily. [ABSTRACT FROM AUTHOR]

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The Ti-7Al-1Mo-0.5V-0.1C alloy exhibits low density and good mechanical properties, and has potential applications in aerospace industries. The microstructure features of titanium alloys, such as the morphology and volume fraction of the primary α phase (αp) and the precipitation of the secondary α phase (αs), are sensitive to heat treatment parameters, especially the cooling rate from the two-phase region. In this work, we have characterized the precipitation of the secondary α phase and ordered α2 phase in Ti-7Al-1Mo-0.5V-0.1C alloy under water quenching, air cooling, and furnace cooling, and have investigated their effects on the mechanical properties of the Ti-7Al-1Mo-0.5V-0.1C alloy. The results show that the secondary α phase is significantly coarsened in the air-cooled alloy and leads to an increase in the strength but decrease in the ductility of the alloy, while the equiaxed microstructure generated in the furnace-cooled alloy, with no precipitation of the secondary α phase and an increase in size of the ordered α2 precipitation phase within the primary α phase, contributes to a further increase in ductility. [ABSTRACT FROM AUTHOR]

Bone marrow mesenchymal stem cell derived exosomes (BMSC-exos) are a crucial means of intercellular communication and can regulate a range of biological processes by reducing inflammation, decreasing apoptosis and promoting tissue repair. The process of intervertebral disc degeneration (IVDD) is accompanied by increased reactive oxygen species (ROS) because of a decrease in the expression of Nrf2, a critical transcription factor that resists excessive ROS. Our study demonstrated that BMSC-exos decreased ROS production by inhibiting Keap1 and promoting Nrf2 expression, attenuating the apoptosis, inflammation, and degeneration of nucelus pulposus (NP) cells. BMSC-exos promoted an increase in Nrf2 and nuclear translocation, while NF-κB expression was downregulated during this process. Additionally, the expression of antioxidative proteins was elevated after treatment with BMSC-exos. In vivo, we found more NP tissue retention in the BMSC-exos-treated group, along with more expression of Nrf2 and antioxidant-related proteins. Our findings demonstrated for the first time that BMSC-exos could restore the down-regulated antioxidant response system in degenerating NP cells by modulating the Keap1/Nrf2 axis. BMSC-exos could be used as an immediate ROS modulator in the treatment of intervertebral disc degeneration. When BMSC-exos were uptaken by NPCs, the expression of Keap1 decreased and this led to increased expression of Nrf2. Nuclear translocation of Nrf2 then promoted the synthesis of antioxidants against ROS and inhibited NF-kB signalling. Cellular inflammation, apoptosis, and ECM-related indicators were further reduced. Together, the process of IVDD was alleviated [ABSTRACT FROM AUTHOR]

Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection. cfDNA is a promising tool to detect early cancer, however, it has been limited by detection limits and technological ability. Here, the authors develop a method for simultaneous cfDNA methylation, fragmentation and copy number alteration sequencing and apply to a cohort of healthy and cancer patients. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2) is an important epigenetic regulator, and is associated with the malignant progression of lung cancer. However, the mechanisms of EZH2 on lung adenocarcinoma (LUAD) remain unclear. The relationship between EZH2 and SPOCK2 or SPRED1 was confirmed by dual-luciferase reporter assay. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to examine the expression of SPOCK2 and SPRED1 and their prognostic values of LUAD. The effects of SPOCK2 and SPRED1 on the biological characters of LUAD cells were identified on functional assays in vitro and in vivo. Our results showed that EZH2 suppressed the expression and transcriptional activity of SPOCK2 and SPRED1, and these effects were reversed by the EZH2 inhibitor, Tazemetostat. SPOCK2 and SPRED1 were expressed at low levels in LUAD patients, and a high expression level of SPOCK2 or SPRED1 predicted better survival. Moreover, overexpression of SPOCK2 or SPRED1 could inhibit tumoral proliferation, migration ratio, and invasion activity in vitro as well as retard tumor growth in vivo. However, EZH2 elevation could rescue these impacts and accelerate LUAD progression. Our findings reveal that SPOCK2 and SPRED1 are epigenetically suppressed by EZH2 and may act as novel regulators to inhibit the proliferation, migration, and invasion of LUAD cells. [ABSTRACT FROM AUTHOR]

