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1.  Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis 
Neoplasia (New York, N.Y.)  2016;19(2):75-83.
Mutation of the PARK2 gene can promote both Parkinson's Disease and cancer, yet the underlying mechanisms of how PARK2 controls cellular physiology is incompletely understood. Here, we show that the PARK2 tumor suppressor controls the apoptotic regulator BCL-XL and modulates programmed cell death. Analysis of approximately 10,000 tumor genomes uncovers a striking pattern of mutual exclusivity between PARK2 genetic loss and amplification of BCL2L1, implicating these genes in a common pathway. PARK2 directly binds to and ubiquitinates BCL-XL. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL both in vitro and in vivo, and cancer-specific mutations in PARK2 abrogate the ability of the ubiquitin E3 ligase to target BCL-XL for degradation. Furthermore, PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Thus, like genes at the nodal points of growth arrest pathways such as p53, the PARK2 tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death.
doi:10.1016/j.neo.2016.12.006
PMCID: PMC5198112  PMID: 28038320
2.  Structural mechanism of the enhanced glass-forming ability in multicomponent alloys with positive heat of mixing 
Scientific Reports  2016;6:38098.
The issue, microalloying certain element with positive heat of mixing leading to the enhanced glass forming ability (GFA) in multicomponent alloys, has been investigated by systematic experimental measurements coupled with theoretical calculations. It is found that in the Nb-doped CuZr alloys, strong interaction between Nb and Zr atoms leads to a shortened pair distance. In addition, fraction of the icosahedral-like local structures increases with Nb addition and Nb solutes are apt to be separated with each other. These factors contribute to an increase of the atomic level efficiency to fill space and formation of the short-to-medium range orderings. As a result, the amorphous structure is stabilized and the GFA is enhanced accordingly. This work provides an in-depth understanding of microalloying-induced high GFAs in multicomponent alloys and is helpful for guiding the development of more metallic glasses with high GFAs via microalloying, despite the positive heat of mixing between the constituent elements.
doi:10.1038/srep38098
PMCID: PMC5126686  PMID: 27897257
3.  Widespread use of gastric acid inhibitors in infants: Are they needed? Are they safe? 
Gastroesophageal reflux is a common phenomenon in infants, but the differentiation between gastroesophageal reflux and gastroesophageal reflux disease can be difficult. Symptoms are non-specific and there is increasing evidence that the majority of symptoms may not be acid-related. Despite this, gastric acid inhibitors such as proton pump inhibitors are widely and increasingly used, often without objective evidence or investigations to guide treatment. Several studies have shown that these medications are ineffective at treating symptoms associated with reflux in the absence of endoscopically proven oesophagitis. With a lack of evidence for efficacy, attention is now being turned to the potential risks of gastric acid suppression. Previously assumed safety of these medications is being challenged with evidence of potential side effects including GI and respiratory infections, bacterial overgrowth, adverse bone health, food allergy and drug interactions.
doi:10.4292/wjgpt.v7.i4.531
PMCID: PMC5095572  PMID: 27867686
Gastroesophageal reflux; Infants; Proton pump inhibitors; Ranitidine; Safety; Adverse events
5.  Hemodynamic Monitoring Using Switching Autoregressive Dynamics of Multivariate Vital Sign Time Series 
Computing in cardiology  2016;42:1065-1068.
In a critical care setting, shock and resuscitation endpoints are often defined based on arterial blood pressure values. Patient-specific fluctuations and interactions between heart rate (HR) and blood pressure (BP), however, may provide additional prognostic value to stratify individual patients’ risks for adverse outcomes at different blood pressure targets. In this work, we use the switching autoregressive (SVAR) dynamics inferred from the multivariate vital sign time series to stratify mortality risks of intensive care units (ICUs) patients receiving vasopressor treatment. We model vital sign observations as generated from latent states from an autoregressive Hidden Markov Model (AR-HMM) process, and use the proportion of time patients stayed in different latent states to predict outcome. We evaluate the performance of our approach using minute-by-minute HR and mean arterial BP (MAP) of an ICU patient cohort while on vasopressor treatment. Our results indicate that the bivariate HR/MAP dynamics (AUC 0.74 [0.64, 0.84]) contain additional prognostic information beyond the MAP values (AUC 0.53 [0.42, 0.63]) in mortality prediction. Further, HR/MAP dynamics achieved better performance among a subgroup of patients in a low MAP range (median MAP < 65 mmHg) while on pressors. A realtime implementation of our approach may provide clinicians a tool to quantify the effectiveness of interventions and to inform treatment decisions.
doi:10.1109/CIC.2015.7411098
PMCID: PMC5072525  PMID: 27774489
6.  Intestinal microbiota could transfer host Gut characteristics from pigs to mice 
BMC Microbiology  2016;16:238.
