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Ming-Ming Ma,1,* Yao-Yao Xu,2,* Li-Hua Sun,1,* Wen-Jie Cui,1 Miao Fan,3 Su Zhang,4 Lei Liu,5 Ling-Zhi Wu,6 Liu-Cheng Li7 1Department of Diagnostic Ultrasound & Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China; 2Department of Pharmacy, The People’s Hospital of Pingyang, Wenzhou, 325400, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, People’s Republic of China; 4Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China; 5Department of Orthopaedics, Shaoxing Hospital of Traditional Chinese Medicine, Shaoxing, 312000, People’s Republic of China; 6Department of Pharmacy, The Affiliated Hospital of Jiaxing University (The First Hospital of Jiaxing), Jiaxing, 314000, People’s Republic of China; 7Department of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liu-Cheng Li, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Road, Hangzhou, 310016, People’s Republic of China, Email 3415116@zju.edu.cn Ling-Zhi Wu, The Affiliated Hospital of Jiaxing University (The First Hospital of Jiaxing), No. 1882 South Central Road, Jiaxing, 314000, People’s Republic of China, Email wulingzhi1992@163.comAbstract: Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who ofte

Su Zhang,1 Ke Xu,2 Su-Xiao Liu,3 Xiao-Lan Ye,1 Ping Huang,1 Hong-Juan Jiang1 1Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 2Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 3Center for Reproductive Medicine, Department of Obstetrics, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Hong-Juan Jiang, Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China, Tel +86 571 85893143, Fax +86 571 87666666, Email tigergirl@126.comPurpose: Ureaplasma urealyticum and Mycoplasma hominis began to show resistance to azithromycin, a macrolide antibiotic commonly used in pregnancy. Unfortunately, there are few effective and safe drugs in the clinic for genital mycoplasmas in pregnant women. In the present study, we investigated the prevalence of azithromycin-resistant U. urealyticum and M. hominis infections in pregnant women. The secondary research objects were possible influencing factors and consequences of insensitive Mycoplasma infection.Patients and methods: A retrospective analysis was carried out in pregnant women who underwent cervical Mycoplasma culture between October 2020 and October 2021 at a large general hospital in eastern China. The sociological characteristics and clinical information of these women were collected and analyzed.Results: A total of 375 pregnant women were enrolled, and 402 cultured mycoplasma specimens were collected. Overall, 186 (49.60%) patients te

Yang Zhang,1,2,* Anqing Lu,2– 4,* Zixuan Zhuang,1,2 Su Zhang,5 Sicheng Liu,5 Haining Chen,1,2 Xuyang Yang,1,2 Ziqiang Wang1,2 1Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 3Department of Central Transportation, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 4West China School of Nursing, Sichuan University, Chengdu, 610041, People’s Republic of China; 5Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-Related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziqiang Wang; Xuyang Yang, Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email wangziqiang@scu.edu.cn; yangxuyang@wchscu.cnAbstract: Extracellular vesicles (EVs) are small membrane-bound vesicles that are released by cells into the extracellular environment. The role of EVs in tumors has been extensively studied, and they have been shown to play a crucial role in tumor growth, progression, and metastasis. Past research has mainly used 2D-cultured cell line models to investigate the role of EVs in tumors, which poorly simulate the tumor microenvironment. Organoid technology has gradually matured in recent years. Organoids are similar in composition and behavior to physiological cells and have the potential to recapitulate the architecture and function of the original tissue. It has been widely used in organogenesis, drug screening, gene editing, precision medicine and other fields. The integration of

We used two multimodal models for continuous valence-arousal recognition using visual, audio, and linguistic information. The first model is the same as we used in ABAW2 and ABAW3, which employs the leader-follower attention. The second model has the same architecture for spatial and temporal encoding. As for the fusion block, it employs a compact and straightforward channel attention, borrowed from the End2You toolkit. Unlike our previous attempts that use Vggish feature directly as the audio feature, this time we feed the pre-trained VGG model using logmel-spectrogram and finetune it during the training. To make full use of the data and alleviate over-fitting, cross-validation is carried out. The code is available at https://github.com/sucv/ABAW3., Comment: 6 pages. 1 figure. arXiv admin note: substantial text overlap with arXiv:2203.13031

Influence Maximization(IM) aims to identify highly influential nodes to maximize influence spread in a network. Previous research on the IM problem has mainly concentrated on single-layer networks, disregarding the comprehension of the coupling structure that is inherent in multilayer networks. To solve the IM problem in multilayer networks, we first propose an independent cascade model (MIC) in a multilayer network where propagation occurs simultaneously across different layers. Consequently, a heuristic algorithm, i.e., Adaptive Coupling Degree (ACD), which selects seed nodes with high spread influence and a low degree of overlap of influence, is proposed to identify seed nodes for IM in a multilayer network. By conducting experiments based on MIC, we have demonstrated that our proposed method is superior to the baselines in terms of influence spread and time cost in 6 synthetic and 4 real-world multilayer networks.

This paper primarily focuses on analyzing the problems and proposing solutions for the probabilistic truncation protocol in existing PPML works from the perspectives of accuracy and efficiency. In terms of accuracy, we reveal that precision selections recommended in some of the existing works are incorrect. We conduct a thorough analysis of their open-source code and find that their errors were mainly due to simplified implementation, more specifically, fixed numbers are used instead of random numbers in probabilistic truncation protocols. Based on this, we provide a detailed theoretical analysis to validate our views. We propose a solution and a precision selection guideline for future works. Regarding efficiency, we identify limitations in the state-of-the-art comparison protocol, Bicoptor's (S\&P 2023) DReLU protocol, which relies on the probabilistic truncation protocol and is heavily constrained by the security parameter to avoid errors, significantly impacting the protocol's performance. To address these challenges, we introduce the first non-interactive deterministic truncation protocol, replacing the original probabilistic truncation protocol. Additionally, we design a non-interactive modulo switch protocol to enhance the protocol's security. Finally, we provide a guideline to reduce computational and communication overhead by using only a portion of the bits of the input, i.e., the key bits, for DReLU operations based on different model parameters. With the help of key bits, the performance of our DReLU protocol is further improved. We evaluate the performance of our protocols on three GPU servers, and achieve a 10x improvement in DReLU protocol, and a 6x improvement in the ReLU protocol over the state-of-the-art work Piranha-Falcon (USENIX Sec 22). Overall, the performance of our end-to-end (E2E) privacy-preserving machine learning (PPML) inference is improved by 3-4 times., Comment: 17 pages, 5 figures

