bluuebunny/crossref_metadata_2025 huggingface dataset:
High resolution analysis of tropical forest fragmentation and its impact on the global carbon cycle
Authors: Brinck Katharina , Fischer Rico , Groeneveld Jürgen , Lehmann Sebastian , Dantas De Paula Mateus , Pütz Sandro , Sexton Joseph O. , Song Danxia , Huth Andreas
Published: March 2017

Deforestation in the tropics is not only responsible for direct carbon emissions but also extends the forest edge wherein trees suffer increased mortality. Here we combine high-resolution (30 m) satellite maps of forest cover with estimates of the edge effect and show that 19% of the remaining area of tropical forests lies within 100 m of a forest edge. The tropics house around 50 million forest fragments and the length of the world’s tropical forest edges sums to nearly 50 million km. Edge effects in tropical forests have caused an additional 10.3 Gt (2.1–14.4 Gt) of carbon emissions, which translates into 0.34 Gt per year and represents 31% of the currently estimated annual carbon releases due to tropical deforestation. Fragmentation substantially augments carbon emissions from tropical forests and must be taken into account when analysing the role of vegetation in the global carbon cycle.
Correction: Corrigendum: ASC filament formation serves as a signal amplification mechanism for inflammasomes
Authors: Dick Mathias S. , Sborgi Lorenzo , Rühl Sebastian , Hiller Sebastian , Broz Petr
Published: March 2017

Nature Communications 7: Article number: 11929 (2016); Published 22 June 2016; Updated 17 March 2017 In this Article, residues D128 and D132 of ASC are consistently referred to incorrectly as D130 and D134, respectively. These errors appear in the Results, Methods, Fig. 2, Fig. 3 and Supplementary Fig.
New cofactors and inhibitors for a DNA-cleaving DNAzyme: superoxide anion and hydrogen peroxide mediated an oxidative cleavage process
Authors: Sun Yanhong , Ma Rulong , Wang Shijin , Li Guiying , Sheng Yongjie , Rui Hongyue , Zhang Jin , Xu Jiacui , Jiang Dazhi
Published: March 2017

Herein, we investigated the effects of new cofactors and inhibitors on an oxidative cleavage of DNA catalysis, known as a pistol-like DNAzyme (PLDz), to discuss its catalytic mechanism. PLDz performed its catalytic activity in the presence of ascorbic acid (AA), in which Cu2+ promoted, whereas Fe2+ significantly inhibited the catalytic function. Since Fe2+/AA-generated hydroxyl radicals are efficient on DNA damage, implying that oxidative cleavage of PLDz had no relation with hydroxyl radical. Subsequently, we used Fe2+/H2O2 and Cu2+/H2O2 to identify the role of hydroxyl radicals in PLDz catalysis. Data showed that PLDz lost its activity with Fe2+/H2O2, but exhibited significant cleavage with Cu2+/H2O2. Because Fe2+/H2O2 and Cu2+/H2O2 are popular reagents to generate hydroxyl radicals and the latter also produces superoxide anions, we excluded the possibility that hydroxyl radical participated in oxidative cleavage and confirmed that superoxide anion was involved in PLDz catalysis. Moreover, pyrogallol, riboflavin and hypoxanthine/xanthine oxidase with superoxide anion and hydrogen peroxide generation also induced self-cleavage of PLDz, where catalase inhibited but superoxide dismutase promoted the catalysis, suggesting that hydrogen peroxide played an essential role in PLDz catalysis. Therefore, we proposed a catalytic mechanism of PLDz in which superoxide anion and hydrogen peroxide mediated an oxidative cleavage process.
2D hybrid analysis: Approach for building three-dimensional atomic model by electron microscopy image matching
Authors: Matsumoto Atsushi , Miyazaki Naoyuki , Takagi Junichi , Iwasaki Kenji
Published: March 2017

In this study, we develop an approach termed “2D hybrid analysis” for building atomic models by image matching from electron microscopy (EM) images of biological molecules. The key advantage is that it is applicable to flexible molecules, which are difficult to analyze by 3DEM approach. In the proposed approach, first, a lot of atomic models with different conformations are built by computer simulation. Then, simulated EM images are built from each atomic model. Finally, they are compared with the experimental EM image. Two kinds of models are used as simulated EM images: the negative stain model and the simple projection model. Although the former is more realistic, the latter is adopted to perform faster computations. The use of the negative stain model enables decomposition of the averaged EM images into multiple projection images, each of which originated from a different conformation or orientation. We apply this approach to the EM images of integrin to obtain the distribution of the conformations, from which the pathway of the conformational change of the protein is deduced.
A Steep-Slope Transistor Combining Phase-Change and Band-to-Band-Tunneling to Achieve a sub-Unity Body Factor
Authors: Vitale Wolfgang A. , Casu Emanuele A. , Biswas Arnab , Rosca Teodor , Alper Cem , Krammer Anna , Luong Gia V. , Zhao Qing-T. , Mantl Siegfried , Schüler Andreas , Ionescu A. M.
Published: March 2017

