bluuebunny/crossref_metadata_2025 huggingface dataset:
End‐functionalized polylactides using a calcium‐based precatalyst: Synthesis and insights by mass spectrometry
Authors: Yildirim Ilknur , Crotty Sarah , Loh Claas H. , Festag Grit , Weber Christine , Caponi Pier‐Francesco , Gottschaldt Michael , Westerhausen Matthias , Schubert Ulrich S.
Published: August 2015

A simple and convenient method for the synthesis of end functionalized polylactides (PLAs) under mild conditions by ring opening polymerization (ROP) in the absence of potentially toxic catalysts is described. Various alcohols were used as initiators in combination with Ca[N(SiMe3)2]2(THF)2 as the precatalyst in THF at room temperature. Tailored end functionalities were obtained in a controlled fashion. Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐ToF‐MS) and electrospray ionization quadrupole time of flight mass spectrometry (ESI‐Q‐ToF‐MS) analysis were performed to investigate the end groups. The results confirmed that the end group fidelity was maintained in the isolated PLAs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 437–448
Investigation of Abnormal Long‐Wavelength Fluorescence Emissions Occurring in Binary Organic Nanoparticle Films
Authors: Xu Xinjun , Xu Zhengyin , Ye Shanghui , Liu Yunqi , Wu Meng , Li Lidong
Published: August 2015

In some fluorophores with planar groups, a long‐wavelength emission band different from their native one can sometimes be observed. The main cause of this long‐wavelength band is excimer formation. It is generally accepted that once condensed in the solid state, whether fluorophores can exhibit excimer emission or not depends only on their molecular structure and packing. However, here it is shown that there are exceptions when fluorophores are present in nanoparticles (NPs), where excimer emission can be affected by the environment surrounding the NPs, even in the solid state. It is found that in some binary NP films consisting of fluorophore NPs and other NPs, unusual long‐wavelength bands ascribed to excimer emission can be activated, even though these bands are absent from the photoluminescence spectra of the pure fluorophore NP films. This finding is beneficial to better understand and control excimer emissions. In addition, such a binary NP system provides an ideal platform to investigate the interplay between two fluorophores, because it keeps them effectively separated while maintaining suitable spatial distances for exciton migration and dipole–dipole interactions. This work also provides evidence for the long‐debated origin of the green emission band (g‐band) of fluorene‐based fluorophores.
A community resource of experimental data for NMR / X‐ray crystal structure pairs
Authors: Everett John K. , Tejero Roberto , Murthy Sarath B. K. , Acton Thomas B. , Aramini James M. , Baran Michael C. , Benach Jordi , Cort John R. , Eletsky Alexander , Forouhar Farhad , Guan Rongjin , Kuzin Alexandre P. , Lee Hsiau‐Wei , Liu Gaohua , Mani Rajeswari , Mao Binchen , Mills Jeffrey L. , Montelione Alexander F. , Pederson Kari , Powers Robert , Ramelot Theresa , Rossi Paolo , Seetharaman Jayaraman , Snyder David , Swapna G. V. T. , Vorobiev Sergey M. , Wu Yibing , Xiao Rong , Yang Yunhuang , Arrowsmith Cheryl H. , Hunt John F. , Kennedy Michael A. , Prestegard James H. , Szyperski Thomas , Tong Liang , Montelione Gaetano T.
Published: August 2015

We have developed an online NMR / X‐ray Structure Pair Data Repository. The NIGMS Protein Structure Initiative (PSI) has provided many valuable reagents, 3D structures, and technologies for structural biology. The Northeast Structural Genomics Consortium was one of several PSI centers. NESG used both X‐ray crystallography and NMR spectroscopy for protein structure determination. A key goal of the PSI was to provide experimental structures for at least one representative of each of hundreds of targeted protein domain families. In some cases, structures for identical (or nearly identical) constructs were determined by both NMR and X‐ray crystallography. NMR spectroscopy and X‐ray diffraction data for 41 of these “NMR / X‐ray” structure pairs determined using conventional triple‐resonance NMR methods with extensive sidechain resonance assignments have been organized in an online NMR / X‐ray Structure Pair Data Repository. In addition, several NMR data sets for perdeuterated, methyl‐protonated protein samples are included in this repository. As an example of the utility of this repository, these data were used to revisit questions about the precision and accuracy of protein NMR structures first outlined by Levy and coworkers several years ago (Andrec et al., Proteins 2007;69:449–465). These results demonstrate that the agreement between NMR and X‐ray crystal structures is improved using modern methods of protein NMR spectroscopy. The NMR / X‐ray Structure Pair Data Repository will provide a valuable resource for new computational NMR methods development.
Structural, electronic, elastic, and thermodynamic properties of the spin‐gapless semiconducting Mn2CoAl inverse Heusler alloy under pressure
Authors: Chen Xiao‐Rui , Zhong Ming‐Min , Feng Yu , Zhou Ying , Yuan Hong‐Kuan , Chen Hong
Published: August 2015

Abstractauthoren Structural, electronic, elastic, and thermodynamic properties of the spin‐gapless semiconducting (SGS) Mn2CoAl inverse Heusler alloy under pressure are investigated by using the density functional theory (DFT) and the quasi‐harmonic Debye model. The calculated equilibrium lattice parameter and SGS behavior agree with the experimental and other theoretical data. It is only when the external pressure is beyond about 25 GPa that the SGS behavior and dynamical stability are destroyed, indicating that the SGS behavior is robust against pressure less than 25 GPa in everyday experiments. Furthermore, the thermal properties, including bulk modulus B, thermal expansivity , Grüneisen parameter , heat capacity C, and Debye temperature of Mn2CoAl are evaluated up to 25 GPa. These thermodynamic properties will be referenced in the further experiments.

