bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic engineering of a temperate phage-based delivery system for CRISPR/Cas9 antimicrobials against Staphylococcus aureus
Authors: Park Joo Youn , Moon Bo Youn , Park Juw Won , Thornton Justin A. , Park Yong Ho , Seo Keun Seok 
Published: March 2017

AbstractDiscovery of clustered, regularly interspaced, short palindromic repeats and the Cas9 RNA-guided nuclease (CRISPR/Cas9) system provides a new opportunity to create programmable gene-specific antimicrobials that are far less likely to drive resistance than conventional antibiotics. However, the practical therapeutic use of CRISPR/Cas9 is still questionable due to current shortcomings in phage-based delivery systems such as inefficient delivery, narrow host range, and potential transfer of virulence genes by generalized transduction. In this study, we demonstrate genetic engineering strategies to overcome these shortcomings by integrating CRISPR/Cas9 system into a temperate phage genome, removing major virulence genes from the host chromosome, and expanding host specificity of the phage by complementing tail fiber protein. This significantly improved the efficacy and safety of CRISPR/Cas9 antimicrobials to therapeutic levels in both in vitro and in vivo assays. The genetic engineering tools and resources established in this study are expected to provide an efficacious and safe CRISPR/Cas9 antimicrobial, broadly applicable to Staphylococcus aureus.
Tumor Wide Horizontal Invasion Predicts Local Recurrence for Scrotal Extramammary Paget’s Disease
Authors: Wang Lujia , Feng Chenchen , Zhou Minwei , Zhou Zhongwen , Ding Guanxiong , Gao Peng , Ding Qiang , Wu Zhong 
Published: March 2017

AbstractExtramammary Paget’s disease (EMPD) is a rare malignancy, and little was known about its prognostic factors and optimal treatment. In the current study, we aimed to discuss clinical and pathological features of scrotal EMPD and determine the prognostic factors for cancer-specific survival and local recurrence. A total of 206 patients with scrotal EMPD lesions surgically treated at our institute were studied. All clinical and pathological data were reviewed. Immunohistochemical staining of TP53 and Ki67 was examined as well. At the last follow-up, 175 patients (84.95%) were alive. Twelve patients (5.83%) had died of the disease due to distant metastases. Fifteen patients (7.28%) developed local recurrences of scrotal EMPD. Ki67 expression was significantly elevated in patients with wide horizontal invasion (P = 0.003). In univariate analysis, high invasion level, presence of nodule, presence of lymphovascular invasion, adnexa invasion, lymph node metastasis and high p53 expression were significant factors for poor cancer-specific survival. In multivariate analysis, high p53 expression was significantly correlated with poor cancer-specific survival. Wide horizontal invasion was independently correlated with local recurrence-free survival of scrotal EMPD. In conclusion, wide horizontal invasion is an independent risk factor for local recurrence-free survival in the patients with scrotal EMPD.
Imaging tissue-mimic with light sheet microscopy: A comparative guideline
Authors: Andilla Jordi , Jorand Raphael , Olarte Omar E. , Dufour Alexandre C. , Cazales Martine , Montagner Yoann L. E. , Ceolato Romain , Riviere Nicolas , Olivo-Marin Jean-Christophe , Loza-Alvarez Pablo , Lorenzo Corinne 
Published: March 2017

AbstractTissue mimics (TMs) on the scale of several hundred microns provide a beneficial cell culture configuration for in vitro engineered tissue and are currently under the spotlight in tissue engineering and regenerative medicine. Due to the cell density and size, TMs are fairly inaccessible to optical observation and imaging within these samples remains challenging. Light Sheet Fluorescence Microscopy (LSFM)- an emerging and attractive technique for 3D optical sectioning of large samples- appears to be a particularly well-suited approach to deal with them. In this work, we compared the effectiveness of different light sheet illumination modalities reported in the literature to improve resolution and/or light exposure for complex 3D samples. In order to provide an acute and fair comparative assessment, we also developed a systematic, computerized benchmarking method. The outcomes of our experiment provide meaningful information for valid comparisons and arises the main differences between the modalities when imaging different types of TMs.
Sweet taste in apple: the role of sorbitol, individual sugars, organic acids and volatile compounds
Authors: Aprea Eugenio , Charles Mathilde , Endrizzi Isabella , Laura Corollaro Maria , Betta Emanuela , Biasioli Franco , Gasperi Flavia 
Published: March 2017