Background: SPECT myocardial perfusion imaging (SPECT MPI) and invasive coronary angiography (ICA) provide complementary clinical information in the diagnosis of coronary artery disease (CAD). We have developed an approach for 3D fusion of perfusion data from SPECT MPI and coronary anatomy from ICA. In this study, we aimed to evaluate its clinical value when compared to the traditional side-by-side readings. Methods: Thirty-six CAD patients who had at least one stenosis ≥ 50% were retrospectively enrolled. Based on the presence of a perfusion defect in a territory subtended by a coronary vessel, all vessels were classified as matched, unmatched, or normal groups via both the fusion and side-by-side analysis. The treatments recommended by the fusion and side-by-side analysis were compared with those that the patients received. Major adverse cardiac events (MACE), defined as all-cause death, myocardial infarction, unstable angina requiring hospitalization, and unplanned revascularization, were assessed. Results: The overall vessel-based concordance was 78.7% between the fusion and side-by-side analysis. Compared with the side-by-side analysis, 23 coronary arteries (29 equivocal segments) of 19 patients were reclassified via fusion of data. In the matched, unmatched, and normal groups, the numbers of vessels with hemodynamically significant stenosis which caused reversible defect were 37 vs 53, 28 vs 14, and 43 vs 41 (P <.01) when comparing the side-by-side analysis with the fusion, and the revascularization ratios per vessel were 69% vs 88%, 29% vs 10%, and 2% vs 2% between them. During the five-year follow-up, 8 patients (22.2%) experienced MACE. Patients who received the same treatment as the guidance of 3D fusion results (n = 22) had superior outcomes when compared with those who did not (n = 14) (P <.01). Conclusions: Compared with the side-by-side analysis, the 3D fusion of SPECT MPI and ICA provided incremental diagnostic and prognostic value. [ABSTRACT FROM AUTHOR]

Evidence has shown that risks of cognitive impairment differ between genders. This cross-sectional study sought to determine the prevalence of mild cognitive impairment (MCI) in Chinese community-dwelling women aged above 60 years and identify risks of MCI by multivariate logistic regression analysis. Totally, 1760 Chinese community-dwelling women entered the study. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). MCI was diagnosed by Petersen's criteria. Sociodemographic information, past medical conditions, and age at menopause were screened. The primary study outcome was prevalence of MCI. MCI was diagnosed in 378 (21.5%) women. Older age was a significant risk of MCI (OR 1.621, 95%CI 1.386–1.894; P < 0.001). Low education was associated a 4-fold increase in the risk of MCI (OR 4.036, 95%CI 3.168–5.142). Furthermore, current depression was associated with 2.6-fold increase in the risk of MCI (OR 2.618, 95%CI 1.499–4.587, P = 0.001). Moreover, frequent physical exercise and more leisure and social time activities were associated with significantly reduced risks of MCI, while poor financial status was associated with a significantly increased risk of MCI. Slightly more than 20% of Chinese women aged above 60 years had MCI, and independent risks included older age, low education status, and current depression, highlighting the importance of screening for and removing or minimizing risks of MCI in this specific population. [ABSTRACT FROM AUTHOR]

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II–IIIA non-small cell lung cancer (NSCLC). However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy. Adjuvant gefitinib improves outcomes in non-small cell lung cancer (NSCLC) patients compared to chemotherapy, but not in all cases. Here, the authors find genomic biomarkers of response to gefitinib in NSCLC patients from the ADJUVANT trial, and propose a score to stratify them by potential benefit from the treatment. [ABSTRACT FROM AUTHOR]