Steep-slope transistors allow to scale down the supply voltage and the energy per computed bit of information as compared to conventional field-effect transistors (FETs), due to their sub-60 mV/decade subthreshold swing at room temperature. Currently pursued approaches to achieve such a subthermionic subthreshold swing consist in alternative carrier injection mechanisms, like quantum mechanical band-to-band tunneling (BTBT) in Tunnel FETs or abrupt phase-change in metal-insulator transition (MIT) devices. The strengths of the BTBT and MIT have been combined in a hybrid device architecture called phase-change tunnel FET (PC-TFET), in which the abrupt MIT in vanadium dioxide (VO2) lowers the subthreshold swing of strained-silicon nanowire TFETs. In this work, we demonstrate that the principle underlying the low swing in the PC-TFET relates to a sub-unity body factor achieved by an internal differential gate voltage amplification. We study the effect of temperature on the switching ratio and the swing of the PC-TFET, reporting values as low as 4.0 mV/decade at 25 °C, 7.8 mV/decade at 45 °C. We discuss how the unique characteristics of the PC-TFET open new perspectives, beyond FETs and other steep-slope transistors, for low power electronics, analog circuits and neuromorphic computing.
Evaluation of the effects of irrigation and fertilization on tomato fruit yield and quality: a principal component analysis
Authors: Wang Xiukang , Xing Yingying
Published: March 2017

Irrigation and fertilization are key practices for improving the fruit quality and yield of vegetables grown in greenhouses. We carried out an experiment in a solar greenhouse spanning three consecutive growing seasons to evaluate the effects of irrigation and fertilization on the fruit yield and quality, water use efficiency (WUE) and fertilizer partial factor productivity (PFP) of tomatoes. Interactions between irrigation and fertilization treatments and individual factors of irrigation and fertilization significantly (p < 0.01) affected fruit yield, WUE and PFP. WUE and fruit yield and quality were more sensitive to changes in irrigation than to changes in fertilizer, but PFP showed the opposite trend. Interestingly, the treatment with moderate irrigation (W2: 75% ET
0
) and high fertilizer level (F1: 240N−120P2O5−150K2O kg ha−1) was twice ranked first after a combinational evaluation. In conclusion, the proper application of drip fertigation (W2F1) may be a good compromise for solar greenhouse-grown tomatoes with regard to fruit yield and quality, WUE, and PFP. The present study sheds light on the contributions of these practices, clarifies their impacts, and provides a basis for evaluating and selecting better management practices for growing greenhouse vegetables.
Developmental Whole Brain White Matter Alterations in Transgenic Huntington’s Disease Monkey
Authors: Meng Yuguang , Jiang Jie , Bachevalier Jocelyne , Zhang Xiaodong , Chan Anthony W. S.
Published: March 2017

Transgenic Huntington’s disease monkey (HD monkey) model provides great opportunity for studying disease progression that could lead to new insight for developing biomarker, early intervention and novel therapeutics. Whole brain white matter integrity of HD-monkeys was examined longitudinally from 6 to 48 months using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS). Progressive developmental white matter alterations in HD monkeys were widespread and were observed not only in fiber bundles connecting cortical areas to the striatum (e.g. striatal bundle and external capsule), but also in long association fiber pathways, commissural fibers, and subcortical fiber bundle. In all fiber tracts, the data indicate an arrest in white matter development around 23 months followed by slight decline until adulthood in HD monkeys. The microstructural changes parallel the progressive motor, memory and cognitive decline previously reported as HD monkeys aged. The findings revealed the widespread progressive temporal-spatial microstructural changes in HD monkey brains from infancy to adulthood, suggesting differentiated degenerations across different brain areas during brain development.
Internal valence modulates the speed of object recognition
Authors: Panichello Matthew F. , Kveraga Kestutis , Chaumon Maximilien , Bar Moshe , Barrett Lisa Feldman
Published: March 2017

Brain regions that process affect are strongly connected with visual regions, but the functional consequences of this structural organization have been relatively unexplored. How does the momentary affect of an observer influence perception? We induced either pleasant or unpleasant affect in participants and then recorded their neural activity using magnetoencephalography while they completed an object recognition task. We hypothesized, and found, that affect influenced the speed of object recognition by modulating the speed and amplitude of evoked responses in occipitotemporal cortex and regions important for representing affect. Furthermore, affect modulated functional interactions between affective and perceptual regions early during perceptual processing. These findings indicate that affect can serve as an important contextual influence on object recognition processes.
Kaposi’s sarcoma-associated herpesvirus ORF34 is essential for late gene expression and virus production
Authors: Nishimura Mayu , Watanabe Tadashi , Yagi Syota , Yamanaka Takahiro , Fujimuro Masahiro
Published: March 2017

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. KSHV establishes a life-long infection in its host and alternates between a latent and lytic infection state. During lytic infection, lytic-related genes are expressed in a temporal manner and categorized as immediate early, early, and late gene transcripts. ORF34 is an early-late gene that interacts with several viral transcription-associated factors, however its physiological importance remains poorly understood. Here, we investigated the role of ORF34 during KSHV infection by generating ORF34-deficient KSHV, using a bacterial artificial chromosome system. Our results reveal that ORF34-deficient KSHV exhibited significantly attenuated late gene expression and viral production but did not affect viral DNA replication. ORF34 interacted with transcription factors ORF18, ORF24, ORF31, and ORF66, and a novel ORF34-interaction partner, ORF23. The C-terminal region of ORF34 was important for interaction with ORF24 and viral production. Our data support a model, in which ORF34 serves as a hub for recruiting a viral transcription complex to ORF24 to promote late viral gene expression.
Co-expression of BirA with biotin bait achieves in vivo biotinylation of overexpressed stable N-glycosylated sRAGE in transgenic silkworms
Authors: Kumano-Kuramochi Miyuki , Tatematsu Ken-ichiro , Ohnishi-Kameyama Mayumi , Maeda-Yamamoto Mari , Kobori Toshiro , Sezutsu Hideki , Machida Sachiko
Published: March 2017