The calculated phonon dispersion curves of Mn2CoAl at different pressures.
Distinct Responses of Cytotoxic Ganoderma lucidum Triterpenoids in Human Carcinoma Cells
Authors: Ruan Weimei , Wei Ying , Popovich David G.
Published: August 2015

The medicinal mushroom Ganoderma lucidum is well recognized for its effective cancer‐preventative and therapeutic properties, while specific components responsible for these anticancer effects are not well studied. Six triterpenoids that are ganolucidic acid E, lucidumol A, ganodermanontriol, 7‐oxo‐ganoderic acid Z, 15‐hydroxy‐ganoderic acid S, and ganoderic acid DM were isolated and identified from an extract of the mushroom. All compounds reduced cell growth in three human carcinoma cells (Caco‐2, HepG2, and HeLa cells) dose dependently with LC50s from 20.87 to 84.36 μM. Moreover, the six compounds induced apoptosis in HeLa cells with a maximum increase (22%) of sub‐G1 accumulations and 43.03% apoptotic cells in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay (15‐hydroxy‐ganoderic acid S treatment). Apoptosis was further confirmed by annexin‐V staining. Four of the compounds also caused apoptosis in Caco‐2 cells with maximum 9.5% increase of sub‐G1 accumulations (7‐oxo‐ganoderic acid Z treatment) and maximum 29.84% apoptotic cells in TUNEL assay (ganoderic acid DM treatment). Contrarily, none of the compounds induced apoptosis in HepG2 cells. The different responses of the three cell lines following these treatments indicated that the bioactive properties of these compounds may vary from cells of different sites of origin and are likely acting under diverse regulatory mechanisms. Copyright © 2015 John Wiley & Sons, Ltd.
Emergency Management of Gallbladder Disease: Are Acute Surgical Units the New Gold Standard?
Authors: Shakerian Rose , Skandarajah Anita , Gorelik Alexandra , Thomson Benjamin
Published: August 2015

Introduction

Since 2011, all acute general surgical admissions have been managed by the consultant‐led emergency general surgery service (EGS) at our institution. We aim to compare EGS management of acute biliary disease to its preceding model.

Materials and methods

Retrospective review of prospectively collated databases was performed to capture consecutive emergency admissions with biliary disease from 1st February 2009 to 31st January 2013. Patient demographics, surgical intervention, use of diagnostic radiology, histological diagnosis, complications and hospital length of stay (LOS) were retrieved.

Results

A total of 566 patients were included (pre‐EGS 254 vs. EGS 312). In the EGS period, the number of patients having surgery on index admission increased from 43.7 to 58.7 % (p < 0.001) as did use of intra‐operative cholangiography from 75.7 to 89.6 % (p = 0.003). The conversion to open cholecystectomy rate also was reduced from 14.4 to 3.3 % (p < 0.001). Overall, a 14 % reduction in use of multiple (>1) imaging modalities for diagnosis was noted (p = 0.003). There was a positive trend in reduction of bile leaks but no significant difference in the overall morbidity and mortality. Time to theatre was reduced by 1 day [pre‐EGS 2.7 (IQR 1.5–5.0) vs. EGS 1.7 (IQR 1.2–2.6) p < 0.001]. The overall hospital LOS was reduced by 1.5 days [pre‐EGS 5.0 (IQR 3–7) vs. EGS 3.5 (IQR 2–5) p < 0.001].

Conclusion

Since the advent of EGS, more judicious use of diagnostic radiology, reduced complications, reduced LOS, reduced time to theatre and an increased rate of definitive management during the index admission were demonstrated.
Surgical and Radiological Studies on the Length of the Hepatic Ducts
Authors: Hirose Tomoaki , Igami Tsuyoshi , Ebata Tomoki , Yokoyama Yukihiro , Sugawara Gen , Mizuno Takashi , Mori Kensaku , Ando Masahiko , Nagino Masato
Published: August 2015

Background

Right‐sided hepatectomy is often selected for perihilar cholangiocarcinoma, due to the anatomic consideration that “the left hepatic duct is longer than that of the right hepatic duct”. However, only one study briefly mentioned the length of the hepatic ducts. Our aim is to investigate whether the consideration is correct.

Methods

In surgical study, the lengths of the resected bile duct were measured using pictures of the resected specimens in 475 hepatectomized patients with perihilar cholangiocarcinoma. In radiological study, the estimated lengths of the bile duct to be resected were measured using cholangiograms reconstructed from computed tomography images in 61 patients with distal bile duct obstruction.