Microvascular hyperpermeability is a leading mechanism responsible for occurrence of edema in remote organs and tissues in patients with burn injury. Accumulated evidence has shown that exosomes can be transported into target cells, where they are capable of regulating biological functions and physiology. Of exosomal proteins contributing to enhanced inflammation and vascular permeability, S100 calcium binding protein A9 (S100A9) has received increasing attention. Here we hypothesized that S100A9-containing serum exosomes of patients with burn injury contribute to pathogenesis of hyperpermeability of microvascular structure in lung by transferring signaling molecules into it and activating downstream signaling pathways, ultimately leading to disruption of the tight junctions (TJs) and endothelial barrier. A use of enzyme-linked immunosorbent assay revealed that total serum concentrations of S100A9 were significantly augmented in burn injury patients in comparison to normal controls. With use of human pulmonary microvascular endothelial cells (HPMECs) as an in vitro model, we found that patients' serum exosomes were effectively internalized by HPMECs. We further found that serum exosomes of stage II/II burn patients inhibited zonula occludens (ZO-1) and occludin protein levels, which are essential for TJs integrity and endothelial barrier function, but activated p38 MAPK signaling pathway in HPMECs. As expected, such exosomes-mediated effects on HPMECs were reversed by a simultaneous treatment of anti-S100A9 neutralizing antibody. Finally, we found that a recombinant human S100A9 treatment led to inhibition of expression of occludin and ZO-1 but an activation of p38 signaling in HPMECs, and that such effects were reversed when p38 activity was repressed, implying that S100A9 may stimulate p38 activity to inhibit ZO-1 and occludin in HPMECs. Collectively, these data suggest that S100A9-containing serum exosomes may play a critical role in contributing to pulmonary microvascular hyperpermeability, thus supporting that blocking exosomes' access to HPMECs could hold a promise strategy for treatment of lung edema resulting from burn injuries. [ABSTRACT FROM AUTHOR]

The turbulent cavitating flow around the propelling pump tip clearance is numerically simulated using the large eddy simulation (LES) method coupled with the Zwart-Gerber-Belamri (ZGB) cavitation model to investigate the cavitation-vortex interaction mechanism. The calculated cavitation structures around the blades are in a remarkable agreement with the experimental results. The distributions of the tip clearance vortex under two cavitation conditions are obtained and compared. The results show that the cavitation development enhances the vorticity generation and the flow unsteadiness around the tip clearance of a propelling pump. Vortices are basically located around the cavitation areas, particularly in the tip clearance region, during the cavitation. The relative vorticity transport equation is applied for the cavitating turbulent flows and it is further indicated that the vortex stretching term makes the main contribution in the vortex production, and the baroclinic torque and dilation terms are important source terms for the vorticity generation in the cavitating flow. In addition, the viscous diffusion term and the Coriolis force term are significant in modifying the vorticity field inside the blade tip clearance. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) may lead to severe motor and sensory dysfunction, causing high mortality and disability rates. Adipose tissue-derived mesenchymal stem/stromal cells (ADSCs), especially hypoxia-pretreated ADSCs, represent an effective therapy for SCI by promoting the secretion of exosomes (Exos). Here, we investigated the therapeutic efficacy of exosomes secreted by ADSCs under hypoxia (HExos) and explored potential target molecules. We utilized nanoparticle tracking analysis, electron microscopy, qRT-PCR, and western blotting to analyze differences between HExos and Exos groups. The expression of long noncoding RNAs (lncRNAs) was examined by high-throughput sequencing. The therapeutic effects of different Exos treatments were compared in vitro and in an SCI model in vivo. The interaction between lncRNAs, microRNAs, and mRNA was examined by luciferase reporter experiments. We employed enzyme-linked immunosorbent assay and immunofluorescence to measure inflammatory factor expression and microglial polarization. The results showed that HExos was more effective than Exos for repairing SCI by suppressing inflammatory factor expression, promoting functional recovery, and shifting microglia from M1 to M2 polarization. High-throughput sequencing showed that LncGm37494 expression was significantly higher in HExos than Exos, and its upregulation promoted microglial M1/M2 polarization by inhibiting miR-130b-3p and promoting PPARγ expression, as shown by luciferase reporter experiments. Exos from lncGm37494 overexpressing ADSCs showed a similar therapeutic effect than HExos. The results indicated that HExos repair SCI by delivering lncGm37494, advising that lncGm3749 functions importantly in microenvironmental regulation and shows possibility for SCI treatments. [ABSTRACT FROM AUTHOR]