AbstractSweetness is one of the main drivers of consumer preference, and thus is given high priority in apple breeding programmes. Due to the complexity of sweetness evaluation, soluble solid content (SSC) is commonly used as an estimation of this trait. Nevertheless, it has been demonstrated that SSC and sweet taste are poorly correlated. Though individual sugar content may vary greatly between and within apple cultivars, no previous study has tried to investigate the relationship between the amount of individual sugars, or ratios of these, and apple sweetness. In this work, we quantified the major sugars (sucrose, glucose, fructose, xylose) and sorbitol and explored their influence on perceived sweetness in apple; we also related this to malic acid content, SSC and volatile compounds. Our data confirmed that the correlation between sweetness and SSC is weak. We found that sorbitol content correlates (similarly to SSC) with perceived sweetness better than any other single sugar or total sugar content. The single sugars show no differentiable importance in determining apple sweetness. Our predictive model based on partial least squares regression shows that after sorbitol and SSC, the most important contribution to apple sweetness is provided by several volatile compounds, mainly esters and farnesene.
Optimising reliability of mouse performance in behavioural testing: the major role of non-aversive handling
Authors: Gouveia Kelly , Hurst Jane L. 
Published: March 2017

AbstractHandling laboratory animals during test procedures is an important source of stress that may impair reliability of test responses. Picking up mice by the tail is aversive, stimulating stress and anxiety. Responses among anxious animals can be confounded further by neophobia towards novel test environments and avoidance of test stimuli in open areas. However, handling stress can be reduced substantially by using a handling tunnel, or cupping mice without restraint on the open hand. Here we establish whether non-aversive handling, brief prior familiarisation with the test arena and alternative stimulus placement could significantly improve performance of mice in behavioural tests. We use a simple habituation-dishabituation paradigm in which animals must discriminate between two urine stimuli in successive trials, a task that mice can easily perform. Tail handled mice showed little willingness to explore and investigate test stimuli, leading to poor test performance that was only slightly improved by prior familiarisation. By contrast, those handled by tunnel explored readily and showed robust responses to test stimuli regardless of prior familiarisation or stimulus location, though responses were more variable for cup handling. Our study shows that non-aversive tunnel handling can substantially improve mouse performance in behavioural tests compared to traditional tail handling.
An Expanded Multi-scale Monte Carlo Simulation Method for Personalized Radiobiological Effect Estimation in Radiotherapy: a feasibility study
Authors: Zhang Ying , Feng Yuanming , Wang Wei , Yang Chengwen , Wang Ping 
Published: March 2017

AbstractA novel and versatile “bottom-up” approach is developed to estimate the radiobiological effect of clinic radiotherapy. The model consists of multi-scale Monte Carlo simulations from organ to cell levels. At cellular level, accumulated damages are computed using a spectrum-based accumulation algorithm and predefined cellular damage database. The damage repair mechanism is modeled by an expanded reaction-rate two-lesion kinetic model, which were calibrated through replicating a radiobiological experiment. Multi-scale modeling is then performed on a lung cancer patient under conventional fractionated irradiation. The cell killing effects of two representative voxels (isocenter and peripheral voxel of the tumor) are computed and compared. At microscopic level, the nucleus dose and damage yields vary among all nucleuses within the voxels. Slightly larger percentage of cDSB yield is observed for the peripheral voxel (55.0%) compared to the isocenter one (52.5%). For isocenter voxel, survival fraction increase monotonically at reduced oxygen environment. Under an extreme anoxic condition (0.001%), survival fraction is calculated to be 80% and the hypoxia reduction factor reaches a maximum value of 2.24. In conclusion, with biological-related variations, the proposed multi-scale approach is more versatile than the existing approaches for evaluating personalized radiobiological effects in radiotherapy.
Distribution of Bathyarchaeota Communities Across Different Terrestrial Settings and Their Potential Ecological Functions
Authors: Xiang Xing , Wang Ruicheng , Wang Hongmei , Gong Linfeng , Man Baiying , Xu Ying 
Published: March 2017