Results

In surgical study, the length of the resected left hepatic duct was 25.1 ± 6.4 mm in right trisectionectomy (n = 37) and 14.9 ± 5.7 mm in right hepatectomy (n = 167). The length of the right hepatic duct was 14.1 ± 5.7 mm in left hepatectomy (n = 149) and 21.3 ± 6.4 mm in left trisectionectomy (n = 122). In radiological study, the lengths of the bile duct corresponding to the surgical study were 34.1 ± 7.8, 22.4 ± 7.1, 20.8 ± 4.8, and 31.6 ± 5.3 mm, respectively. Both studies determined that the lengths of the resected bile ducts were (1) similar between right and left hepatectomies, (2) significantly shorter in right hepatectomy than in left trisectionectomy, and (3) the longest in right trisectionectomy.

Conclusions

The aforementioned anatomical assumption is a surgeon’s biased view. Based on our observations, a flexible procedure selection is recommended.
Prognostic Significance of Muscle Attenuation in Pancreatic Cancer Patients Treated with Neoadjuvant Chemoradiotherapy
Authors: Akahori Takahiro , Sho Masayuki , Kinoshita Shoichi , Nagai Minako , Nishiwada Satoshi , Tanaka Toshihiro , Tamamoto Tetsuro , Ohbayashi Chiho , Hasegawa Masatoshi , Kichikawa Kimihiko , Nakajima Yoshiyuki
Published: August 2015

Background

Emerging evidences have gradually revealed the skeletal muscle attenuation (MA) was not only reflected the accumulation of lipids in skeletal muscle but also associated with physiological and pathological states. The aim of this study was to evaluate the impact of MA on the prognosis of pancreatic cancer patients treated with neoadjuvant chemoradiotherapy (NACRT).

Methods

Eighty‐three patients with pancreatic cancer who received NACRT were enrolled. Patients were divided according to their Hounsfield units of the skeletal muscle at the third lumbar vertebra in CT. The lower quartile was defined as MA group and the remainder as control group.

Results

There was no significant difference in overall survival between pre‐NACRT MA and control groups. In contrast, patients with post‐NACRT MA had a significantly poorer prognosis than patients without. The patients in the post‐NACRT MA group were significantly older than patients in the control group. There were no significant differences in most clinicopathological and perioperative factors between both groups. However, patients with post‐NACRT MA had a longer hospital stay than patients without. Furthermore, the incompletion rate of the proposed adjuvant chemotherapy was significantly higher in the MA group than control. Importantly, multivariate analysis indicated that post‐NACRT MA was an independent prognostic factor.

Conclusions

Muscle attenuation may have a significant impact in pancreatic cancer patients treated with multimodal therapy. Therefore, our data may provide new insights into perioperative patient care to improve the prognosis of resectable pancreatic cancer.
Accelerated Fat Bloom in Chocolate Model Systems: Solid Fat Content and Temperature Fluctuation Frequency
Authors: Jin Jiayang , Hartel Richard W.
Published: August 2015

Chocolate model systems were designed with high‐melting fat (cocoa butter stearin, CB‐S) mixed with low‐melting fats (sunflower oil, canola oil, cottonseed oil, peanut oil) to give 45, 55, and 65 % solid fat content (SFC). Defatted cocoa powder provided a 50 % particulate level in the model chocolates. The effects of SFC, low‐melting fat type and storage temperature fluctuation frequency on bloom whiteness were investigated. Both SFC and storage condition had significant influences on bloom whiteness (p < 0.0001), although the type of low‐melting fat did not (p = 0.1223). Increasing the SFC significantly reduced bloom formation, as did more rapid temperature fluctuations.
Dynamics of harmonically excited, reacting bluff body wakes near the global hydrodynamic stability boundary
Authors: Emerson Benjamin , Lieuwen Tim
Published: August 2015

This paper describes linear and nonlinear interactions between forced axial acoustic oscillations and the global mode of the reacting wake. This work is motivated by the problem of combustion instabilities, where acoustic oscillations associated with natural combustor modes excite hydrodynamic instabilities of the flow that, in turn, induce heat release oscillations. Wake flows with density stratification can be globally stable or unstable at high Reynolds numbers, and so the density change across the flame has significant influence on the natural flame and flow dynamics. Measurements were obtained in a facility in which flame density ratio, lip velocity and forcing frequency are independently varied using 5 kHz particle image velocimetry and Mie scattering measurements. By varying the density ratio, the hydrodynamic global mode growth rate can be systematically varied. In addition, measurements and analyses were performed where the forcing frequency is varied relative to the global mode frequency. While axial forcing excites a varicose response of the shear layers, the sinuous mode is the most rapidly growing. As expected, forcing at a frequency near the wake’s global mode frequency leads to rapid growth in vortical disturbance amplitude, and the symmetric vortices quickly stagger as they convect downstream leading to a large scale, sinuous flapping of the wake and flame. A linear, local stability analysis, together with a nonlinear analysis, help elucidate the physics that govern the vortex staggering. The study concludes with an analysis of the heat release dynamics. Significantly, the study shows that the heat release exhibits quite different sensitivities than the fluid dynamics; e.g. axial forcing of the flow near its global mode frequency leads to a reduction in heat release oscillations. This is true even though this forcing frequency maximizes the local degree of vortically induced flame flapping. Thus, the results of this study show some phenomena that contradict conventional notions, namely that conditions which align the frequency of a hydrodynamic global mode with that of an acoustic mode may lead to diminished forced heat release oscillations in bluff body combustors.
An experimental investigation of resonant interaction of a rectangular jet with a flat plate
Authors: Zaman K. B. M. Q. , Fagan A. F. , Bridges J. E. , Brown C. A.
Published: August 2015