Here, we demonstrated the expression of the N-glycosylated extracellular ligand binding domain of receptor for advanced glycation end products (sRAGE) in middle silk glands (MSGs) of transgenic silkworms using the GAL4/UAS system. Over 1 mg of sRAGE was obtained from one transgenic silkworm. sRAGE purified from the silkworm exhibited good stability and maintained specific ligand-binding ability. In addition, N-glycan analysis of sRAGE revealed that N-glucan completely lacked potentially allergenic fucose. Moreover, co-expression of biotin ligase (BirA) with C-terminal BioEase-tagged sRAGE in MSGs resulted in efficient biotinylation of sRAGE after addition of biotin bait. C-terminal biotinylated sRAGE could be immobilized onto a solid surface in one direction through binding to streptavidin without any loss of ability. The dissociation constant of sRAGE with fructose-BSA, a typical RAGE ligand, was 7.25 × 10−7 M, consistent with that on the mammalian cell surface. Thus, we developed a novel, innovative silkworm expression system for efficient expression of recombinant sRAGE, which could serve as a basis for the elucidation of RAGE-ligand interactions and facilitate the search for new ligands and inhibitors.
PET Radiomics in NSCLC: state of the art and a proposal for harmonization of methodology
Authors: Sollini M. , Cozzi L. , Antunovic L. , Chiti A. , Kirienko M.
Published: March 2017

Imaging with positron emission tomography (PET)/computed tomography (CT) is crucial in the management of cancer because of its value in tumor staging, response assessment, restaging, prognosis and treatment responsiveness prediction. In the last years, interest has grown in texture analysis which provides an “in-vivo” lesion characterization, and predictive information in several malignances including NSCLC; however several drawbacks and limitations affect these studies, especially because of lack of standardization in features calculation, definitions and methodology reporting. The present paper provides a comprehensive review of literature describing the state-of-the-art of FDG-PET/CT texture analysis in NSCLC, suggesting a proposal for harmonization of methodology.
TP53 Arg72Pro, mortality after cancer, and all-cause mortality in 105,200 individuals
Authors: Kodal Jakob B. , Vedel-Krogh Signe , Kobylecki Camilla J. , Nordestgaard Børge G. , Bojesen Stig E.
Published: March 2017

Rs1042522 (Arg72Pro) is a functional polymorphism of TP53. Pro72 has been associated with lower all-cause mortality and lower mortality after cancer. We hypothesized that TP53 Pro72 is associated with lower mortality after cancer, lower all-cause mortality, and with increased cancer incidence in the general population in a contemporary cohort. We genotyped 105,200 individuals aged 20–100 years from the Copenhagen General Population Study, recruited in 2003–2013, and followed them in Danish health registries. During follow-up 5,531 individuals died and 5,849 developed cancer. Hazard ratios for mortality after cancer were 1.03 (95% confidence interval:0.93–1.15) for Arg/Pro and 0.96 (95% CI:0.79–1.18) for Pro/Pro versus Arg/Arg. Hazard ratios for all-cause mortality were 0.99 (95% CI:0.93–1.04) for Arg/Pro and 1.09 (95% CI:0.98–1.21) for Pro/Pro versus Arg/Arg. Risk of cancer specific mortality, cardiovascular mortality, and respiratory mortality were not associated with Arg72Pro genotype overall; however, in exploratory subgroup analyses, genotype-associated risks of malignant melanoma and diabetes were altered. Considering multiple comparisons the latter findings may represent play of chance. The TP53 Arg72Pro genotype was not associated with mortality after cancer, all-cause mortality, or cancer incidence in the general population in a contemporary cohort. Our main conclusion is therefore a lack of reproducing an effect of TP53 Arg72Pro genotype on mortality.
Combination of Electroencephalography and Near-Infrared Spectroscopy in Evaluation of Mental Concentration during the Mental Focus Task for Wisconsin Card Sorting Test
Authors: Chen Che-Wei , Sun Chia-Wei
Published: March 2017

Near-infrared spectroscopy (NIRS) is a noninvasive neuroimaging tool for measuring evoked functional changes in brain oxygenation. Electroencephalography (EEG) can be used to evaluate the functionality of cortical connections and obtain information on regional cortical activity. Coregistration of EEG–NIRS is a recent technique that has been applied for measuring changes in electrical and hemodynamic activity in the human brain. EEG–NIRS coregistration facilitates the avoidance of misleading interpretations of NIRS, particularly in the diagnosis of neurological disorders. In this study, we investigated an approach for enhancing accuracy of NIRS by using EEG to monitor physiological activity during a mental focus task. Using the Wisconsin Card Sorting Test for the subjects mental focus task, we identified two trend types in the EEG and NIRS signals of normal subjects. These data can assist in understanding brain activation statuses and enable determining subjects’ degree of mental concentration. If the data can be standardized for the diagnosis of neurological disorders, they can provide a new index to improve traditional methods (e.g., questionnaires) to assist clinical doctors in diagnosing cognitive disorders.
Exploring Approaches for Detecting Protein Functional Similarity within an Orthology-based Framework
Authors: Weichenberger Christian X. , Palermo Antonia , Pramstaller Peter P. , Domingues Francisco S.
Published: March 2017