The cavitating flow field in waterjet pumps is complex, especially tip leakage cavitation (TLC), which has been a puzzle to researchers for decades. In this study, high-speed video (HSV) of the instantaneous inner structures of tip cavitation flow is used to show the evolution of TLC. Numerical simulation is conducted with the scale adaptive simulation (SAS) turbulence model and Zwart-Gerber-Belamri (ZGB) cavitation model to understand the cavitation-vortex interaction in the blade tip region. The predicted cavitation performance curve exhibits reasonable agreement with the experimental results, and the time-dependent vapor iso-surfaces (αv = 0.1) are consistent with HSV at different times in a typical cycle. Numerical simulation results show that cavitation can enhance the turbulent kinetic energy in the unstable vortex cavitation region and downstream tip leakage vortex region along the blade. Different vortex identification methods, including vorticity, Q criterion, λci, λ2 criterion, Ω, and Liutex/Rortex, are investigated. Analysis and comparison of the iso-surfaces of the different vortex identification methods indicate that the Ω and Liutex iso-surfaces can effectively predict the tip leakage vortex core and vortex pair in the unstable vortex cavitation region. Analysis of the fifth clip contours shows that no obvious difference exists between Q and λ2 criteria in terms of predicting the vortex core. All vortex identification methods can accurately predict the tip separation vortex in the blade tip region, but only the Ω and Liutex iso-surfaces can predict weak vortices in the cavitation region. The influence of the small parameter ε of the Ω method on tip vortex identification is also discussed. [ABSTRACT FROM AUTHOR]

In most of the existing compressed sensing (CS) based channel estimation schemes for multiple-input multiple-output (MIMO) orthogonal frequency division multiplexing (OFDM) systems, the randomly allocated pilot is difficult to be implemented in real applications and introduces additional pilot overhead for transmitting the information on pilot locations which is required in channel reconstruction at receiver. In this paper, a channel estimation scheme based on deterministic compressed sensing is proposed to cut down the pilot overhead in MIMO OFDM systems. To be specific, a deterministic pilot placement scheme is proposed to select the subset of the subcarriers for pilot transmission. Since this deterministic pilot placement leads a new kind of deterministic measurement matrices in CS model, the mutual coherence property of the deterministic matrix is verified to establish theoretical guarantee for the pilot placement scheme. Then an improved reconstruction algorithm is proposed to match the structure of the deterministic matrix. Numerical results demonstrate that even without the pilot locations information, the proposed channel estimation scheme based on deterministic compressed sensing achieves similar estimation accuracy as conventional estimator with random pilot placement. [ABSTRACT FROM AUTHOR]

Current treatments for cancer and the central nervous system diseases are limited, partly due to the difficulties posed by the insolubility, poor distribution of drugs among cells and lack of selectivity of drugs, the inability of drugs to cross cellular barriers and blood brain barrier (BBB). Carbon nanotubes (CNTs) possess many distinct properties including good electronic properties, remarkably penetrating capability on the cell membrane, high drug-loading and pH-dependent therapeutic unloading capacities, thermal properties, large surface area and easy modification with molecules, which render them as a suitable candidate to deliver drugs to cancer and brain. CNTs as a drug delivery could achieve a high efficacy, enhance specificity and diminish side effects. Whereas CNTs have been primarily employed in cancer treatment, a few studies have focused on the treatment and diagnosis of the central nervous system diseases using CNTs. Here, we review the current progress of in vitro and in vivo researches of CNTs-based drug delivery to cancer involving CNTs-based tumor-targeted drug delivery systems (DDS), photodynamic therapy (PDT) and photothermal therapy (PTT). Meanwhile, we also review the current progress of in vitro and in vivo researches of CNTs-based drug delivery to brain. [ABSTRACT FROM AUTHOR]