The interaction between an 8:1 aspect ratio rectangular jet and a flat plate, placed parallel to the jet, is addressed in this study. At high subsonic conditions and for certain relative locations of the plate, a resonance takes place with accompanying audible tones. Even when the tone is not audible the sound pressure level spectra are often marked by conspicuous peaks. The frequencies of these peaks, as functions of the plate’s length, its location relative to the jet as well as jet Mach number, are studied in an effort to understand the flow mechanism. It is demonstrated that the tones are not due to a simple feedback between the nozzle exit and the plate’s trailing edge; the leading edge also comes into play in determining the frequency. With parametric variation, it is found that there is an order in the most energetic spectral peaks; their frequencies cluster in distinct bands. The lowest frequency band is explained by an acoustic feedback involving diffraction at the plate’s leading edge. Under the resonant condition, a periodic flapping motion of the jet column is seen when viewed in a direction parallel to the plate. Phase-averaged Mach number data on a cross-stream plane near the plate’s trailing edge illustrate that the jet cross-section goes through large contortions within the period of the tone. Farther downstream a clear ‘axis switching’ takes place for the time-averaged cross-section of the jet that does not occur otherwise for a non-resonant condition.
Phase diagram for droplet impact on superheated surfaces
Authors: Staat Hendrik J. J. , Tran Tuan , Geerdink Bart , Riboux Guillaume , Sun Chao , Gordillo José Manuel , Lohse Detlef
Published: August 2015

We experimentally determine the phase diagram for impacting ethanol droplets on a smooth, sapphire surface in the parameter space of Weber number $\mathit{We}$ versus surface temperature $T$. We observe two transitions, namely the one towards splashing (disintegration of the droplet) with increasing $\mathit{We}$, and the one towards the Leidenfrost state (no contact between the droplet and the plate due to a lasting vapour film) with increasing $T$. Consequently, there are four regimes: contact and no splashing (deposition regime), contact and splashing (contact–splash regime), neither contact nor splashing (bounce regime), and finally no contact, but splashing (film–splash regime). While the transition temperature $T_{L}$ to the Leidenfrost state depends weakly, at most, on $\mathit{We}$ in the parameter regime of the present study, the transition Weber number $\mathit{We}_{C}$ towards splashing shows a strong dependence on $T$ and a discontinuity at $T_{L}$. We quantitatively explain the splashing transition for $T<T_{L}$ by incorporating the temperature dependence of the physical properties in the theory by Riboux & Gordillo (Phys. Rev. Lett., vol. 113(2), 2014, 024507; J. Fluid Mech., vol. 772, 2015, pp. 630–648).
Egg intake and cancers of the breast, ovary and prostate: a dose–response meta-analysis of prospective observational studies
Authors: Keum N. , Lee D. H. , Marchand N. , Oh H. , Liu H. , Aune D. , Greenwood D. C. , Giovannucci E. L.
Published: August 2015

Evidence suggests that egg intake may be implicated in the aetiology of sex hormone-related cancers. However, dose–response relationships between egg intake and such cancers are unclear. Thus, we conducted a dose–response meta-analysis to summarise the dose–response relationships between egg consumption and the risk of breast, prostate and gynaecological cancers. A literature search was performed using PubMed and Embase up to April 2015 to identify relevant prospective observational studies. Summary relative risk (RR) and 95 % CI were estimated using a random-effects model. For breast cancer, the linear dose–response meta-analysis found a non-significantly increased risk (RR for an increase of 5 eggs consumed/week: 1·05, 95 % CI 0·99, 1·11, n 16 023 cases). Evidence for non-linearity was not statistically significant (Pnon-linearity= 0·50, n 15 415 cases) but consuming ≥ 5 eggs/week was significantly associated with an increased risk of breast cancer compared with no egg consumption, with the summary RR being 1·04 (95 % CI 1·01, 1·07) for consuming 5 eggs/week and 1·09 (95 % CI 1·03, 1·15) for consuming about 9 eggs/week. For other cancers investigated, the summary RR for an increase of 5 eggs consumed/week was 1·09 (95 % CI 0·96, 1·24, n 2636 cases) for ovarian cancer; 1·47 (95 % CI 1·01, 2·14, n 609 cases) for fatal prostate cancer, with evidence of small-study effects (PEgger= 0·04). No evidence was found for an association with the risk of total prostate cancer. While our conclusion was tempered by the potential for publication bias and confounding, high egg intake may be associated with a modestly elevated risk of breast cancer, and a positive association between egg intake and ovarian and fatal prostate cancers cannot be ruled out.
HEALTH PROFESSIONALS’ USER EXPERIENCE OF THE INTELLIGENT BED IN PATIENTS’ HOMES
Authors: Cai Hao , Toft Egon , Hejlesen Ole , Hansen John , Oestergaard Claus , Dinesen Birthe
Published: August 2015