Protein functional similarity based on gene ontology (GO) annotations serves as a powerful tool when comparing proteins on a functional level in applications such as protein-protein interaction prediction, gene prioritization, and disease gene discovery. Functional similarity (FS) is usually quantified by combining the GO hierarchy with an annotation corpus that links genes and gene products to GO terms. One large group of algorithms involves calculation of GO term semantic similarity (SS) between all the terms annotating the two proteins, followed by a second step, described as “mixing strategy”, which involves combining the SS values to yield the final FS value. Due to the variability of protein annotation caused e.g. by annotation bias, this value cannot be reliably compared on an absolute scale. We therefore introduce a similarity z-score that takes into account the FS background distribution of each protein. For a selection of popular SS measures and mixing strategies we demonstrate moderate accuracy improvement when using z-scores in a benchmark that aims to separate orthologous cases from random gene pairs and discuss in this context the impact of annotation corpus choice. The approach has been implemented in Frela, a fast high-throughput public web server for protein FS calculation and interpretation.
An Integrated H-G Scheme Identifying Areas for Soil Remediation and Primary Heavy Metal Contributors: A Risk Perspective
Authors: Zou Bin , Jiang Xiaolu , Duan Xiaoli , Zhao Xiuge , Zhang Jing , Tang Jingwen , Sun Guoqing
Published: March 2017

Traditional sampling for soil pollution evaluation is cost intensive and has limited representativeness. Therefore, developing methods that can accurately and rapidly identify at-risk areas and the contributing pollutants is imperative for soil remediation. In this study, we propose an innovative integrated H-G scheme combining human health risk assessment and geographical detector methods that was based on geographical information system technology and validated its feasibility in a renewable resource industrial park in mainland China. With a discrete site investigation of cadmium (Cd), arsenic (As), copper (Cu), mercury (Hg) and zinc (Zn) concentrations, the continuous surfaces of carcinogenic risk and non-carcinogenic risk caused by these heavy metals were estimated and mapped. Source apportionment analysis using geographical detector methods further revealed that these risks were primarily attributed to As, according to the power of the determinant and its associated synergic actions with other heavy metals. Concentrations of critical As and Cd, and the associated exposed CRs are closed to the safe thresholds after remediating the risk areas identified by the integrated H-G scheme. Therefore, the integrated H-G scheme provides an effective approach to support decision-making for regional contaminated soil remediation at fine spatial resolution with limited sampling data over a large geographical extent.
Analysis of factors affecting the therapeutic effect of propranolol for infantile haemangioma of the head and neck
Authors: Dong Jian-Yong , Ning Jie-Xin , Li Kai , Liu Chao , Wang Xu-Xia , Li Rong-Hui , Yue Lin-Lin , Huang Ying-Ying , Liu Shao-Hua
Published: March 2017

Infantile haemangiomas (IHs) are the most common congenital vascular tumours of infancy. Propranolol has been demonstrated to be effective for IHs; however, the factors affecting its therapeutic effect remain unknown. We enrolled 169 infants with IHs of the head and neck region treated with oral propranolol at a dose of 2.0 mg/kg/day. We evaluated the therapeutic responses 6 months after treatment and the end of treatment, which were categorized into four grades. The type and location of the lesions and the infant age at treatment initiation were analysed. The clinical response rate (III + IV) was 91.72% at 6 months after treatment and 97.63% at the end of treatment. The average treatment duration was 9.99 (2–24) months. The group aged 4–6 months exhibited a greater therapeutic response rate (98.48%). The treatment duration was shorter (9.52 months) for mixed-type IHs. Better therapeutic responses were observed for IHs located around the parotid, periorbital, cheek, and neck regions and for multiple IH lesions. Our study indicated that propranolol is effective for IHs affecting the head and neck. The age at treatment initiation and the location of the lesions had a significant effect on the therapeutic response, whereas the lesion type might affect the treatment duration.
Determination of leaf carbon isotope discrimination in C4 plants under variable N and water supply
Authors: Yang Hao , Yu Qiang , Sheng Wen-ping , Li Sheng-gong , Tian Jing
Published: March 2017

Understanding the mechanisms underlying variations in carbon isotope discrimination (Δ) in C4 plants is critical for predicting the C3/C4 ratio in C3/C4 mixed grassland. The value of Δ is determined by bundle sheath leakiness (Ф) and the ratio of intercellular to ambient CO2 concentration (C
i
/C
a
). Leaf nitrogen concentration (N
leaf
) is considered a driver of Δ in C4 plants. However, little is known about how N
leaf
affects Ф and C
i
/C
a
, and subsequently Δ. Here leaf carbon isotope composition, N
leaf
, Ф, and leaf gas exchange were measured in Cleistogenes squarrosa, a dominant C4 species in the Inner Mongolia grassland. Δ remained relatively stable under variable N and water supply. Higher N supply and lower water supply increased N
leaf
, stimulated photosynthesis and further decreased C
i
/C
a
. High N supply increased Ф, which responded weakly to water supply. N
leaf
exerted similar effects on C
i
/C
a
and on Ф in the field and pot experiments. Pooling all the data, N
leaf
explained 73% of the variation in C
i
/C
a
. Overall, both Ф and C
i
/C
a
determined Δ; however, the contribution of Ф was stronger. N
leaf
influenced Δ primarily though C
i
/C
a
, rather than Ф. Ф should be considered in estimating Δ of C4 endmember.
Reconstruction of Large-scale Defects with a Novel Hybrid Scaffold Made from Poly(L-lactic acid)/Nanohydroxyapatite/Alendronate-loaded Chitosan Microsphere: in vitro and in vivo Studies
Authors: Wu Hongwei , Lei Pengfei , Liu Gengyan , Shrike Zhang Yu , Yang Jingzhou , Zhang Longbo , Xie Jie , Niu Wanting , Liu Hua , Ruan Jianming , Hu Yihe , Zhang Chaoyue
Published: March 2017