Emotion recognition using electroencephalogram (EEG) mainly has two scenarios: classification of the discrete labels and regression of the continuously tagged labels. Although many algorithms were proposed for classification tasks, there are only a few methods for regression tasks. For emotion regression, the label is continuous in time. A natural method is to learn the temporal dynamic patterns. In previous studies, long short-term memory (LSTM) and temporal convolutional neural networks (TCN) were utilized to learn the temporal contextual information from feature vectors of EEG. However, the spatial patterns of EEG were not effectively extracted. To enable the spatial learning ability of TCN towards better regression and classification performances, we propose a novel unified model, named MASA-TCN, for EEG emotion regression and classification tasks. The space-aware temporal layer enables TCN to additionally learn from spatial relations among EEG electrodes. Besides, a novel multi-anchor block with attentive fusion is proposed to learn dynamic temporal dependencies. Experiments on two publicly available datasets show MASA-TCN achieves higher results than the state-of-the-art methods for both EEG emotion regression and classification tasks. The code is available at https://github.com/yi-ding-cs/MASA-TCN., Comment: 12 pages, 4 figures. This work has been submitted to the IEEE for possible publication. Copyright may be transferred without notice, after which this version may no longer be accessible

Broflanilide is a novel insecticide with a unique mode of action on the insect GABA receptor and is registered worldwide for the control of agricultural pests. It shows high efficacy in controlling the fall armyworm (FAW) Spodoptera frugiperda, which is a destructive pest to various crops. FAW were exposed to sublethal concentrations of broflanilide to determine its impact on insect development. Sublethal doses (LD10 and LD30) caused failure of ecdysis, reduced body length of larvae, malformation of pupae, and vestigial wing formation in adults. Also, broflanilide at LD30 significantly reduced the amount of molting hormone (MH) . After exposure to LD10 or LD30 broflanilide, expression of five Halloween genes, which participate in MH biosynthesis, were found to be altered. Specifically, the transcript levels of SfrCYP307A1 (Spook), SfrCYP314A1 (Shade) and SfrCYP315A1 (Shadow) in 3rd day larvae were significantly decreased as well as SfrCYP302A1 (Disembodied) and SfrCYP306A1 (Phantom) in 5th day pupae. In contrast, the transcript levels of SfrCYP302A1 in 3rd day larvae, SfrCYP307A1 and SfrCYP314A1 in 5th day pupae, and SfrCYP306A1, SfrCYP307A1 and SfrCYP315A1 in 0.5th day adults were significantly increased. Our results demonstrate that broflanilide caused the failure of ecdysis in FAW possibly by influencing the intake of cholesterol through inhibition of feeding and also via altering expression of genes important for MH biosynthesis.

Broflanilide, a novel meta-diamide insecticide, has been registered worldwide to control agricultural pests, and cause negative influence to insect under not only lethal but also sublethal level in the field. Fall armyworm (FAW) Spodoptera frugiperda is a worldwide distributed insect frequently controlled by using insecticides, and the potential regulating mechanism of broflanilide on this key insect prompt careful characterization. In the present study, we exposed FAW larvae to sublethal dose (LD5), low lethal doses (LD10 and LD30) and median lethal dose (LD50) of broflanilide and measured various subsequent physiological sublethal effects. FAW larvae body length became shorter (LD5-LD50), the larvae and pupae duration were increased by 0.96-4.63 days (LD5-LD50), and the juvenile hormone (JH) titer significantly increased up to 134.46% (LD10-LD30). Meanwhile, the JH acid methyltransferase gene (JHAMT) and farnesyl diphosphate synthase 1 (FPPS1), which are critical enzymes of JH biosynthesis, increased by 2.07- and 2.18- fold in LD10 broflanilide-treated group, and by 2.22- and 1.78- fold in LD30 broflanilide-treated group in 3rd day larvae of FAW, respectively. In the 12-hour-old adults, SfrFPPS1 increased to 1.92-fold in LD30 broflanilide-treated group. Broflanilide induced multiple physiological sublethal effects on the biosynthesis of JH by regulating the expression of SfrFPPS and SfrJHAMT genes in FAW and likely in other insects (both pests and non-target organisms). Therefore, its potential for Integrated Pest Management should be further assessed.

We propose a cross-modal co-attention model for continuous emotion recognition using visual-audio-linguistic information. The model consists of four blocks. The visual, audio, and linguistic blocks are used to learn the spatial-temporal features of the multi-modal input. A co-attention block is designed to fuse the learned features with the multi-head co-attention mechanism. The visual encoding from the visual block is concatenated with the attention feature to emphasize the visual information. To make full use of the data and alleviate over-fitting, cross-validation is carried out on the training and validation set. The concordance correlation coefficient (CCC) centering is used to merge the results from each fold. The achieved CCC on the test set is $0.520$ for valence and $0.602$ for arousal, which significantly outperforms the baseline method with the corresponding CCC of 0.180 and 0.170 for valence and arousal, respectively. The code is available at https://github.com/sucv/ABAW3., Comment: 5 pages, 1 figure. arXiv admin note: substantial text overlap with arXiv:2107.01175

Limin Zhang,1 Yujia Liu,2 Shuai Zhao,1 Zhen Wang,1 Miaomiao Zhang,1 Su Zhang,1 Xinzhuo Wang,1 Shuang Zhang,1 Wenyan Zhang,1 Liying Hao,3 Guangyu Jiao1 1Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China; 2College of Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110032, People’s Republic of China; 3Department of Pharmaceutical Pharmacology and Toxicology, China Medical University, Shenyang, Liaoning, 110000, People’s Republic of ChinaCorrespondence: Guangyu Jiao, Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Sanhao Street, Shenyang, Liaoning, 110004, People’s Republic of China, Tel +8618940251105, Email jiao_gy@163.comPurpose: Chronic obstructive pulmonary disease (COPD)-related pulmonary hypertension (PH) is one of the most common comorbidities of COPD, and often leads to a worse prognosis. Although the estimated prevalence and risk factors of COPD-related PH have been widely reported, these results have not been well integrated. This study aimed to review the worldwide incidence and prevalence of COPD-related PH and explore possible factors affecting its prevalence.Patients and Methods: We searched four electronic databases (Web of Science, Embase, Cochrane, and MEDLINE) to identify all observational studies on the prevalence of COPD-related PH from database creation until July 20, 2021. Eligibility screening, quality assessment, and data extraction of the retrieved studies were independently conducted by two reviewers. Meta-analyses were performed to determine the prevalence of PH in the COPD population. Random-effects meta-regression model analyses were conducted to investigate the sources of heterogeneity.Results: Altogether, 38 articles were included in the meta-analyses. The pooled prevalence was 39.2% (95% CI: 34.0– 44.4, I2 = 97.6%) for