It is recognized that prenatal care plays an important role in reducing adverse birth. Chinese pregnant women with medical condition were required to seek additional health care based on the recommended at least 5 times health care visits. This study was to estimate the association between prenatal care utilization (PCU) and preterm birth (PTB), and to investigate if medical conditions during pregnancy modified the association. This population-based case control study sampled women with PTB as cases; one control for each case was randomly selected from women with term births. The Electronic Perinatal Health Care Information System (EPHCIS) and a questionnaire were used for data collection. The PCU was measured by a renewed Prenatal Care Utilization (APNCU) index. Logistic regression models were used to estimate odds ratios (OR) and the 95% confidence interval (95% CI). Totally, 2393 women with PTBs and 4263 women with term births were collected. In this study, 695 (10.5%) women experienced inadequate prenatal care, and 5131 (77.1%) received adequate plus prenatal care. Inadequate PCU was associated with PTB (adjusted OR: 1.41, 95% CI: 1.32-1.84); the similar positive association was found between adequate plus PCU and PTB. Among women with medical conditions, these associations still existed; but among women without medical conditions, the association between inadequate PCU and PTB disappeared. Our data suggests that women receiving inappropriate PCU are at an increased risk of having PTB, but it does depend on whether the woman has a medical condition during pregnancy. [ABSTRACT FROM AUTHOR]

Purpose: To identify risk factors for intestinal metaplasia in a southeastern Chinese population. Methods: Subjects who underwent upper GI endoscopy and endoscopic biopsy in the First Affiliated Hospital of Nanjing Medical University from 2008 to 2013 were included into this study. Various demographic, geographic, clinical and pathological data were analyzed separately to identify risk factors for intestinal metaplasia. Results: The incidence of intestinal metaplasia differed significantly in 17 municipal areas ranging from 16.79 to 38.56% and was positively correlated with the age range of 40-70 years, male gender, gastric ulcer, bile reflux, Helicobacter pylori infection, atrophic gastritis, dysplasia, gastric cancer, degree of chronic and acute inflammation, and gross domestic product per capita ( P < 0.01). Multivariate linear regression analysis indicated that only gross domestic product per capita revealed a significant difference in the incidence of intestinal metaplasia among all factors mentioned. Conclusion: This study confirms age, male gender, gastric ulcer, bile reflux, H. pylori infection, severe degree of chronic and acute inflammation to be the risk factors for intestinal metaplasia. We speculate that the gross domestic product per capita of different areas may be a potential independent risk factor impacting the incidence of intestinal metaplasia. [ABSTRACT FROM AUTHOR]

This present study aims to determine trends in the prevalence of H. pylori infections in Southeastern China between 2003 and 2012, and investigate corresponding changes in the prevalence of upper gastrointestinal diseases. This retrospective study screened 196,442 patients with a mean age of 47.49 ± 14.47 years (age range 5-100 years) in Southeastern China, and a total of 134,812 cases of an endoscopy-referral patient population with digestive symptoms between 2003 and 2012 were enrolled. Based on esophago-gastro-duodenoscopy and pathology, patients diagnosed with chronic gastritis, peptic ulcer, gastric cancer or reflux esophagitis were included in this study. Basic demographic and clinical characteristics such as H. pylori infection status and endoscopic findings were collected and analyzed. Among the 134,812 subjects, mean prevalence of H. pylori infection was 31.97 %; which demonstrated a linear downward trend from 42.40 to 23.82 % ( P < 0.001) at an annual rate of 2 % from 2003 to 2012. Similarly, the prevalence of duodenal and gastric ulcer rapidly decreased from 12.65 to 6.57 % and from 7.51 to 3.78 %, respectively; while the prevalence of gastric cancer (from 3.76 to 2.34 %) did not significantly change in the same time period. In contrast, the prevalence of reflux esophagitis increased from 6.19 to 12.80 %. The progressively decreasing prevalence of H. pylori infections from 2003 to 2012 in Southeastern China appears to be linked with the decline of related upper gastrointestinal diseases and increase of some gastrointestinal motility diseases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles, and neuronal loss. Cumulative evidence supports that neuroinflammation is an important factor for the pathogenesis of AD and contributes to amyloid beta (Aβ) generation. However, there has been no effective treatment for AD. Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) have a potential therapeutic effect in the treatment for neurological diseases. In the present study, we evaluated the therapeutic effect of WJ-MSC transplantation on the neuropathology and memory deficits in amyloid precursor protein (APP) and presenilin-1 (PS1) double-transgenic mice and discussed the mechanism. WJ-MSCs were intravenously transplanted into the APP/PS1 mice. Four weeks after treatment, WJ-MSCs significantly improved the spatial learning and alleviated the memory decline in the APP/PS1 mice. Aβ deposition and soluble Aβ levels were significantly reduced after WJ-MSC treatment. Furthermore, WJ-MSCs significantly increased the expression of the anti-inflammatory cytokine, IL-10. Meanwhile, pro-inflammatory microglial activation and the expressions of pro-inflammatory cytokines, IL-1β and TNFα, were significantly down-regulated by WJ-MSC treatment. Thus, our findings suggest that WJ-MSCs might produce beneficial effects on the prevention and treatment for AD through modulation of neuroinflammation. [ABSTRACT FROM AUTHOR]