A chitosan-based microsphere delivery system has been fabricated for controlled release of alendronate (AL). The present study aimed to incorporate the chitosan/hydroxyapatite microspheres-loaded with AL (CH/nHA-AL) into poly(L-lactic acid)/nanohydroxyapatite (PLLA/nHA) matrix to prepare a novel microspheres-scaffold hybrid system (CM-ALs) for drug delivery and bone tissue engineering application. The characteristics of CM-ALs scaffolds containing 10% and 20% CH/nHA-AL were evaluated in vitro, including surface morphology and porosity, mechanical properties, drug release, degradation, and osteogenic differentiation. The in vivo bone repair for large segmental radius defects (1.5 cm) in a rabbit model was evaluated by radiography and histology. In vitro study showed more sustained drug release of CM-AL-containing scaffolds than these of CM/nHA-AL and PLLA/nHA/AL scaffolds, and the mechanical and degradation properties of CM-ALs (10%) scaffolds were comparable to that of PLLA/nHA control. The osteogenic differentiation of adipose-derived stem cells (ASCs) was significantly enhanced as indicated by increased alkaline phosphates (ALP) activity and calcium deposition. In vivo study further showed better performance of CM-ALs (10%) scaffolds with complete repair of large-sized bone defects within 8 weeks. A microspheres-scaffold-based release system containing AL-encapsulated chitosan microspheres was successfully fabricated in this study. Our results suggested the promising application of CM-ALs (10%) scaffolds for drug delivery and bone tissue engineering.
The gene expression profiles in response to 102 traditional Chinese medicine (TCM) components: a general template for research on TCMs
Authors: Lv Chao , Wu Xueting , Wang Xia , Su Juan , Zeng Huawu , Zhao Jing , Lin Shan , Liu Runhui , Li Honglin , Li Xuan , Zhang Weidong
Published: March 2017

Traditional Chinese medicines (TCMs) have important therapeutic value in long-term clinical practice. However, because TCMs contain diverse ingredients and have complex effects on the human body, the molecular mechanisms of TCMs are poorly understood. In this work, we determined the gene expression profiles of cells in response to TCM components to investigate TCM activities at the molecular and cellular levels. MCF7 cells were separately treated with 102 different molecules from TCMs, and their gene expression profiles were compared with the Connectivity Map (CMAP). To demonstrate the reliability and utility of our approach, we used nitidine chloride (NC) from the root of Zanthoxylum nitidum, a topoisomerase I/II inhibitor and α-adrenoreceptor antagonist, as an example to study the molecular function of TCMs using CMAP data as references. We successfully applied this approach to the four ingredients in Danshen and analyzed the synergistic mechanism of TCM components. The results demonstrate that our newly generated TCM data and related methods are valuable in the analysis and discovery of the molecular actions of TCM components. This is the first work to establish gene expression profiles for the study of TCM components and serves as a template for general TCM research.
Molecular Classification of Lobular Carcinoma of the Breast
Authors: Fu Denggang , Zuo Qi , Huang Qi , Su Li , Ring Huijun Z. , Ring Brian Z.
Published: March 2017

The morphology of breast tumors is complicated and diagnosis can be difficult. We present here a novel diagnostic model which we validate on both array-based and RNA sequencing platforms which reliably distinguishes this tumor type across multiple cohorts. We also examine how this molecular classification predicts sensitivity to common chemotherapeutics in cell-line based assays. A total of 1845 invasive breast cancer cases in six cohorts were collected, split into discovery and validation cohorts, and a classifier was created and compared to pathological diagnosis, grade and survival. In the validation cohorts the concordance of predicted diagnosis with a pathological diagnosis was 92%, and 97% when inconclusively classified cases were excluded. Tumor-derived cell lines were classified with the model as having predominantly ductal or lobular-like molecular physiologies, and sensitivity of these lines to relevant compounds was analyzed. A diagnostic tool can be created that reliably distinguishes lobular from ductal carcinoma and allows the classification of cell lines on the basis of molecular profiles associated with these tumor types. This tool may assist in improved diagnosis and aid in explorations of the response of lobular type breast tumor models to different compounds.
Total Extracellular Small RNA Profiles from Plasma, Saliva, and Urine of Healthy Subjects
Authors: Yeri Ashish , Courtright Amanda , Reiman Rebecca , Carlson Elizabeth , Beecroft Taylor , Janss Alex , Siniard Ashley , Richholt Ryan , Balak Chris , Rozowsky Joel , Kitchen Robert , Hutchins Elizabeth , Winarta Joseph , McCoy Roger , Anastasi Matthew , Kim Seungchan , Huentelman Matthew , Van Keuren-Jensen Kendall
Published: March 2017