AbstractHigh abundance and widespread distribution of the archaeal phylum Bathyarchaeota in marine environment have been recognized recently, but knowledge about Bathyarchaeota in terrestrial settings and their correlation with environmental parameters is fairly limited. Here we reported the abundance of Bathyarchaeota members across different ecosystems and their correlation with environmental factors by constructing 16S rRNA clone libraries of peat from the Dajiuhu Peatland, coupling with bioinformatics analysis of 16S rRNA data available to date in NCBI database. In total, 1456 Bathyarchaeota sequences from 28 sites were subjected to UniFrac analysis based on phylogenetic distance and multivariate regression tree analysis of taxonomy. Both phylogenetic and taxon-based approaches showed that salinity, total organic carbon and temperature significantly influenced the distribution of Bathyarchaeota across different terrestrial habitats. By applying the ecological concept of ‘indicator species’, we identify 9 indicator groups among the 6 habitats with the most in the estuary sediments. Network analysis showed that members of Bathyarchaeota formed the “backbone” of archaeal community and often co-occurred with Methanomicrobia. These results suggest that Bathyarchaeota may play an important ecological role within archaeal communities via a potential symbiotic association with Methanomicrobia. Our results shed light on understanding of the biogeography, potential functions of Bathyarchaeota and environment conditions that influence Bathyarchaea distribution in terrestrial settings.
Signalling mechanisms mediating Zn2+-induced TRPM2 channel activation and cell death in microglial cells
Authors: Mortadza Sharifah Syed , Sim Joan A. , Stacey Martin , Jiang Lin-Hua 
Published: March 2017

AbstractExcessive Zn2+ causes brain damage via promoting ROS generation. Here we investigated the role of ROS-sensitive TRPM2 channel in H2O2/Zn2+-induced Ca2+ signalling and cell death in microglial cells. H2O2/Zn2+ induced concentration-dependent increases in cytosolic Ca2+ concentration ([Ca2+]c), which was inhibited by PJ34, a PARP inhibitor, and abolished by TRPM2 knockout (TRPM2-KO). Pathological concentrations of H2O2/Zn2+ induced substantial cell death that was inhibited by PJ34 and DPQ, PARP inhibitors, 2-APB, a TRPM2 channel inhibitor, and prevented by TRPM2-KO. Further analysis indicate that Zn2+ induced ROS production, PARP-1 stimulation, increase in the [Ca2+]c and cell death, all of which were suppressed by chelerythrine, a protein kinase C inhibitor, DPI, a NADPH-dependent oxidase (NOX) inhibitor, GKT137831, a NOX1/4 inhibitor, and Phox-I2, a NOX2 inhibitor. Furthermore, Zn2+-induced PARP-1 stimulation, increase in the [Ca2+]c and cell death were inhibited by PF431396, a Ca2+-sensitive PYK2 inhibitor, and U0126, a MEK/ERK inhibitor. Taken together, our study shows PKC/NOX-mediated ROS generation and PARP-1 activation as an important mechanism in Zn2+-induced TRPM2 channel activation and, TRPM2-mediated increase in the [Ca2+]c to trigger the PYK2/MEK/ERK signalling pathway as a positive feedback mechanism that amplifies the TRPM2 channel activation. Activation of these TRPM2-depenent signalling mechanisms ultimately drives Zn2+-induced Ca2+ overloading and cell death.
Therapy targeted to the metastatic niche is effective in a model of stage IV breast cancer
Authors: Yoo Byunghee , Kavishwar Amol , Wang Ping , Ross Alana , Pantazopoulos Pamela , Dudley Michael , Moore Anna , Medarova Zdravka 
Published: March 2017