An efficient novel algorithm was developed to estimate the Density of States (DOS) for large systems by calculating the ensemble means of an extensive physical variable, such as the potential energy, U, in generalized canonical ensembles to interpolate the interior reverse temperature curve $${\beta _s}\left( U \right) \equiv \frac{{\partial S\left( U \right)}}{{\partial U}}$$, where S( U) is the logarithm of the DOS. This curve is computed with different accuracies in different energy regions to capture the dependence of the reverse temperature on U without setting prior grid in the U space. By combining with a U-compression transformation, we decrease the computational complexity from O( N) in the normal Wang Landau type method to O( N) in the current algorithm, as the degrees of freedom of system N. The efficiency of the algorithm is demonstrated by applying to Lennard Jones fluids with various N, along with its ability to find different macroscopic states, including metastable states. [ABSTRACT FROM AUTHOR]

In this study, the precipitation behavior of the pretwinned extruded Mg–6Al–1Zn alloy was investigated. It was observed that the precipitates preferentially nucleated at the twin boundaries or within the preexistent twins. This distribution of the precipitates led to the distinguishing influences on subsequent compression and tension process, which were dominated by twinning and detwinning of the preexistent twins, respectively. The compressive yield strength after aging was a little lower than the stress when the precompression was interrupted, which meant that the impeding effect of precipitation on twin expansion was relatively smaller than that of dislocations induced by precompression. However, the tensile yield strength of aged samples was extremely higher than that of non-aged samples as the migration of the twin boundaries during detwinning was considerably hindered because of the preferential precipitation within the preexistent {10-12} twins. [ABSTRACT FROM PUBLISHER]

Influenza A H3N2 virus as the cause of 1968 pandemic has since been circulating in human and swine. Our earlier study has shown that mutations of one or two cysteines in the transmembrane domain of H3 hemagglutinin (HA) affected the thermal stability and fusion activity of recombinant HA proteins. Here, we report the successful generation of three recombinant H3N2 mutant viruses (C540S, C544L, and 2C/SL) with mutations of one or two transmembrane cysteines of HA in the background of A/swine/Guangdong/01/98 [H3N2] using reverse genetics, indicating that the mutated cysteines were not essential for virus assembly and growth. Further characterization revealed that recombinant H3N2 mutant viruses exhibited larger plaque sizes, increased growth rate in cells, enhanced fusion activity, reduced thermal and acidic resistances, and increased virulence in embryonated eggs. These results demonstrated that the transmembrane cysteines (C540 and C544) in H3 HA have profound effects on the virological features of H3N2 viruses. [ABSTRACT FROM AUTHOR]