Interest in circulating RNAs for monitoring and diagnosing human health has grown significantly. There are few datasets describing baseline expression levels for total cell-free circulating RNA from healthy control subjects. In this study, total extracellular RNA (exRNA) was isolated and sequenced from 183 plasma samples, 204 urine samples and 46 saliva samples from 55 male college athletes ages 18–25 years. Many participants provided more than one sample, allowing us to investigate variability in an individual’s exRNA expression levels over time. Here we provide a systematic analysis of small exRNAs present in each biofluid, as well as an analysis of exogenous RNAs. The small RNA profile of each biofluid is distinct. We find that a large number of RNA fragments in plasma (63%) and urine (54%) have sequences that are assigned to YRNA and tRNA fragments respectively. Surprisingly, while many miRNAs can be detected, there are few miRNAs that are consistently detected in all samples from a single biofluid, and profiles of miRNA are different for each biofluid. Not unexpectedly, saliva samples have high levels of exogenous sequence that can be traced to bacteria. These data significantly contribute to the current number of sequenced exRNA samples from normal healthy individuals.
The development of novel LTA4H modulators to selectively target LTB4 generation
Authors: Low Caroline M. , Akthar Samia , Patel Dhiren F. , Löser Stephan , Wong Chi-Tung , Jackson Patricia L. , Blalock J. Edwin , Hare Stephen A. , Lloyd Clare M. , Snelgrove Robert J.
Published: March 2017

The pro-inflammatory mediator leukotriene B4(LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4hydrolase (LTA4H) catalyses the distal step in LTB4synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.
Effect of 1.8 GHz radiofrequency electromagnetic radiation on novel object associative recognition memory in mice
Authors: Wang Kai , Lu Jun-Mei , Xing Zhen-He , Zhao Qian-Ru , Hu Lin-Qi , Xue Lei , Zhang Jie , Mei Yan-Ai
Published: March 2017

Mounting evidence suggests that exposure to radiofrequency electromagnetic radiation (RF-EMR) can influence learning and memory in rodents. In this study, we examined the effects of single exposure to 1.8 GHz RF-EMR for 30 min on subsequent recognition memory in mice, using the novel object recognition task (NORT). RF-EMR exposure at an intensity of >2.2 W/kg specific absorption rate (SAR) power density induced a significant density-dependent increase in NORT index with no corresponding changes in spontaneous locomotor activity. RF-EMR exposure increased dendritic-spine density and length in hippocampal and prefrontal cortical neurons, as shown by Golgi staining. Whole-cell recordings in acute hippocampal and medial prefrontal cortical slices showed that RF-EMR exposure significantly altered the resting membrane potential and action potential frequency, and reduced the action potential half-width, threshold, and onset delay in pyramidal neurons. These results demonstrate that exposure to 1.8 GHz RF-EMR for 30 min can significantly increase recognition memory in mice, and can change dendritic-spine morphology and neuronal excitability in the hippocampus and prefrontal cortex. The SAR in this study (3.3 W/kg) was outside the range encountered in normal daily life, and its relevance as a potential therapeutic approach for disorders associated with recognition memory deficits remains to be clarified.
Efficient Generation of Chemically Induced Mesenchymal Stem Cells from Human Dermal Fibroblasts
Authors: Lai Pei-Lun , Lin Hsuan , Chen Shang-Fu , Yang Shang-Chih , Hung Kuo-Hsuan , Chang Ching-Fang , Chang Hsiang-Yi , Lu Frank Leigh , Lee Yi-Hsuan , Liu Yu-Chuan , Huang Hsiao-Chun , Lu Jean
Published: March 2017

Human mesenchymal stromal/stem cells (MSCs) are multipotent and currently undergoing hundreds of clinical trials for disease treatments. To date, no studies have generated induced MSCs from skin fibroblasts with chemicals or growth factors. Here, we established the first chemical method to convert primary human dermal fibroblasts into multipotent, induced MSC-like cells (iMSCs). The conversion method uses a defined cocktail of small molecules and growth factors, and it can achieve efficient conversion with an average rate of 38% in 6 days. The iMSCs have much higher clonogenicity than fibroblasts, and they can be maintained and expanded in regular MSC medium for at least 8 passages and further differentiated into osteoblasts, adipocytes, and chondrocytes. Moreover, the iMSCs can suppress LPS-mediated acute lung injury as effectively as bone marrow-derived mesenchymal stem cells. This finding may greatly benefit stem cell biology, cell therapy, and regenerative medicine.
Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy
Authors: Revilla Nuria , de la Morena-Barrio María Eugenia , Miñano Antonia , López-Gálvez Raquel , Toderici Mara , Padilla José , García-Avello Ángel , Lozano María Luisa , Lefeber Dirk J. , Corral Javier , Vicente Vicente
Published: March 2017

An in-depth focused study of specific cases of patients with recurrent thrombosis may help to identify novel circumstances, genetic and acquired factors contributing to the development of this disorder. The aim of this study was to carry out a detailed and sequential analysis of samples from a patient suffering from early and recurrent venous and arterial thrombosis. We performed thrombophilic tests, biochemical, functional, genetic and glycomic analysis of antithrombin and other plasma proteins. The patient carried a new type I antithrombin mutation (p.Ile218del), whose structural relevance was verified in a recombinant model. Experiments with N-glycosidase F and neuraminidase suggested a nearly full desialylation of plasma proteins, which was confirmed by mass spectrometry analysis of transferrin glycoforms. However, partial desialylation and normal patterns were detected in samples collected at other time-points. Desialylation was noticeable after arterial events and was associated with low antithrombin activity, reduced platelet count and glomerular filtration rate. This is the first description of a global and transient desialylation of plasma proteins associated with thrombosis. The decrease in the strong electronegative charge of terminal glycans may modulate hemostatic protein-protein interactions, which in combination with a strong prothrombotic situation, such as antithrombin deficiency, could increase the risk of thrombosis.
Sub-pixel correlation length neutron imaging: Spatially resolved scattering information of microstructures on a macroscopic scale
Authors: Harti Ralph P. , Strobl Markus , Betz Benedikt , Jefimovs Konstantins , Kagias Matias , Grünzweig Christian
Published: March 2017