Background: The intelligent bed is a medical bed with several home healthcare functions. It includes, among others, an “out of bed” detector, a moisture detector, and a catheter bag detector. The design purpose of the intelligent bed is to assist patients in their daily living, facilitate the work of clinical staff, and improves the quality of care. The aim of this sub-study of the iCare project was to explore how health professionals (HPs) experience and use the intelligent bed in patients’ homes.

Methods: The overall research design is inspired by case study methodology. A triangulation of data collection techniques has been used: log book, documentation study, participant observations (n = 45 hr), and qualitative interviews (n = 23). The data have been analyzed by means of Nvivo 9.0.

Findings: We identified several themes: HP transformation from passive technology recipient to innovator; individualized care; work flow redesign; and sensor technology intruding on patient privacy.

Conclusions: It is suggested that functions of the intelligent bed can result in more individualized care, workflow redesign, and time savings for the health professionals in caring for elderly patients. However, the technology intruded on patients’ privacy.
How Threats to Masculinity Sequentially Cause Public Discomfort,	Anger, and Ideological Dominance Over Women
Authors: Dahl Julia , Vescio Theresa , Weaver Kevin
Published: August 2015

Abstract. This research examined whether threats to masculinity both inspired men’s efforts to reestablish their power over women via the promotion of ideologies that implicitly subordinate women and occurred when men were outperformed by women in masculine domains. Masculinity was threatened by telling men they scored like women on a gender knowledge test ( Rudman & Fairchild, 2004 ), which sequentially led to more concern about how they were perceived by others, increased anger, and the increased endorsement of social dominance orientation (Study 1a) and benevolent sexism (Study 1b). Study 2 additionally shows that men experienced threats to masculinity when outperformed by women in masculine domains; when outperformed by a woman, men reported more concern about how they looked to others, which predicted increased anger and the subsequent sexualization of the woman. The findings link masculinity threats to the promotion of ideologies that implicitly subordinate women; the consequences of these linkages are discussed.
Contribution of neutral processes to the assembly of gut microbial communities in the zebrafish over host development
Authors: Burns Adam R , Stephens W Zac , Stagaman Keaton , Wong Sandi , Rawls John F , Guillemin Karen , Bohannan Brendan J M
Published: August 2015

Despite their importance to host health and development, the communities of microorganisms associated with humans and other animals are characterized by a large degree of unexplained variation across individual hosts. The processes that drive such inter-individual variation are not well understood. To address this, we surveyed the microbial communities associated with the intestine of the zebrafish, Danio rerio, over developmental time. We compared our observations of community composition and distribution across hosts with that predicted by a neutral assembly model, which assumes that community assembly is driven solely by chance and dispersal. We found that as hosts develop from larvae to adults, the fit of the model to observed microbial distributions decreases, suggesting that the relative importance of non-neutral processes, such as microbe-microbe interactions, active dispersal, or selection by the host, increases as hosts mature. We also observed that taxa which depart in their distributions from the neutral prediction form ecologically distinct sub-groups, which are phylogenetically clustered with respect to the full metacommunity. These results demonstrate that neutral processes are sufficient to generate substantial variation in microbiota composition across individual hosts, and suggest that potentially unique or important taxa may be identified by their divergence from neutral distributions.
Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals
Authors: Nagasaki Masao , Yasuda Jun , Katsuoka Fumiki , Nariai Naoki , Kojima Kaname , Kawai Yosuke , Yamaguchi-Kabata Yumi , Yokozawa Junji , Danjoh Inaho , Saito Sakae , Sato Yukuto , Mimori Takahiro , Tsuda Kaoru , Saito Rumiko , Pan Xiaoqing , Nishikawa Satoshi , Ito Shin , Kuroki Yoko , Tanabe Osamu , Fuse Nobuo , Kuriyama Shinichi , Kiyomoto Hideyasu , Hozawa Atsushi , Minegishi Naoko , Douglas Engel James , Kinoshita Kengo , Kure Shigeo , Yaegashi Nobuo ,   ToMMo Japanese Reference Panel Project, Tsuboi Akito , Nagami Fuji , Kawame Hiroshi , Tomita Hiroaki , Tsuji Ichiro , Nakaya Jun , Sugawara Junichi , Suzuki Kichiya , Kikuya Masahiro , Abe Michiaki , Nakaya Naoki , Osumi Noriko , Yamashita Riu , Ogishima Soichi , Takai Takako , Tominaga Teiji , Taki Yasuyuki , Suzuki Yoichi , Yamamoto Masayuki
Published: August 2015