Feeding is essential for animal survival and reproduction and is regulated by both internal states and external stimuli. However, little is known about how internal states influence the perception of external sensory cues that regulate feeding behavior. Here, we investigated the neuronal and molecular mechanisms behind nutritional state-mediated regulation of gustatory perception in control of feeding behavior in the brown planthopper and Drosophila. We found that feeding increases the expression of the cholecystokinin-like peptide, sulfakinin (SK), and the activity of a set of SK-expressing neurons. Starvation elevates the transcription of the sugar receptor Gr64f and SK negatively regulates the expression of Gr64f in both insects. Interestingly, we found that one of the two known SK receptors, CCKLR-17D3, is expressed by some of Gr64f-expressing neurons in the proboscis and proleg tarsi. Thus, we have identified SK as a neuropeptide signal in a neuronal circuitry that responds to food intake, and regulates feeding behavior by diminishing gustatory receptor gene expression and activity of sweet sensing GRNs. Our findings demonstrate one nutritional state-dependent pathway that modulates sweet perception and thereby feeding behavior, but our experiments cannot exclude further parallel pathways. Importantly, we show that the underlying mechanisms are conserved in the two distantly related insect species.

Ke Zeng,1,&ast; Jia-Mo Zhang,2,&ast; Xiao-Bin Li,1 Sheng-Xian Peng,3 Su-Chuan Zhang,4 Wen-Xian Xie,5 Chun-Fang Xi,1 Cheng-Jian Cao6 1Department of Urology, First People’s Hospital of Zigong City, Zigong, People’s Republic of China; 2Department of Urology, YongChuan Hospital Chongqing Medical University, Chongqing, People’s Republic of China; 3Scientific Research Department, First People’s Hospital of Zigong City, Zigong, People’s Republic of China; 4Laboratory Department, First People’s Hospital of Zigong City, Zigong, People’s Republic of China; 5Department of Basic Medicine, Sichuan Vocational College of Health and Rehabilitation, Zigong, People’s Republic of China; 6Zigong Academy of Medical Sciences, First People’s Hospital of Zigong City, Zigong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cheng-Jian CaoZigong Academy of Medical Sciences, First People’s Hospital of Zigong City, Zigong, People’s Republic of ChinaEmail cccjj2011@163.comObjective: To analyze the bacterial biofilm (BF) formation in patients with malignancy undergoing double J stent indwelling and its influencing factors.Methods: A total of 167 patients with malignant tumors who received double J stent indwelling in the hospital from January 2018 to January 2021 were included in the study. The urine and double J stent samples were collected for bacterial identification and observed for BF formation on the surface of the urinary catheter under a scanning electron microscope (SEM). Univariate and multivariate logistic regression analyses were used to analyze the influencing factors of BF.Results: The BF formation rate was 34.73% (58/167). The BF formation rate of positive specimens cultured in urine and double J stent was significantly higher than that of negative ones (P< 0.05). Staphylococcus was the main BF bacteria in double J stent and urine culture specimens, followed by Enterococcus, Pseudomonas, Enterobacte

We propose an audio-visual spatial-temporal deep neural network with: (1) a visual block containing a pretrained 2D-CNN followed by a temporal convolutional network (TCN); (2) an aural block containing several parallel TCNs; and (3) a leader-follower attentive fusion block combining the audio-visual information. The TCN with large history coverage enables our model to exploit spatial-temporal information within a much larger window length (i.e., 300) than that from the baseline and state-of-the-art methods (i.e., 36 or 48). The fusion block emphasizes the visual modality while exploits the noisy aural modality using the inter-modality attention mechanism. To make full use of the data and alleviate over-fitting, cross-validation is carried out on the training and validation set. The concordance correlation coefficient (CCC) centering is used to merge the results from each fold. On the test (validation) set of the Aff-Wild2 database, the achieved CCC is 0.463 (0.469) for valence and 0.492 (0.649) for arousal, which significantly outperforms the baseline method with the corresponding CCC of 0.200 (0.210) and 0.190 (0.230) for valence and arousal, respectively. The code is available at https://github.com/sucv/ABAW2., Comment: 8 pages, 2 figures, 2 tables, accepted to the ICCV 2021: 2nd Workshop and Competition on Affective Behavior Analysis in-the-wild (ABAW2)

The high temporal resolution and the asymmetric spatial activations are essential attributes of electroencephalogram (EEG) underlying emotional processes in the brain. To learn the temporal dynamics and spatial asymmetry of EEG towards accurate and generalized emotion recognition, we propose TSception, a multi-scale convolutional neural network that can classify emotions from EEG. TSception consists of dynamic temporal, asymmetric spatial, and high-level fusion layers, which learn discriminative representations in the time and channel dimensions simultaneously. The dynamic temporal layer consists of multi-scale 1D convolutional kernels whose lengths are related to the sampling rate of EEG, which learns the dynamic temporal and frequency representations of EEG. The asymmetric spatial layer takes advantage of the asymmetric EEG patterns for emotion, learning the discriminative global and hemisphere representations. The learned spatial representations will be fused by a high-level fusion layer. Using more generalized cross-validation settings, the proposed method is evaluated on two publicly available datasets DEAP and MAHNOB-HCI. The performance of the proposed network is compared with prior reported methods such as SVM, KNN, FBFgMDM, FBTSC, Unsupervised learning, DeepConvNet, ShallowConvNet, and EEGNet. TSception achieves higher classification accuracies and F1 scores than other methods in most of the experiments. The codes are available at https://github.com/yi-ding-cs/TSception, Comment: Accepted as a regular paper in IEEE Transactions on Affective Computing. A version after proof-reading. Some typos in the Early Access version of IEEE Xplore are corrected

Poly(ionic liquid)s (PILs), as an innovative class of polyelectrolytes, are composed of polymeric backbones with IL species in each repeating unit. The combined merits of the polymers and ILs make them promising materials for composites in materials science. Particularly, the integration of PILs with functional substances (PIL composites) opens up a new dimension in utilizing ionic polymers by offering novel properties and improved functions, which impacts multiple subfields of our chemical society. This review summarizes recent developments of PIL composites with a special emphasis on the preparation techniques that are based on the intrinsic properties of the PILs and the synergistic effects between the PILs and substances of interest for diverse applications.