The hemagglutinin (HA) protein as the predominant antigen, executes receptor binding and membrane fusion, which critically influence the virological characteristics of influenza viruses. The literature contained scattered data showing reduction-sensitive HA oligomers when HA proteins were analyzed under non-reducing conditions. However, whether the reduction-sensitive HA oligomers are inter-monomer disulfide-bonded has not been studied. Here, we showed: (1) the detection of β-mercaptoethanol-sensitive H3 HA oligomers was not affected by the treatment of cells with iodoacetamide prior to cell solubilization; (2) H3 HA oligomers were present on cell surfaces; (3) H3 HA oligomers had higher density than monomers; and (4) mutation of all the five C-terminal cysteines completely abolished the formation of H3 HA oligomers. Furthermore, mutant HAs with mutations of TM cysteines, CT cysteines or all five cysteines had decreased thermal stability but increased fusion activity in comparison with wildtype HA. In conclusion, this study has presented enough evidence for the existence of inter-monomer S-S H3 HA oligomers formed by five C-terminal cysteines, and suggested that all five C-terminal cysteines exerted opposite effects on HA thermal stability and fusion activity. [ABSTRACT FROM AUTHOR]

The 12 and 13 terminal nucleotides in the 3′- and 5′-untranslated regions (UTRs) of the influenza A virus genome, respectively, are important for the transcription of the viral RNA and the translation of mRNA. However, the functions of the segment-specific regions of the UTRs are not well known. We utilized an enhanced green fluorescent protein (eGFP) flanked at both ends by different UTRs (from the eight segments of H1N1 PR8/34) as a reporter gene to evaluate the effects of these UTRs on protein expression in vitro. The results showed that the protein expression levels of NP-eGFP, NS-eGFP, and HA-eGFP were higher than those of the other reporters and that the protein level of PB1-eGFP remained at a relatively low amount 48-h post-transfection. The results revealed that the UTRs of all segments differently affected the protein expression levels and that the effect of the UTRs of PB1 segment on protein expression was significant. The deletion of “UAAA” and “UAAACU” motifs in the PB1-3′-UTR significantly increased the protein expression level by 49.8 and 142.6 %, respectively. This finding suggests that the “UAAACU” motif in the PB1-3′-UTR is at least partly responsible for the low protein expression level. By introducing the “UAAACU” motif into other 3′-UTRs (PA, NS, NP, and HA) at similar locations, the eGFP expression was reduced as expected by 56, 61, 22, and 22 %, respectively. This result further confirmed that the “UAAACU” motif of the PB1-3′-UTR can inhibit protein expression. Our findings suggest that the segment-specific regions in the UTRs and not just the conserved regions of the UTRs play an important role in the viral protein expression. Additionally, the reported findings may also shed light on novel regulatory mechanism for the influenza A virus genome. [ABSTRACT FROM AUTHOR]

Influenza A H3N2 virus caused 1968 Hong Kong influenza pandemic, and has since been one of the most prevalent seasonal influenza viruses in global populations, representing a credible pandemic candidate in future. Previous studies have established that the hemagglutinin (HA) protein is the predominant antigen and executes receptor binding and membrane fusion. Homologous sequence analysis of all HA subtypes of influenza viruses revealed that two cysteine residues (540 and 544) are uniquely present in the transmembrane domain (TM) of HA proteins from all influenza A H3N2 viruses. However, the functions of these two cysteines have not been fully studied. Here, we generated three mutants (C540S, C544L, and 2C/SL) to investigate the effects of the two TM cysteines on the biological functions of H3 HA. We herein presented evidences that the mutations of one or two of the cysteines did not affect the proper expressions of HA proteins in cells, and more importantly all mutant H3 HAs showed decreased thermal stability but increased fusion activity in comparison with wildtype HA. Our results taken together demonstrated that the two TM cysteines are important for the biological functions of H3 HA proteins. [ABSTRACT FROM AUTHOR]

With the rapid development of next-generation sequencing technologies, bacterial identification becomes a very important and essential step in processing genomic data, especially for metagenomic data. Many computational methods have been developed and some of them are widely used to address the problems in bacterial identification. In this article we review the algorithms of these methods, discuss their drawbacks, and propose future computational methods that use genomic data to characterize bacteria. In addition, we tackle two specific computational problems in bacterial identification, namely, the detection of host-specific bacteria and the detection of disease-associated bacteria, by offering potential solutions as a starting point for those who are interested in the area. [ABSTRACT FROM AUTHOR]