The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 × on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants. The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency ≥0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies.
Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells
Authors: Ruiz Sergio , Lopez-Contreras Andres J. , Gabut Mathieu , Marion Rosa M. , Gutierrez-Martinez Paula , Bua Sabela , Ramirez Oscar , Olalde Iñigo , Rodrigo-Perez Sara , Li Han , Marques-Bonet Tomas , Serrano Manuel , Blasco Maria A. , Batada Nizar N. , Fernandez-Capetillo Oscar
Published: August 2015

The generation of induced pluripotent stem cells (iPSC) from adult somatic cells is one of the most remarkable discoveries in recent decades. However, several works have reported evidence of genomic instability in iPSC, raising concerns on their biomedical use. The reasons behind the genomic instability observed in iPSC remain mostly unknown. Here we show that, similar to the phenomenon of oncogene-induced replication stress, the expression of reprogramming factors induces replication stress. Increasing the levels of the checkpoint kinase 1 (CHK1) reduces reprogramming-induced replication stress and increases the efficiency of iPSC generation. Similarly, nucleoside supplementation during reprogramming reduces the load of DNA damage and genomic rearrangements on iPSC. Our data reveal that lowering replication stress during reprogramming, genetically or chemically, provides a simple strategy to reduce genomic instability on mouse and human iPSC.
Ubiquitination switches EphA2 vesicular traffic from a continuous safeguard to a finite signalling mode
Authors: Sabet Ola , Stockert Rabea , Xouri Georgia , Brüggemann Yannick , Stanoev Angel , Bastiaens Philippe I. H.
Published: August 2015

Autocatalytic phosphorylation of receptor tyrosine kinases (RTKs) enables diverse, context-dependent responses to extracellular signals but comes at the price of autonomous, ligand-independent activation. Using a conformational biosensor that reports on the kinase activity of the cell guidance ephrin receptor type-A (EphA2) in living cells, we observe that autonomous EphA2 activation is suppressed by vesicular recycling and dephosphorylation by protein tyrosine phosphatases 1B (PTP1B) near the pericentriolar recycling endosome. This spatial segregation of catalytically superior PTPs from RTKs at the plasma membrane is essential to preserve ligand responsiveness. Ligand-induced clustering, on the other hand, promotes phosphorylation of a c-Cbl docking site and ubiquitination of the receptor, thereby redirecting it to the late endosome/lysosome. We show that this switch from cyclic to unidirectional receptor trafficking converts a continuous suppressive safeguard mechanism into a transient ligand-responsive signalling mode.
Automated adaptive inference of phenomenological dynamical models
Authors: Daniels Bryan C. , Nemenman Ilya
Published: August 2015

Dynamics of complex systems is often driven by large and intricate networks of microscopic interactions, whose sheer size obfuscates understanding. With limited experimental data, many parameters of such dynamics are unknown, and thus detailed, mechanistic models risk overfitting and making faulty predictions. At the other extreme, simple ad hoc models often miss defining features of the underlying systems. Here we develop an approach that instead constructs phenomenological, coarse-grained models of network dynamics that automatically adapt their complexity to the available data. Such adaptive models produce accurate predictions even when microscopic details are unknown. The approach is computationally tractable, even for a relatively large number of dynamical variables. Using simulated data, it correctly infers the phase space structure for planetary motion, avoids overfitting in a biological signalling system and produces accurate predictions for yeast glycolysis with tens of data points and over half of the interacting species unobserved.
Correction: Corrigendum: miR-218 is essential to establish motor neuron fate as a downstream effector of Isl1–Lhx3
Authors: Thiebes Karen P. , Nam Heejin , Cambronne Xiaolu A. , Shen Rongkun , Glasgow Stacey M. , Cho Hyong-Ho , Kwon Ji-sun , Goodman Richard H. , Lee Jae W. , Lee Seunghee , Lee Soo-Kyung
Published: August 2015

Nature Communications 6: Article number: 7718 (2015); Published: 27 July 2014; Updated: 21 August 2015. The financial support for this Article was not fully acknowledged. The second sentence of the Acknowledgements should have read: This research was supported by grants from NIH/NINDS (R01 NS054941), the March of Dimes Foundation and the Christopher and Dana Reeve Foundation (to S.
Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia
Authors: Pillinger Genevra , Abdul-Aziz Amina , Zaitseva Lyubov , Lawes Matthew , MacEwan David J. , Bowles Kristian M. , Rushworth Stuart A.
Published: August 2015

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton’s tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML.
Rheostatic Regulation of the SERCA/Phospholamban Membrane Protein Complex Using Non-Coding RNA and Single-Stranded DNA oligonucleotides
Authors: Soller Kailey J. , Verardi Raffaello , Jing Meng , Abrol Neha , Yang Jing , Walsh Naomi , Vostrikov Vitaly V. , Robia Seth L. , Bowser Michael T. , Veglia Gianluigi
Published: August 2015