© 2020 Elsevier Ltd Antimony has attracted a substantial amount of attention and has been proven to be the most promising anode material for sodium-ion batteries (SIBs) due to its suitable sodium insertion plateaus and high theoretical storage capacity. However, the dramatic volume expansion (up to 390%) during sodiation/desodiation results in severe structural deterioration and rapid capacity decay. As a consequence, antimony anodes exhibit poor cycling stability. Herein, we report a binder-free Sb/NiSb alloy prepared by a controllable electrodeposition process. The inactive nickel provided both good conductivity and structural reinforcement to reduce the large volume expansion/contraction, which endowed the Sb/NiSb anode with excellent cycle stability (521 mAh∙g−1 upon 100 cycles) and rate performance (above 400 mAh∙g−1 at 2000 mA∙g−1) that were superior to those of the bare Sb anode. The excellent Na storage performance of the Sb/NiSb anode was attributed to the synergistic effect of its cauliflower-like structure and the alloying effect of the Sb/NiSb. The operando XRD results indicated that the reaction mechanism resembled that of analogous transition metal antimonides. In addition, a stable solid electrolyte interface (SEI) was observed with operando XRD and HR-TEM of the Sb/NiSb anode. The cost-effective preparation of Sb/NiSb composite anodes and their excellent electrochemical properties offer the potential to prepare a broad spectrum of binder-free metallic alloys (e.g., Bi and Sn) as high-performance anode materials for SIBs.

Exploration of metal clusters (MCs) adaptive to both aqueous and oil phases without disturbing their size is promising for a broad scope of applications. The state-of-the-art approach via ligandbinding may perturb MCs' size due to varied metal-ligand binding strength when shuttling between solvents of different polarity. Herein, we applied physical confinement of a series of small noble MCs (<1 nm) inside ionic organic cages (I-Cages), which by means of anion exchange enables reversible transfer of MCs between aqueous and hydrophobic solutions without varying their ultrasmall size. Moreover, the MCs@I-Cage hybrid serves as a recyclable, reaction-switchable catalyst featuring high activity in liquid-phase NH3BH3 (AB) hydrolysis reaction with a turnover frequency (TOF) of 115 min(-1).

Yanhong Shang,1,2,* Dexi Li,2,* Xinxin Shan,2 Stefan Schwarz,3 Su-Mei Zhang,2 Yu-Xia Chen,2 Wuqing Ouyang,1 Xiang-Dang Du21Department of Basic Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Shaanxi 712100, People’s Republic of China; 2Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, People’s Republic of China; 3Institute of Microbiology and Epizootics, Centre for Infection Medicine, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany*These authors contributed equally to this workBackground: The acquired optrA gene, which encodes a ribosomal protection protein of the ABC-F family, can confer cross-resistance to linezolid and florfenicol, posing a serious therapeutic challenge to both human and veterinary medicine.Purpose: The objective of this study was to investigate the two Enterococcus faecalis (E. faecalis) plasmids for their fine structure, their transferability and the presence of mobile antimicrobial resistance loci.Methods: To elucidate their fine structure, the two plasmids were completely sequenced and the sequences analysed. Besides conjugation experiments, inverse PCR assays were conducted to see whether minicircles are produced from the mobile antimicrobial resistance loci.Results: Two pheromone-responsive conjugative optrA-carrying plasmids from E. faecalis, pE211 and pE508 were identified, which can transfer with frequencies of 2.6 ×10−2 and 3.7 ×10−2 (transconjugant per donor), respectively. In both plasmids, optrA was located on the novel mobile optrA locus with different sizes (12,834 bp in pE211 and 7,561 bp in pE508, respectively), flanked by two copies of IS1216 genes in the same orientation. Inverse PCR revealed that circular forms can be generated, consisting of optrA and one copy of IS1216, indicating they are all active.

We propose two new double projection algorithms for solving the split feasibility problem (SFP). Different from the extragradient projection algorithms, the proposed algorithms do not require fixed stepsize and do not employ the same projection region at different projection steps. We adopt flexible rules for selecting the stepsize and the projection region. The proposed algorithms are shown to be convergent under certain assumptions. Numerical experiments show that the proposed methods appear to be more efficient than the relaxed- CQ algorithm.

Fashion is a unique domain for developing recommender systems (RS). Personalization is critical to fashion users. As a result, highly accurate recommendations are not sufficient unless they are also specific to users. Moreover, fashion data is characterized by a large majority of new users, so a recommendation strategy that performs well only for users with prior interaction history is a poor fit to the fashion problem. Critical to addressing these issues in fashion recommendation is an evaluation strategy that: 1) includes multiple metrics that are relevant to fashion, and 2) is performed within segments of users with different interaction histories. Here, we present our multifaceted offline strategy for evaluating fashion RS. Using our proposed evaluation methodology, we compare the performance of three different algorithms, a most popular (MP) items strategy, a collaborative filtering (CF) strategy, and a content-based (CB) strategy. We demonstrate that only by considering the performance of these algorithms across multiple metrics and user segments can we determine the extent to which each algorithm is likely to fulfill fashion users' needs.

The Cyber-Physical System (CPS) is considered to be the next generation of intelligent industrial automation systems that integrate computing, communication and control technologies. In CPS, the interoperability requirements between devices and processes are growing rapidly. However, the diversity and heterogeneity of technologies and standards between information technology (IT) and operational technology (OT) in industrial systems pose significant challenges. Service-Oriented Architecture (SOA) provides a software design pattern in which software components are connected only through messaging, which is consistent with the fundamentals of modularity and communication in distributed automation systems. SOA is considered to be a key technology for improving interoperability in next-generation industrial automation systems. This paper introduces the latest research advances in applying SOA paradigms to CPS to improve interoperability, including: Open Platform Communications Unified Architecture (OPC UA) and related extensions, implementing SOA at the manufacturing device level, integrating legacy systems in SOA-based automation systems, Plug-and-Play in SOA-based automation systems, dynamic configuration in SOA-based automation systems and the combination of SOA with Multi-Agent Systems and Evolvable Production Systems., Comment: 6 pages, 0 figures

Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis., National Institute of Child Health and Human Development (U.S.) (P01HD076892), National Institute of Child Health and Human Development (U.S.) (U54HD090255), National Institute of Child Health and Human Development (U.S.) (U54HD090256), National Science Foundation (U.S.). Division of Materials Research (DMR-1310266), National Science Foundation (U.S.). Division of Materials Research (DMR-1420570), National Institutes of Health (U.S.) (P01HL120839-03), National Institutes of Health (U.S.) (P01GM096971)