Neutron imaging and scattering give data of significantly different nature and traditional methods leave a gap of accessible structure sizes at around 10 micrometers. Only in recent years overlap in the probed size ranges could be achieved by independent application of high resolution scattering and imaging methods, however without providing full structural information when microstructures vary on a macroscopic scale. In this study we show how quantitative neutron dark-field imaging with a novel experimental approach provides both sub-pixel resolution with respect to microscopic correlation lengths and imaging of macroscopic variations of the microstructure. Thus it provides combined information on multiple length scales. A dispersion of micrometer sized polystyrene colloids was chosen as a model system to study gravity induced crystallisation of microspheres on a macro scale, including the identification of ordered as well as unordered phases. Our results pave the way to study heterogeneous systems locally in a previously impossible manner.
All-passive pixel super-resolution of time-stretch imaging
Authors: Chan Antony C. S. , Ng Ho-Cheung , Bogaraju Sharat C. V. , So Hayden K. H. , Lam Edmund Y. , Tsia Kevin K.
Published: March 2017

Based on image encoding in a serial-temporal format, optical time-stretch imaging entails a stringent requirement of state-of-the-art fast data acquisition unit in order to preserve high image resolution at an ultrahigh frame rate — hampering the widespread utilities of such technology. Here, we propose a pixel super-resolution (pixel-SR) technique tailored for time-stretch imaging that preserves pixel resolution at a relaxed sampling rate. It harnesses the subpixel shifts between image frames inherently introduced by asynchronous digital sampling of the continuous time-stretch imaging process. Precise pixel registration is thus accomplished without any active opto-mechanical subpixel-shift control or other additional hardware. Here, we present the experimental pixel-SR image reconstruction pipeline that restores high-resolution time-stretch images of microparticles and biological cells (phytoplankton) at a relaxed sampling rate (≈2–5 GSa/s)—more than four times lower than the originally required readout rate (20 GSa/s) — is thus effective for high-throughput label-free, morphology-based cellular classification down to single-cell precision. Upon integration with the high-throughput image processing technology, this pixel-SR time-stretch imaging technique represents a cost-effective and practical solution for large scale cell-based phenotypic screening in biomedical diagnosis and machine vision for quality control in manufacturing.
MicroRNAs miR-203-3p, miR-664-3p and miR-708-5p are associated with median strain lifespan in mice
Authors: Lee Benjamin P. , Burić Ivana , George-Pandeth Anupriya , Flurkey Kevin , Harrison David E. , Yuan Rong , Peters Luanne L. , Kuchel George A. , Melzer David , Harries Lorna W.
Published: March 2017

MicroRNAs (miRNAs) are small non-coding RNA species that have been shown to have roles in multiple processes that occur in higher eukaryotes. They act by binding to specific sequences in the 3’ untranslated region of their target genes and causing the transcripts to be degraded by the RNA-induced silencing complex (RISC). MicroRNAs have previously been reported to demonstrate altered expression in several aging phenotypes such as cellular senescence and age itself. Here, we have measured the expression levels of 521 small regulatory microRNAs (miRNAs) in spleen tissue from young and old animals of 6 mouse strains with different median strain lifespans by quantitative real-time PCR. Expression levels of 3 microRNAs were robustly associated with strain lifespan, after correction for multiple statistical testing (miR-203-3p [β-coefficient = −0.6447, p = 4.8 × 10−11], miR-664-3p [β-coefficient = 0.5552, p = 5.1 × 10−8] and miR-708-5p [β-coefficient = 0.4986, p = 1.6 × 10−6]). Pathway analysis of binding sites for these three microRNAs revealed enrichment of target genes involved in key aging and longevity pathways including mTOR, FOXO and MAPK, most of which also demonstrated associations with longevity. Our results suggests that miR-203-3p, miR-664-3p and miR-708-5p may be implicated in pathways determining lifespan in mammals.
A scalable diffraction-based scanning 3D colour video display as demonstrated by using tiled gratings and a vertical diffuser
Authors: Jia Jia , Chen Jhensi , Yao Jun , Chu Daping
Published: March 2017

A high quality 3D display requires a high amount of optical information throughput, which needs an appropriate mechanism to distribute information in space uniformly and efficiently. This study proposes a front-viewing system which is capable of managing the required amount of information efficiently from a high bandwidth source and projecting 3D images with a decent size and a large viewing angle at video rate in full colour. It employs variable gratings to support a high bandwidth distribution. This concept is scalable and the system can be made compact in size. A horizontal parallax only (HPO) proof-of-concept system is demonstrated by projecting holographic images from a digital micro mirror device (DMD) through rotational tiled gratings before they are realised on a vertical diffuser for front-viewing.
External validation of a COPD prediction model using population-based primary care data: a nested case-control study
Authors: Nwaru Bright I , Simpson Colin R , Sheikh Aziz , Kotz Daniel
Published: March 2017