The membrane protein complex between sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLN) is a prime therapeutic target for reversing cardiac contractile dysfunctions caused by calcium mishandling. So far, however, efforts to develop drugs specific for this protein complex have failed. Here, we show that non-coding RNAs and single-stranded DNAs (ssDNAs) interact with and regulate the function of the SERCA/PLN complex in a tunable manner. Both in HEK cells expressing the SERCA/PLN complex, as well as in cardiac sarcoplasmic reticulum preparations, these short oligonucleotides bind and reverse PLN’s inhibitory effects on SERCA, increasing the ATPase’s apparent Ca2+ affinity. Solid-state NMR experiments revealed that ssDNA interacts with PLN specifically, shifting the conformational equilibrium of the SERCA/PLN complex from an inhibitory to a non-inhibitory state. Importantly, we achieved rheostatic control of SERCA function by modulating the length of ssDNAs. Since restoration of Ca2+ flux to physiological levels represents a viable therapeutic avenue for cardiomyopathies, our results suggest that oligonucleotide-based drugs could be used to fine-tune SERCA function to counterbalance the extent of the pathological insults.
Enhanced marine sulphur emissions offset global warming and impact rainfall
Authors: Grandey B. S. , Wang C.
Published: August 2015

Artificial fertilisation of the ocean has been proposed as a possible geoengineering method for removing carbon dioxide from the atmosphere. The associated increase in marine primary productivity may lead to an increase in emissions of dimethyl sulphide (DMS), the primary source of sulphate aerosol over remote ocean regions, potentially causing direct and cloud-related indirect aerosol effects on climate. This pathway from ocean fertilisation to aerosol induced cooling of the climate may provide a basis for solar radiation management (SRM) geoengineering. In this study, we investigate the transient climate impacts of two emissions scenarios: an RCP4.5 (Representative Concentration Pathway 4.5) control; and an idealised scenario, based on RCP4.5, in which DMS emissions are substantially enhanced over ocean areas. We use mini-ensembles of a coupled atmosphere-ocean configuration of CESM1(CAM5) (Community Earth System Model version 1, with the Community Atmosphere Model version 5). We find that the cooling effect associated with enhanced DMS emissions beneficially offsets greenhouse gas induced warming across most of the world. However, the rainfall response may adversely affect water resources, potentially impacting human livelihoods. These results demonstrate that changes in marine phytoplankton activity may lead to a mixture of positive and negative impacts on the climate.
Rapid Particle Patterning in Surface Deposited Micro-Droplets of Low Ionic Content via Low-Voltage Electrochemistry and Electrokinetics
Authors: Sidelman Noam , Cohen Moshik , Kolbe Anke , Zalevsky Zeev , Herrman Andreas , Richter Shachar
Published: August 2015

Electrokinetic phenomena are a powerful tool used in various scientific and technological applications for the manipulation of aqueous solutions and the chemical entities within them. However, the use of DC-induced electrokinetics in miniaturized devices is highly limited. This is mainly due to unavoidable electrochemical reactions at the electrodes, which hinder successful manipulation. Here we present experimental evidence that on-chip DC manipulation of particles between closely positioned electrodes inside micro-droplets can be successfully achieved and at low voltages. We show that such manipulation, which is considered practically impossible, can be used to rapidly concentrate and pattern particles in 2D shapes in inter-electrode locations. We show that this is made possible in low ion content dispersions, which enable low-voltage electrokinetics and an anomalous bubble-free water electrolysis. This phenomenon can serve as a powerful tool in both microflow devices and digital microfluidics for rapid pre-concentration and particle patterning.
The Architecture of the TIR Domain Signalosome in the Toll-like Receptor-4 Signaling Pathway
Authors: Guven-Maiorov Emine , Keskin Ozlem , Gursoy Attila , VanWaes Carter , Chen Zhong , Tsai Chung-Jung , Nussinov Ruth
Published: August 2015

Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro- and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro- and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro- and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways.
Carbon dioxide level and form of soil nitrogen regulate assimilation of atmospheric ammonia in young trees
Authors: Silva Lucas C. R. , Salamanca-Jimenez Alveiro , Doane Timothy A. , Horwath William R.
Published: August 2015

The influence of carbon dioxide (CO2) and soil fertility on the physiological performance of plants has been extensively studied, but their combined effect is notoriously difficult to predict. Using Coffea arabica as a model tree species, we observed an additive effect on growth, by which aboveground productivity was highest under elevated CO2 and ammonium fertilization, while nitrate fertilization favored greater belowground biomass allocation regardless of CO2 concentration. A pulse of labelled gases (13CO2 and 15NH3) was administered to these trees as a means to determine the legacy effect of CO2 level and soil nitrogen form on foliar gas uptake and translocation. Surprisingly, trees with the largest aboveground biomass assimilated significantly less NH3 than the smaller trees. This was partly explained by declines in stomatal conductance in plants grown under elevated CO2. However, unlike the 13CO2 pulse, assimilation and transport of the 15NH3 pulse to shoots and roots varied as a function of interactions between stomatal conductance and direct plant response to the form of soil nitrogen, observed as differences in tissue nitrogen content and biomass allocation. Nitrogen form is therefore an intrinsic component of physiological responses to atmospheric change, including assimilation of gaseous nitrogen as influenced by plant growth history.
Population genetic diversity and hybrid detection in captive zebras
Authors: Ito Hideyuki , Langenhorst Tanya , Ogden Rob , Inoue-Murayama Miho
Published: August 2015