Roadway pavement surface distress information is essential for effective pavement asset management, and subsequently, transportation agencies at all levels dedicate a large amount of time and money to routinely collect data on pavement surface distress conditions as the core of their asset management programs. These data are used by these agencies to make maintenance and repair decisions. Current methods for pavement surface distress evaluation are time-consuming and expensive. Geospatial technologies provide new methods for evaluating pavement surface distress condition that can supplement or substitute for currently-adopted evaluation methods. However, few previous studies have explored the utility of geospatial technologies for pavement surface distress evaluation. The primary scope of this research is to evaluate the potential of three geospatial techniques to improve the efficiency of pavement surface distress evaluation, including empirical analysis of high-spatial resolution natural color digital aerial photography (HiSR-DAP), empirical analysis of hyper-spatial resolution natural color digital aerial photography (HySR-DAP), and inferential geospatial modeling based on traffic volume, environmental conditions, and topographic factors. Pavement surface distress rates estimated from the aforementioned geospatial technologies are validated against distress data manually collected using standard protocols. Research results reveal that straightforward analysis of the spectral response extracted from HiSR-DAP can permit assessment of overall pavement surface conditions. In addition, HySR-DAP acquired from S-UAS can provide accurate and reliable information to characterize detailed pavement surface distress conditions. Research results also show that overall pavement surface distress condition can be effectively estimated based on the extent of geospatial data and inferential modeling techniques. In the near term, these proposed methods could be used to rapidly a

The corticospinal tract (CST) is the most important motor system in humans, yet robust regeneration of this projection after spinal cord injury (SCI) has not been accomplished. In murine models of SCI, we report robust corticospinal axon regeneration, functional synapse formation and improved skilled forelimb function after grafting multipotent neural progenitor cells into sites of SCI. Corticospinal regeneration requires grafts to be driven toward caudalized (spinal cord), rather than rostralized, fates. Fully mature caudalized neural grafts also support corticospinal regeneration. Moreover, corticospinal axons can emerge from neural grafts and regenerate beyond the lesion, a process that is potentially related to the attenuation of the glial scar. Rat corticospinal axons also regenerate into human donor grafts of caudal spinal cord identity. Collectively, these findings indicate that spinal cord 'replacement' with homologous neural stem cells enables robust regeneration of the corticospinal projection within and beyond spinal cord lesion sites, achieving a major unmet goal of SCI research and offering new possibilities for clinical translation.

A fundamental process in construction cost estimation is the appropriate adjustment of costs to reflect project location. Unfortunately, location adjustment factors are not available for all locations. To overcome this lack of data, cost estimators in the United States often use adjustment factors from adjacent locations, referred to as the nearest neighbor (NN) method. However, these adjacent locations may not have similar economic conditions which limit the accuracy of the NN method. This research proposes a new method of using nighttime light satellite imagery (NLSI) to estimate location adjustment factors where they do not exist. The NLSI method for estimating location adjustment factors was evaluated against an established cost index database and results show that NLSI can be used to effectively estimate location adjustment factors. When compared with NN and other alternative location adjustment methods, the proposed NLSI method leads to a 25-40% reduction of the median absolute error. This work contributes to the body of knowledge by introducing a more accurate method for estimating location adjustment factors which can improve cost estimates for construction projects where location adjustment factors do not currently exist.

Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.

CH3NH3PbI3 is commonly used in perovskite solar cells due to its long diffusion length and good crystallinity. In this paper, in the one-step approach using CH3NH3I and PbCl2 for forming the perovskite, we present a new low temperature annealing approach of gradually increasing the temperature to fabricate perovskite films. Various temperatures and temperature ranges for the formation of perovskite films have been studied. Using the gradual annealing process, we can tune the amount of chlorine in the atomic ratio of chlorine/iodine from 1.2 to 4.0%. Meanwhile, the gradual annealing process influences the quality of the perovskite film and importantly the device performance. The results show that through the optimized process, the film quality is improved with high surface coverage and good photoluminescence and reproducibility. We find that a higher amount of chlorine in the perovskite film plays a positive role in the device performance in the approach for achieving a power conversion efficiency of 14.9% with no obvious hysteresis.

Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system.

Electron density profiles of the Venus' ionosphere are inverted from the Venus Express (VEX) one-way open-loop radio occultation experiments carried out by Shanghai 25 m antenna from November 2011 to January 2012 at solar maximum conditions and by New Norcia 35 m antenna from August 2006 to June 2008 at solar intermediate conditions. The electron density profile (from 110 km to 400 km) retrieved from the X-band egress observation at Shanghai station, shows a single peak near 147 km with a peak density of about $2 \times 10^4 \rm{cm}^{-3}$ at a solar zenith angle of 94$^{\circ}$. As a comparison, the VEX radio science (VeRa) observations at New Norcia station were also examined, including S-, X-band and dual-frequency data in the ingress mode. The results show that the electron density profiles retrieved from the S-band data are more analogous to the dual-frequency data in the profile shape, compared with the X-band data. Generally, the S-band results slightly underestimate the magnitude of the peak density, while the X-band results overestimate that. The discrepancy in the X-band profile is probably due to the relatively larger unmodeled orbital errors. It is also expected that the ionopause height is sensitive to the solar wind dynamical pressure in high and intermediate solar activities, usually in the range of 200 km - 1000 km on the dayside and much higher on the nightside. Structural variations ("bulges" and fluctuations) can be found in the electron density profiles in intermediate solar activity, which may be caused by the interaction of the solar wind with the ionosphere. Considerable ionizations can be observed in the Venus' nightside ionosphere, which are unexpected for the Martian nightside ionosphere in most cases., Comment: 12 pages (RAA manuscript style), 5 figures, 1 table. Accepted for publication in 2015 of RAA

Lin Wu, Wei Yang, Su-ning Zhang, Ji-bin Lu Department of Thoracic Surgery, Sheng Jing Hospital of China Medical University, Shenyang, People’s Republic of China Objective: Alpinetin is a novel flavonoid that has demonstrated potent antitumor activity in previous studies. However, the efficacy and mechanism of alpinetin in treating lung cancer have not been determined. Methods: We evaluated the impact of different doses and durations of alpinetin treatment on the cell proliferation, the apoptosis of lung cancer cells, as well as the drug-resistant lung cancer cells. Results: This study showed that the alpinetin inhibited the cell proliferation, enhanced the apoptosis, and inhibited the PI3K/Akt signaling in lung cancer cells. Moreover, alpinetin significantly increased the sensitivity of drug-resistant lung cancer cells to the chemotherapeutic effect of cis-diammined dichloridoplatium. Taken together, this study demonstrated that alpinetin significantly suppressed the development of human lung cancer possibly by influencing mitochondria and the PI3K/Akt signaling pathway and sensitized drug-resistant lung cancer cells. Conclusion: Alpinetin may be used as a potential compound for combinatorial therapy or as a complement to other chemotherapeutic agents when multiple lines of treatments have failed to reduce lung cancer. Keywords: alpinetin, cell proliferation and apoptosis, drug resistance reversal, PI3K/Akt, lung cancer