AbstractTreatment of stage IV metastatic breast cancer patients is limited to palliative options and represents an unmet clinical need. Here, we demonstrate that pharmacological inhibition of miRNA-10b - a master regulator of metastatic cell viability – leads to elimination of distant metastases in a mouse model of metastatic breast cancer. This was achieved using the miRNA-10b inhibitory nanodrug, MN-anti-miR10b, which consists of magnetic nanoparticles, conjugated to LNA-based miR-10b antagomirs. Intravenous injection of MN-anti-miR10b into mice bearing lung, bone, and brain metastases from breast cancer resulted in selective accumulation of the nanodrug in metastatic tumor cells. Weekly treatments of mice with MN-anti-miR-10b and low-dose doxorubicin resulted in complete regression of pre-existing distant metastases in 65% of the animals and a significant reduction in cancer mortality. These observations were supported by dramatic reduction in proliferation and increase in apoptosis in metastatic sites. On a molecular level, we observed a significant increase in the expression of HOXD10, which is a known target of miRNA-10b. These results represent first steps into the uncharted territory of therapy targeted to the metastatic niche.
Squamous epitheliotropism of Enterovirus A71 in human epidermis and oral mucosa
Authors: Phyu Win Kyaw , Ong Kien Chai , Kong Chee Kwan , Alizan Abdul Khalil , Ramanujam Tindivanam Muthurangam , Wong Kum Thong 
Published: March 2017

AbstractHand-foot-and-mouth disease is a self-limiting paediatric infectious disease commonly caused by Enterovirus A71 (Genus: Enterovirus, Family: Picornaviridae). Typical lesions in and around the hands, feet, oral cavity and other places may rarely be complicated by acute flaccid paralysis and acute encephalomyelitis. Although virus is readily cultured from skin vesicles and oral secretions, the cellular target/s of Enterovirus A71 in human skin and oral mucosa are unknown. In Enterovirus A71-infected human skin and oral mucosa organotypic cultures derived from the prepuce and lip biopsies, focal viral antigens and viral RNA were localized to cytoplasm of epidermal and mucosal squamous cells as early as 2 days post-infection. Viral antigens/RNA were associated with cytoplasmic vacuolation and cellular necrosis. Infected primary prepuce epidermal keratinocyte cultures showed cytopathic effects with concomitant detection of viral antigens from 2 days post-infection. Supernatant and/or tissue homogenates from prepuce skin organotypic cultures and primary prepuce keratinocyte cultures showed viral titres consistent with active viral replication. Our data strongly support Enterovirus A71 squamous epitheliotropism in the human epidermis and oral mucosa, and suggest that these organs are important primary and/or secondary viral replication sites that contribute significantly to oral and cutaneous viral shedding resulting in person-to-person transmission, and viraemia, which could lead to neuroinvasion.
The evolutionary origin of jaw yaw in mammals
Authors: Grossnickle David M. 
Published: March 2017

AbstractTheria comprises all but three living mammalian genera and is one of the most ecologically pervasive clades on Earth. Yet, the origin and early history of therians and their close relatives (i.e., cladotherians) remains surprisingly enigmatic. A critical biological function that can be compared among early mammal groups is mastication. Morphometrics and modeling analyses of the jaws of Mesozoic mammals indicate that cladotherians evolved musculoskeletal anatomies that increase mechanical advantage during jaw rotation around a dorsoventrally-oriented axis (i.e., yaw) while decreasing the mechanical advantage of jaw rotation around a mediolaterally-oriented axis (i.e., pitch). These changes parallel molar transformations in early cladotherians that indicate their chewing cycles included significant transverse movement, likely produced via yaw rotation. Thus, I hypothesize that cladotherian molar morphologies and musculoskeletal jaw anatomies evolved concurrently with increased yaw rotation of the jaw during chewing cycles. The increased transverse movement resulting from yaw rotation may have been a crucial evolutionary prerequisite for the functionally versatile tribosphenic molar morphology, which underlies the molars of all therians and is retained by many extant clades.
Flexible frequency selective metamaterials for microwave applications
Authors: Gao Bo , Yuen Matthew M. F , Ye Terry Tao 
Published: March 2017

AbstractMetamaterials have attracted more and more research attentions recently. Metamaterials for electromagnetic applications consist of sub-wavelength structures designed to exhibit particular responses to an incident EM (electromagnetic) wave. Traditional EM (electromagnetic) metamaterial is constructed from thick and rigid structures, with the form-factor suitable for applications only in higher frequencies (above GHz) in microwave band. In this paper, we developed a thin and flexible metamaterial structure with small-scale unit cell that gives EM metamaterials far greater flexibility in numerous applications. By incorporating ferrite materials, the thickness and size of the unit cell of metamaterials have been effectively scaled down. The design, mechanism and development of flexible ferrite loaded metamaterials for microwave applications is described, with simulation as well as measurements. Experiments show that the ferrite film with permeability of 10 could reduce the resonant frequency. The thickness of the final metamaterials is only 0.3mm. This type of ferrite loaded metamaterials offers opportunities for various sub-GHz microwave applications, such as cloaks, absorbers, and frequency selective surfaces.
Erythrocyte glutathione levels as long-term predictor of transition to psychosis
Authors: Lavoie S , Berger M , Schlögelhofer M , Schäfer M R , Rice S , Kim S-W , Hesse J , McGorry P D , Smesny S , Amminger G P 
Published: March 2017