Emerging models for predicting risk of chronic obstructive pulmonary disease (COPD) require external validation in order to assess their clinical value. We validated a previous model for predicting new onset COPD in a different database. We randomly drew 38,597 case-control pairs (total N = 77,194) of individuals aged ≥35 years and matched for sex, age, and general practice from the United Kingdom Clinical Practice Research Datalink database. We assessed accuracy of the model to discriminate between COPD cases and non-cases by calculating area under the receiver operator characteristic (ROCAUC) for the prediction scores. Analogous to the development model, ever smoking (OR 6.70; 95%CI 6.41–6.99), prior asthma (OR 6.43; 95%CI 5.85–7.07), and higher socioeconomic deprivation (OR 2.90; 95%CI 2.72–3.09 for highest vs. lowest quintile) increased the risk of COPD. The validated prediction scores ranged from 0–5.71 (ROCAUC 0.66; 95%CI 0.65–0.66) for males and 0–5.95 (ROCAUC 0.71; 95%CI 0.70–0.71) for females. We have confirmed that smoking, prior asthma, and socioeconomic deprivation are key risk factors for new onset COPD. Our model seems externally valid at identifying patients at risk of developing COPD. An impact assessment now needs to be undertaken to assess whether this prediction model can be applied in clinical care settings.
Microbial community composition of deep-sea corals from the Red Sea provides insight into functional adaption to a unique environment
Authors: Röthig Till , Yum Lauren K. , Kremb Stephan G. , Roik Anna , Voolstra Christian R.
Published: March 2017

Microbes associated with deep-sea corals remain poorly studied. The lack of symbiotic algae suggests that associated microbes may play a fundamental role in maintaining a viable coral host via acquisition and recycling of nutrients. Here we employed 16 S rRNA gene sequencing to study bacterial communities of three deep-sea scleractinian corals from the Red Sea, Dendrophyllia sp., Eguchipsammia fistula, and Rhizotrochus typus. We found diverse, species-specific microbiomes, distinct from the surrounding seawater. Microbiomes were comprised of few abundant bacteria, which constituted the majority of sequences (up to 58% depending on the coral species). In addition, we found a high diversity of rare bacteria (taxa at <1% abundance comprised >90% of all bacteria). Interestingly, we identified anaerobic bacteria, potentially providing metabolic functions at low oxygen conditions, as well as bacteria harboring the potential to degrade crude oil components. Considering the presence of oil and gas fields in the Red Sea, these bacteria may unlock this carbon source for the coral host. In conclusion, the prevailing environmental conditions of the deep Red Sea (>20 °C, <2 mg oxygen L−1) may require distinct functional adaptations, and our data suggest that bacterial communities may contribute to coral functioning in this challenging environment.
Correlation of Cerebral Microbleed Distribution to Amyloid Burden in Patients with Primary Intracerebral Hemorrhage
Authors: Tsai Hsin-Hsi , Tsai Li-Kai , Chen Ya-Fang , Tang Sung-Chun , Lee Bo-Ching , Yen Ruoh-Fang , Jeng Jiann-Shing
Published: March 2017

The underlying pathology of cerebral microbleeds (CMBs) with mixed lobar and deep distribution remains contentious. The aim of this study was to correlate CMBs distribution to β-amyloid burden in patients with primary intracerebral hemorrhage (ICH). Fourty-seven ICH patients underwent magnetic resonance susceptibility-weighted imaging and 11C-Pittsburgh Compound B positron emission tomography. The amyloid burden was expressed as standardized uptake value ratio with reference to cerebellum, and presented as median (interquartile range). Patients were categorized into the lobar, mixed (both lobar and deep regions), and deep types of CMB. Comparing the lobar (17%), mixed (59.6%) and deep (23.4%) CMB types, the global amyloid burden was significantly higher in the mixed type than the deep type (1.10 [1.03–1.25] vs 1.00 [0.97–1.09], p = 0.011), but lower than in the lobar type (1.48 [1.18–1.50], p = 0.048). On multivariable analysis, the ratio of lobar to deep CMB number was positively correlated with global (p = 0.028) and occipital (p = 0.031) amyloid burden. In primary ICH, patients with lobar and mixed CMB types are associated with increased amyloid burden than patients with deep type. The ratio of lobar to deep CMB number is an independent indicator of cerebral β-amyloid deposition.
The immune correlates of protection for an avian influenza H5N1 vaccine in the ferret model using oil-in-water adjuvants
Authors: Wong Sook-San , Duan Susu , DeBeauchamp Jennifer , Zanin Mark , Kercher Lisa , Sonnberg Stephanie , Fabrizio Thomas , Jeevan Trushar , Crumpton Jeri-Carol , Oshansky Christine , Sun Yilun , Tang Li , Thomas Paul , Webby Richard
Published: March 2017

Because of the pathogenicity and low incidence of avian influenza virus infections in humans, the immune correlates of protection for avian influenza vaccines cannot be determined from clinical studies. Here, we used the ferret model to address this for an avian influenza H5N1 vaccine. Using oil-in-water adjuvants, we generated groups of ferrets with undetectable (geometric mean titer [GMT] < 10), low (GMT = 28.3), or high (GMT > 761.1) hemagglutination-inhibition (HAI) titers to the A/Viet Nam/1203/2004 (H5N1) virus. Ferrets were then challenged with the wild-type virus and disease severity and immunologic parameters were studied. The severity of infection and symptom profile were inversely associated with pre-challenge HAI titers in a dose-dependent manner. A vaccinated ferret with no detectable HAI-antibodies but high flu-specific IgG-antibody titers mounted rapid functional antibodies after infection and experienced milder disease compared to other ferrets in the group. Compared to naïve ferrets, all vaccinated ferrets showed improved cellular immunity in the lungs and peripheral blood. High number of IFNγ+ CD8- T cells in the airways was associated with early viral clearance. Thus, while neutralizing antibodies are the best correlate of protection, non-neutralizing antibodies can also be protective. This should be taken into consideration in future avian influenza vaccine trials.