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is closely linked with autism. The genetic basis of FXS is an expansion of CGG repeats in the 5'-untranslated region of the FMR1 gene on the X chromosome leading to the loss of expression of the fragile X mental retardation protein (FMRP). The cause of FXS has been known for over 20 years, yet the full molecular and cellular consequences of this mutation remain unclear. Although mouse and fly models have provided significant understanding of this disorder and its effects on the central nervous system, insight from human studies is limited. We have created human induced pluripotent stem cell (iPSC) lines from fibroblasts obtained from individuals with FXS to enable in vitro modeling of the human disease. Three young boys with FXS who came from a well-characterized cohort representative of the range of affectedness typical for the syndrome were recruited to aid in linking cellular and behavioral phenotypes. The FMR1 mutation is preserved during the reprogramming of patient fibroblasts to iPSCs. Mosaicism of the CGG repeat length in one of the patient's fibroblasts allowed for the generation of isogenic lines with differing CGG repeat lengths from the same patient. FXS forebrain neurons were differentiated from these iPSCs and display defective neurite initiation and extension. These cells provide a well-characterized resource to examine potential neuronal deficits caused by FXS as well as the function of FMRP in human neurons.

The radio interferometric positioning system (RIPS) is a novel positioning solution used in wireless sensor networks. This letter explores the ranging accuracy of RIPS in two configurations. In the linear step-frequency (LSF) configuration, we derive the mean square error (MSE) of the maximum likelihood (ML) estimator. In the random step-frequency (RSF) configuration, we introduce average MSE to characterize the performance of the ML estimator. The simulation results fit well with theoretical analysis. It is revealed that RSF is superior to LSF in that the former is more robust in a jamming environment with similar ranging accuracy., Comment: 10 pages, 1 figure

It is a challenge to specify unambiguous distance (UD) in a phase-based ranging system with hopping frequencies (PRSHF). In this letter, we propose to characterize the UD in a PRSHF by the probability that it takes on its maximum value. We obtain a very simple and elegant expression of the probability with growth estimation techniques from analytic number theory. It is revealed that the UD in a PRSHF usually takes on the maximum value with as few as 10 frequencies in measurement, almost independent of the specific distribution of available bandwidth., Comment: 6 pages, 1 figure

This paper presents a preliminary design for a moving-target defense \201MTD\202 for computer networks to combat an attacker?s asymmetric advantage. The MTD system reasons over a set of abstract models that capture the network?s configuration and its operational and security goals to select adaptations that maintain the operational integrity of the network. The paper examines both a simple \201purely random\202 MTD system as well as an intelligent MTD system that uses attack indicators to augment adaptation selection. A set of simulation-based experiments show that such an MTD system may in fact be able to reduce an attacker?s success likelihood. These results are a preliminary step towards understanding and quantifying the impact of MTDs on computer networks., Presented the International Symposium on Resilient Cyber Systems (ISRCS) (1st) held in San Francisco, CA on 13-15 August 2013. U.S. Government or Federal Rights License

Infections with Streptococcus pyogenes exhibit a wide spectrum of infections ranging from mild pharyngitis to severe Streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most commonly associated with STSS. In the present study, we hypothesized that Rac1 signaling might regulate M1 protein-induced lung injury. We studied the effect of a Rac1 inhibitor (NSC23766) on M1 protein-provoked pulmonary injury. Male C57BL/6 mice received NSC23766 prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Quantitative RT-PCR was used to determine gene expression of CXC chemokines in alveolar macrophages. Treatment with NSC23766 decreased M1 protein-induced neutrophil infiltration, edema formation and tissue injury in the lung. M1 protein challenge markedly enhanced Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Inhibition of Rac1 activity had no effect on M1 protein-induced expression of Mac-1 on neutrophils. However, Rac1 inhibition markedly decreased M1 protein-evoked formation of CXC chemokines in the lung. Moreover, NSC23766 completely inhibited M1 protein-provoked gene expression of CXC chemokines in alveolar macrophages. We conclude that these novel results suggest that Rac1 signaling is a significant regulator of neutrophil infiltration and CXC chemokine production in the lung. Thus, targeting Rac1 activity might be a potent strategy to attenuate streptococcal M1 protein-triggered acute lung damage.

Dysfunction of the blood-brain barrier (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, whether this effect of MAT is through protecting the integrity and function of the BBB is not known. In the present study, we show that MAT treatment had a therapeutic effect comparable to dexamethasone (DEX) in EAE rats, with reduced Evans Blue extravasation, increased expression of collagen IV, the major component of the basement membrane, and the structure of tight junction (TJ) adaptor protein Zonula occludens-1 (ZO-1). Furthermore, MAT treatment attenuated expression of matrix metalloproteinase-9 and -2 (MMP-9/-2), while it increased the expression of tissue inhibitors of metalloproteinase-1 and -2 (TIMP-1/-2). Our findings demonstrate that MAT reduces BBB leakage by strengthening basement membrane, inhibiting activities of MMP-2 and -9, and upregulating their inhibitors. Taken together, our results identify a novel mechanism underlying the effect of MAT, a natural compound that could be a novel therapy for MS.

Sepsis is a major cause of mortality in intensive care units despite decades of scientific efforts. The lung is recognized as the most sensitive and critical organ affected by the hyper-inflammatory response in septic patients. Immune cell dysfunction develops in later phases of sepsis making patients susceptible to infections. The aim of this dissertation was to reveal pro- and anti-inflammatory mechanisms in abdominal sepsis induced by cecal ligation and puncture (CLP). It was found that immunoneutralization of LFA-1 or Mac-1 not only reduced neutrophil infiltration but also protected against sepsis-caused lung damage. We observed that HMG-CoA reductase inhibitor regulates pulmonary accumulation of neutrophils via antagonizing CD40 ligand secretion from platelets and via decreasing CXC chemokine formation in the lung. Moreover, HMG-CoA reductase inhibition maintained CD4 T-cell function in spleen by reducing apoptosis and by improving proliferation as well as by preserving the ability to produce IFN-γ in the spleen. Moreover, inhibition of HMG-CoA reductase decreased sepsis-induced generation of regulatory T-cells. HMG-CoA reductase inhibitor abolished CLP-evoked increase in the plasma levels of HMGB1 and IL-6. In addition, it was noted that NFAT was activated after induction of sepsis, which was found to regulate pulmonary neutrophil recruitment and tissue damage, systemic inflammation, as well as T-cell dysfunction in abdominal sepsis. Thus, these results identify adhesive and signaling mechanisms, which are of particular importance in modulating septic lung injury and immunosuppression. Data from this thesis may pave the way for developing more specific and effective therapies for patients with abdominal sepsis.