In vivo phage display has been used extensively to screen for novel targets of tumor therapy. Phage display peptide libraries can express random peptides or protein fragments and the aim of phage display is to identify peptide molecules that bind stably to a given target. Angiogenesis is essential to tumor development. Both blood and lymphatic vessels of tumors are different from those of normal tissues. Phage display has been used to analyze the structure and molecular diversity of tumor vasculature and to select tumor-specific antigens which have revealed stage- and type-specific markers of tumor blood vessels. Furthermore, peptides identified by in vivo phage display also work as vehicles to transport cargo therapeutic reagents to tumors. These peptides and their corresponding cellular proteins and ligands may provide molecular tools to selectively target the addresses of tumors and their pathological blood vessels and might increase the efficacy of therapy while decreasing side effects. [ABSTRACT FROM AUTHOR]

Constructing two-dimensional (2D) polymers with complex tessellation patterns via synthetic chemistry makes a significant contribution not only to the understanding of the emergence of complex hierarchical systems in living organisms, but also to the fabrication of advanced hierarchical materials. However, to achieve such tasks is a great challenge. In this communication we report a facile and general approach to tessellate 2D covalent organic frameworks (COFs) by three or four geometric shapes/sizes, which affords 2D COFs bearing three or four different kinds of pores and increases structural complexity in tessellations of 2D polymers to a much higher level. The complex tessellation patterns of the COFs are elucidated by powder X-ray diffraction studies, theoretical simulations and high-resolution TEM. Constructing two-dimensional (2D) polymers with complex tessellation patterns is important for the fabrication of advanced materials but achieving such complexity is a great challenge. Here the authors report a tessellated 2D covalent organic framework with increased structural complexity as well as different pore structures. [ABSTRACT FROM AUTHOR]

Immobilization antigens (i-antigens) are surface membrane proteins that are widely recognized to be the ideal candidates as vaccines antigens for immunization against Cryptocaryon irritans. In this study, we cloned a putative i-antigen gene from C. irritans, which was expressed in all three stages of the C. irritans life-cycle, and localized primarily to the cell surface. The recombinant GDCI3 i-antigen was expressed and purified using the free-living ciliate, Tetrahymena thermophila as an expression system. The purified recombinant protein was recognized by rabbit anti-C. irritans antiserum and was capable of eliciting immobilizing antibodies in rabbits and fish suggesting that the antigen itself was correctly folded. Following immunization and parasite challenge, groupers vaccinated with, recombinant GDCI3 i-antigen had a 25% cumulative percent survival rate compared to 8.3% for controls. Both non-specific and parasite-specific IgMs were generated in fish following immunization, with the levels of both increasing following challenge. Parasite-specific IgM in mucus could only be elicited after challenge of the GDCI3 i-antigen vaccinated groupers. To our knowledge, this is the first report using the Tetrahymena expression system to generate C. irritans i-antigens and investigate their use for fish vaccination. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved degradation process that is involved in the clearance of proteins and damaged organelles to maintain intracellular homeostasis and cell integrity. Type 2 diabetes is often accompanied by dyslipidemia with elevated levels of free fatty acids (FFAs). Podocytes, as an important component of the filtration barrier, are susceptible to lipid disorders. The loss of podocytes causes proteinuria, which is involved in the pathogenesis of diabetic nephropathy. In the present study, we demonstrated that palmitic acid (PA) promoted autophagy in podocytes. We further found that PA increased the production of reactive oxygen species (ROS) in podocytes and that NAC (N-acetyl-cysteine), a potent antioxidant, significantly eliminated the excessive ROS and suppressed autophagy, indicating that the increased generation of ROS was associated with the palmitic acid-induced autophagy in podocytes. Moreover, we also found that PA stimulation decreased the mitochondrial membrane potential in podocytes and induced podocyte apoptosis, while the inhibition of autophagy by chloroquine (CQ) enhanced palmitic acid-induced apoptosis accompanied by increased ROS generation, and the stimulation of autophagy by rapamycin (Rap) remarkably suppressed palmitic acid-induced ROS generation and apoptosis. Taken together, these in vitro findings suggest that PA-induced autophagy in podocytes is mediated by ROS production and that autophagy plays a protective role against PA-induced podocyte apoptosis. [ABSTRACT FROM AUTHOR]