Zebras are members of the horse family. There are three species of zebras: the plains zebra Equus quagga, the Grevy’s zebra E. grevyi and the mountain zebra E. zebra. The Grevy’s zebra and the mountain zebra are endangered and hybridization between the Grevy’s zebra and the plains zebra has been documented, leading to a requirement for conservation genetic management within and between the species. We characterized 28 microsatellite markers in Grevy’s zebra and assessed cross-amplification in plains zebra and two of its subspecies, as well as mountain zebra. A range of standard indices were employed to examine population genetic diversity and hybrid populations between Grevy’s and plains zebra were simulated to investigate subspecies and hybrid detection. Microsatellite marker polymorphism was conserved across species with sufficient variation to enable individual identification in all populations. Comparative diversity estimates indicated greater genetic variation in plains zebra and its subspecies than Grevy’s zebra, despite potential ascertainment bias. Species and subspecies differentiation were clearly demonstrated and F1 and F2 hybrids were correctly identified. These findings provide insights into captive population genetic diversity in zebras and support the use of these markers for identifying hybrids, including the known hybrid issue in the endangered Grevy’s zebra.
Erratum: High-frame rate four dimensional optoacoustic tomography enables visualization of cardiovascular dynamics and mouse heart perfusion
Authors: Deán-Ben Xosé Luís , Ford Steven James , Razansky Daniel
Published: August 2015

Functional imaging of mouse models of cardiac health and disease provides a major contribution to our fundamental understanding of the mammalian heart. However, imaging murine hearts presents significant challenges due to their small size and rapid heart rate. Here we demonstrate the feasibility of high-frame-rate, noninvasive optoacoustic imaging of the murine heart. The temporal resolution of 50 three-dimensional frames per second provides functional information at important phases of the cardiac cycle without the use of gating or other motion-reduction methods. Differentiation of the blood oxygenation state in the heart chambers was enabled by exploiting the wavelength dependence of optoacoustic signals. Real-time volumetric tracking of blood perfusion in the cardiac chambers was also evaluated using indocyanine green. Taken together, the newly-discovered capacities offer a unique tool set for in-vivo structural and functional imaging of the whole heart with high spatio-temporal resolution in all three dimensions.
Sacrificial adhesive bonding: a powerful method for fabrication of glass microchips
Authors: Lima Renato S. , Leão Paulo A. G. C. , Piazzetta Maria H. O. , Monteiro Alessandra M. , Shiroma Leandro Y. , Gobbi Angelo L. , Carrilho Emanuel
Published: August 2015

A new protocol for fabrication of glass microchips is addressed in this research paper. Initially, the method involves the use of an uncured SU-8 intermediate to seal two glass slides irreversibly as in conventional adhesive bonding-based approaches. Subsequently, an additional step removes the adhesive layer from the channels. This step relies on a selective development to remove the SU-8 only inside the microchannel, generating glass-like surface properties as demonstrated by specific tests. Named sacrificial adhesive layer (SAB), the protocol meets the requirements of an ideal microfabrication technique such as throughput, relatively low cost, feasibility for ultra large-scale integration (ULSI) and high adhesion strength, supporting pressures on the order of 5 MPa. Furthermore, SAB eliminates the use of high temperature, pressure, or potential, enabling the deposition of thin films for electrical or electrochemical experiments. Finally, the SAB protocol is an improvement on SU-8-based bondings described in the literature. Aspects such as substrate/resist adherence, formation of bubbles and thermal stress were effectively solved by using simple and inexpensive alternatives.
MicroRNA-107 contributes to post-stroke angiogenesis by targeting Dicer-1
Authors: Li Yanan , Mao Ling , Gao Yuan , Baral Suraj , Zhou Yifan , Hu Bo
Published: August 2015

Previous studies have suggested that microRNA-107 (miR-107) regulates cell migration in tumor and promotes Hypoxia Inducible Factor 1α (HIF1α) regulated angiogenesis under hypoxia. We found that miR-107 was strongly expressed in ischemic boundary zone (IBZ) after permanent middle cerebral artery occlusion (pMCAO) in rats and inhibition of miR-107 could reduce capillary density in the IBZ after stroke. Such finding led us to hypothesize that miR-107 might regulate post-stroke angiogenesis and therefore serve as a therapeutic target. We also found that antagomir-107, a synthetic miR-107 inhibitor, decreased the number of capillaries in IBZ and increased overall infarct volume after pMCAO in rats. We demonstrated that miR-107 could directly down-regulate Dicer-1, a gene that encodes an enzyme essential for processing microRNA (miRNA) precursors. This resulted in translational desupression of VEGF (vascular endothelial growth factor) mRNA, thereby increasing expression of endothelial cell-derived VEGF (VEGF165/VEGF164), leading to angiogenesis after stroke. This process might be a protective mechanism for ischemia-induced cerebral injury and miR-107 might be used as a novel tool in stroke treatment.