Wen-Hong Xu,1 Min Han,2 Qi Dong,3 Zhi-Xuan Fu,3 Yuan-Yuan Diao,2 Hai Liu,3 Jing Xu,3 Hong-Liang Jiang,4 Su-Zhan Zhang,3 Shu Zheng,3 Jian-Qing Gao,2 Qi-Chun Wei11Department of Radiation Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 2Institute of Pharmaceutics, College of Pharmaceutical Sciences, 3Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, 4Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, ChinaBackground: The purpose of this study is to evaluate the efficacy of composite doxorubicin-loaded micelles for enhancing doxorubicin radiosensitivity in multicellular spheroids from a non-small cell lung cancer cell line.Methods: A novel composite doxorubicin-loaded micelle consisting of polyethylene glycol-polycaprolactone/Pluronic P105 was developed, and carrier-mediated doxorubicin accumulation and release from multicellular spheroids was evaluated. We used confocal laser scanning microscopy and flow cytometry to study the accumulation and efflux of doxorubicin from A549 multicellular spheroids. Doxorubicin radiosensitization and the combined effects of irradiation and doxorubicin on cell migration and proliferation were compared for the different doxorubicin delivery systems.Results: Confocal laser scanning microscopy and quantitative flow cytometry studies both verified that, for equivalent doxorubicin concentrations, composite doxorubicin-loaded micelles significantly enhanced cellular doxorubicin accumulation and inhibited doxorubicin release. Colony-forming assays demonstrated that composite doxorubicin-loaded micelles are radiosensitive, as shown by significantly reduced survival of cells treated by radiation + composite micelles compared with those treated with radiation + free doxorubicin or radiation alone. The multicellular spheroid migration area and growth ability verifie

Yong-Tai Zhang, Zhe-Bin Huang, Su-Juan Zhang, Ji-Hui Zhao, Zhi Wang, Ying Liu, Nian-Ping FengDepartment of Pharmaceutics, Shanghai University of Traditional Chinese Medicine, Shanghai, The People's Republic of ChinaObjective: To investigate the cellular uptake of evodiamine and rutaecarpine in a microemulsion in comparison with aqueous suspensions and tinctures.Materials and methods: A microemulsion was prepared using the dropwise addition method. Mouse skin fibroblasts were cultured in vitro to investigate the optimal conditions for evodiamine and rutaecarpine uptake with different drug concentrations and administration times. Under optimal conditions, the cellular uptake of microemulsified drugs was assayed and compared to tinctures and aqueous suspensions. Rhodamine B labeling and laser scanning confocal microscopy (LSCM) were used to explore the distribution of fluorochrome transferred with the microemulsion in fibroblasts. Cellular morphology was also investigated, using optical microscopy to evaluate microemulsion-induced cellular toxicity.Results: The maximum cellular drug uptake amounts were obtained with a 20% concentration (v/v) of microemulsion and an 8 hour administration time. Drug uptake by mouse skin fibroblasts was lowest when the drugs were loaded in microemulsion. After incubation with rhodamine B-labeled microemulsion for 8 hours, the highest fluorescence intensity was achieved, and the fluorochrome was primarily distributed in the cytochylema. No obvious cellular morphologic changes were observed with the administration of either the microemulsion or the aqueous suspension; for the tincture group, however, massive cellular necrocytosis was observed.Conclusion: The lower cellular uptake with microemulsion may be due to the fact that most of the drug loaded in the microemulsion vehicle was transported via the intercellular space, while a small quantity of free drug (released from the vehicle) was ingested through transmembrane transport. Mo

Streptococcal toxic shock syndrome is frequently caused by Streptococcus pyogenes of the M1 serotype. The aim of this study was to determine the role of Ras-homologous (Rho)-kinase signaling in M1 protein-provoked lung damage. Male C57BL/6 mice received the Rho-kinase-specific inhibitor Y-27632 before administration of M1 protein. Edema, neutrophil accumulation and CXC chemokines were quantified in the lung 4 h after M1 protein challenge. Flow cytometry was used to determine Mac-1 expression. Quantitative RT-PCR was used to determine gene expression of CXC chemokine mRNA in alveolar macrophages. M1 protein increased neutrophil accumulation, edema and CXC chemokine formation in the lung as well as enhanced Mac-1 expression on neutrophils. Inhibition of Rho-kinase signaling significantly reduced M1 protein-provoked neutrophil accumulation and edema formation in the lung. M1 protein-triggered pulmonary production of CXC chemokine and gene expression of CXC chemokines in alveolar macrophages was decreased by Y-27632. Moreover, Rho-kinase inhibition attenuated M1 protein-induced Mac-1 expression on neutrophils. We conclude that Rho-kinase-dependent neutrophil infiltration controls pulmonary tissue damage in response to streptococcal M1 protein and that Rho-kinase signaling regulates M1 protein-induced lung recruitment of neutrophils via the formation of CXC chemokines and Mac-1 expression.

in UndeterminedOBJECTIVE: Platelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.METHODS: Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to determine expression of Mac-1 on neutrophils and CD40L on platelets. Intravital fluorescence microscopy was used to analyze leukocyte-endothelial cell interactions in the pulmonary microcirculation.RESULTS: The MMP inhibitor reduced sepsis-induced release of CD40L and maintained normal levels of CD40L on platelets. Inhibition of MMP decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration in the lung. Intravital fluorescence microscopy revealed that the MMP inhibitor attenuated leukocyte adhesion in venules whereas capillary trapping of leukocytes was not affected by MMP inhibition.CONCLUSIONS: We describe a novel role of metalloproteinases in regulating platelet-dependent activation and infiltration of neutrophils in septic lung injury which might be related to controlling CD40L shedding from platelets. We conclude that targeting metalloproteinases may be a useful strategy for limiting acute lung injury in abdominal sepsis.