AbstractA high proportion of individuals deemed at elevated risk for psychosis will actually never progress to develop the illness. Pharmaceutical intervention may not be necessary in these cases, and may in fact be damaging depending on the invasiveness of the treatment strategy. This highlights the need for biomarkers that are better able to reliably differentiate between at-risk individuals who will subsequently transition to psychosis and those who will not. Low glutathione (GSH) levels have been observed in schizophrenia and in patients with first-episode psychosis. The aim of this study was to determine the predictive value of erythrocyte GSH levels on the transition to psychosis in individuals at risk of developing the illness. Erythrocyte GSH levels were measured in 36 at-risk individuals, 15 of whom had transitioned to psychosis at the 7-year follow-up. Univariate Cox regression analysis showed that transition to psychosis at the 7-year time point was significantly associated with low GSH levels at baseline. The area under the receiving operating characteristic curve was 0.819, indicating that GSH can be considered a good predictor of outcome. Although these results need to be replicated, adding the criterion ‘low erythrocyte GSH’ to the set of criteria used to identify individuals at risk of psychosis may be indicated.
Experimental medication treatment approaches for depression
Authors: Ionescu D F , Papakostas G I 
Published: March 2017

AbstractDepression is one of the most common psychiatric conditions. Symptoms can lead to significant disability, which result in impairments in overall quality of life. Though there are many approved antidepressant treatments for depression—including selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors—about a third of patients do not respond to these medications. Therefore, it is imperative for drug discovery to continue towards the development of novel and rapidly acting compounds, especially for patients with treatment-resistant depression. After a brief review of the efficacy of approved antidepressant therapies, we will discuss experimental medication treatments for depression. Specifically, we examine novel medications that are thought to primarily modulate the glutamatergic, cholinergic and opioid systems to achieve antidepressant efficacy. We also give examples of anti-inflammatories, neurokinin-1 modulators, vasopressin antagonists and neurogenesis enhancers that may have a therapeutic role in treatment-resistant depression. The current pipeline of antidepressant treatments is shifting towards medications with novel mechanisms, which may lead to important, life-changing discoveries for patients with severe disease.
Citalopram amplifies the influence of living conditions on mood in depressed patients enrolled in the STAR*D study
Authors: Chiarotti F , Viglione A , Giuliani A , Branchi I 
Published: March 2017

AbstractSelective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed antidepressant drugs, have a variable and incomplete efficacy. In order to better understand SSRI action, we explored the hypothesis that SSRIs do not affect mood per se but amplify the influence of the living conditions on mood. To this aim, we exploited the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) data set, selected a subpopulation of 591 patients with an overlapping clinical history and analyzed treatment outcome according to dosage −20 or 40 mg per day of citalopram. We found that sociodemographic characteristics affected treatment response in the same direction in the two dose groups, but these effects reached statistical significance only in the 40 mg per day dose group. In the latter, higher improvement rate was associated with having a working employment status (P=0.0219), longer education (P=0.0053), high income (P=0.01) or a private insurance (P=0.0031), and the higher remission rate was associated with having a working employment status (P=0.0326) or longer education (P=0.0484). Moreover, the magnitude of the effect of the sociodemographic characteristics on mood, measured as the percent of patients showing a positive outcome when exposed to favorable living conditions, was much greater—up to 37-fold—in the 40 compared to the 20 mg per day dose group. Overall, our results indicate that citalopram amplifies the influence of the living conditions on mood in a dose-dependent manner. These findings provide a potential explanation for the variable efficacy of SSRIs and might lead to the development of personalized strategies aimed at enhancing their efficacy.