M1 serotype of Streptococcus pyogenes plays an important role in streptococcal toxic shock syndrome. Simvastatin, a HMG-CoA reductase inhibitor, has been shown to inhibit streptococcal M1 protein-induced acute lung damage although downstream mechanisms remain elusive. Protein isoprenylation, such as farnesylation and geranylgeranylation, has been suggested to regulate anti-inflammatory effects exerted by statins. Herein, we examined the effect of a farnesyltransferase inhibitor (FTI-277) on M1 protein-triggered lung inflammation. Male C57BL/6 mice were treated with FTI-277 prior to M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Flow cytometry was used to determine Mac-1 expression on neutrophils. Gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative RT-PCR. We found that administration of FTI-277 markedly decreased M1 protein-induced accumulation of neutrophils, edema formation and tissue damage in the lung. Notably, inhibition of farnesyltransferase abolished M1 protein-evoked production of CXC chemokines in the lung and gene expression of CXC chemokines in alveolar macrophages. Moreover, FTI-277 completely inhibited chemokine-induced neutrophil migration in vitro. However, farnesyltransferase inhibition had no effect on M1 protein-induced expression of Mac-1 on neutrophils. Our findings suggest that farnesyltransferase is a potent regulator of CXC chemokine formation in alveolar macrophages and that inhibition of farnesyltransferase not only reduces neutrophil recruitment but also attenuates acute lung injury provoked by streptococcal M1 protein. We conclude that farnesyltransferase activity is a potential target in order to attenuate acute lung damage in streptococcal infections.

Quantifying security risk is an important and yet difficult task in enterprise network risk management, critical for proactive mission assurance. Even though metrics exist for individual vulnerabilities, there is currently no standard way of aggregating such metrics. We developed a quantitative model that can be used to aggregate vulnerability metrics in an enterprise network, with a sound computation model. Our model produces quantitative metrics that measure the likelihood that breaches can occur within a given network configuration, taking into consideration the effects of all possible interplays between vulnerabilities. In order to validate the effectiveness (scalability and accuracy) of this approach to realistic networks, we present the empirical study results of the approach on a number of system configurations. We use a real network as the test bed to demonstrate the utility of the approach, show that the sound computation model is crucial for interpreting the metric result., In The 2011 International Conference on Security and Management (SAM'11), special track on Mission Assurance and Critical Infrastructure Protection (STMACIP'11), Las Vegas, CA, July 2011. U.S. Government or Federal Rights License

Yong-Tai Zhang, Ji-Hui Zhao, Su-Juan Zhang, Yang-Zi Zhong, Zhi Wang, Ying Liu, Feng Shi, Nian-Ping FengSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaObjective: The purpose of this study was to improve skin permeation of evodiamine and rutaecarpine for transdermal delivery with microemulsion as vehicle and investigate real-time cutaneous absorption of the drugs via in vivo microdialysis.Methods: Pseudoternary phase diagrams were constructed to evaluate microemulsion regions with various surfactants and cosurfactants. Nine formulations of oil in water microemulsions were selected as vehicles for assessing skin permeation of evodiamine and rutaecarpine in ex vivo transdermal experiments. With a microdialysis hollow fiber membrane implanted in the skin beneath the site of topical drug administration, dialysis sampling was maintained for 10 hours and the samples were detected directly by high performance liquid chromatography. Real-time concentrations of the drugs in rat skin were investigated and compared with those of conventional formulations, such as ointment and tincture. Furthermore, the drugs were applied to various regions of the skin using microemulsion as vehicle.Results: In ex vivo transdermal experiments, cutaneous fluxes of evodiamine and rutaecarpine microemulsions were 2.55-fold to 11.36-fold and 1.17-fold to 6.33-fold higher, respectively, than those of aqueous suspensions. Different drug loadings, microemulsion water content, and transdermal enhancers markedly influenced the permeation of evodiamine and rutaecarpine. In microemulsion application with in vivo microdialysis, the maximum concentration of the drugs (evodiamine: 18.23 ± 1.54 ng/mL; rutaecarpine: 16.04 ± 0.69 ng/mL) were the highest, and the area under the curve0–t of evodiamine and rutaecarpine was 1.52-fold and 2.27-fold higher than ointment and 3.06-fold and 4.23-fold higher than tinctur

In the construction industry, cost estimates are fundamental to the success of a construction project. Location factors are commonly used to adjust cost estimates by project location. However, not all locations have corresponding factors. Nowadays, the construction industry has employed a simple, proximity-based location factor interpolation method which is widely accepted and used. Under this method, for a location without adjustment factor, the factor of the geographically “nearest neighbor” will be selected. Although this approach was statistically substantiated by former research, it was still not sufficiently supported, considering that only one year’s RSMeans City Cost Index (CCI) dataset was tested. With the help of the Global Moran’s I Test in ArcGIS software, this study evaluated the spatial autocorrelation of the changes in RSMeans CCI value from year 2005 to 2009. The evaluation results substantially supported the validity of the proximity-based location factor interpolation method. In addition, evaluation of current and alternative surface interpolation methods reveals that condition nearest neighbor (CNN) method is the best rough surface interpolation method while inverse distance weighted (IDW) method is the best smooth surface interpolation method. Moreover, the Area Cost Factor (ACF) of the Department of Defense (DoD) was incorporated in this research to cross-validate all evaluations. This research is an initial step for identifying surface interpolation methods to develop spatial prediction models for location adjustment based upon several datasets, including construction cost data and socio-economical data.

Skeletal muscles have the potential to regenerate by activation of quiescent satellite cells, however, the molecular signature that governs satellite cells during muscle regeneration is not well defined. Myosin light chains (Myls) are sarcomere-related proteins as traditional regulator of muscle contraction. In this report, we studied the possible role of Myl in the proliferation of skeletal muscle-derived myoblasts. Compared to diaphragm-derived myoblasts, the extraocular muscle-derived myoblasts with lower levels of Myl proliferated faster, maintained a longer proliferation phase, and formed more final myotubes. It was found that blockading Myl with anti-Myl antibody or knockdown of Myll by siRNA targeted against Myll could enhance the myoblast proliferation and delay the differentiation of myoblasts. Our results suggested that Myl, likely Myll, can negatively affect myoblast proliferation by facilitating myoblast withdrawal from cell cycle and differentiation.

Missense mutations and extra copies of the α-Synuclein gene result in Parkinson disease (PD). Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of α-synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type α-synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of α-synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, α-synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, α-synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that α-synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of α-synuclein-related pathologies and allow therapeutic drug screening