Background
The present study was conducted to compare the differences in gut microbiota composition and gut-phenotypes among pig breeds, and determine whether these differences would transmit to mice colonized with fecal microbiota of different pig breeds. A total of 24 1-day-old germ-free BALB/C mice were divided into 3 groups (TFM, YFM and RFM), which were transplanted with intact fecal microbiota of Tibetan pig (TP), Yorkshire pig (YP) and Rongchang pig (RP), respectively.
Results
Results showed that different pig breeds exhibited distinct gut microbiota profile based on high-throughput pyrosequencing. YP exhibited a lower Firmicutes/Bacteroidetes ratio and apparent genera differences compared with RP and TP, and higher levels of bacteria from Spirochaetes were observed in TP compared with RP and YP (P < 0.05). Transplanted porcine microbiota into GF mice replicated the phenotypes of pig donors. Moreover, the three groups of donor pigs and their mice recipients exhibited different intestinal index and morphology. TP and RP had higher intestinal weight and relative CDX2 mRNA expression in ileum than YP, and longer intestine, higher villus height of duodenum and jejunum were observed in TP compared with YP and RP (P < 0.05). TP exhibited higher GLP-2 mRNA expression in duodenum and jejunum than RP (P < 0.05). Similarly, YFM had lower intestine weight and CDX2 mRNA expression in ileum than TFM and RFM (P < 0.05). The intestine length in TFM was longer than that in RFM, and TFM had higher villus height in duodenum and jejunum and GLP-2 mRNA expression in ileum than the other two groups (P < 0.05). Besides, the digestive and absorptive ability was different among the three groups in donor pigs and mice recipients. YP had higher jejunal lactase and maltase activities than TP and RP, while TP had higher activities of jejunal ATPase, γ-GT, and relative SGLT1 mRNA expression in duodenum and jejunum than YP and RP (P < 0.05). Likewise, YFM had higher jejunal sucrase and maltase activities than TFM and RFM, whereas higher jejunal γ-GT activity and relative SGLT1 mRNA expression in duodenum and ileum were observed in TFM compared with YFM and RFM (P < 0.05). In addition, Tibetan pigs-derived microbiota improved gut barrier in mice recipients. The concentration of MDA in YP was higher than that in TP and RP (P = 0.078), and the relative ZO-1 mRNA expression in ileum in TP was higher than that in YP (P < 0.05). Likely, compared with TFM and RFM, YFM exhibited increasing MDA concentration in jejunum (P = 0.098), and the relative ZO-1 mRNA expression in duodenum and ileum in TFM were higher than that in YFM (P < 0.05).
Conclusions
There were huge differences in gut microbiota composition and gut characteristics among pig breeds, and gut microbiota could partially convey host gut characteristics from pigs to mice.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-016-0851-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-016-0851-z
PMCID: PMC5057279  PMID: 27729007
Pig breeds; Intestinal development; Digestive and absorptive activities; Germ-free mice; Fecal microbiota transplantation
7.  Transcription Factor Runx2 Promotes Aortic Fibrosis and Stiffness in Type 2 Diabetes 
Circulation research  2015;117(6):513-524.
Rationale
Accelerated arterial stiffening is a major complication of diabetes with no specific therapy available up to date.
Objective
The present study investigates the role of the osteogenic transcription factor Runx2 as a potential mediator and therapeutic target of aortic fibrosis and aortic stiffening in diabetes.
Methods and Results
Using a murine model of type 2 diabetes (db/db mice) we identify progressive structural aortic stiffening that precedes the onset of arterial hypertension. At the same time, Runx2 is aberrantly upregulated in the medial layer of db/db aortae as well as in thoracic aortic samples from type 2 diabetic patients. Vascular smooth muscle-specific overexpression of Runx2 in transgenic mice increases expression of its target genes, Col1a1 and Col1a2, leading to medial fibrosis and aortic stiffening. Interestingly, increased Runx2 expression per se is not sufficient to induce aortic calcification. Using in vivo and in vitro approaches, we further demonstrate that Runx2 expression in diabetes is regulated via a redox-sensitive pathway that involves a direct interaction of NF-κB with the Runx2 promoter.
Conclusion
In conclusion this study highlights Runx2 as a previously unrecognized inducer of vascular fibrosis in the setting of diabetes, promoting arterial stiffness irrespective of calcification.
doi:10.1161/CIRCRESAHA.115.306341
PMCID: PMC4553105  PMID: 26208651
Arterial stiffness; diabetes mellitus; extracellular matrix; oxidative stress; smooth muscle cell
8.  SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment 
Sun, Y | Zhu, D | Chen, F | Qian, M | Wei, H | Chen, W | Xu, J
Oncogene  2016;35(33):4321-4334.
Most tumors initially respond to cytotoxic treatments, but acquired resistance often follows. The tumor microenvironment (TME) is a major barrier to clinical success by compromising therapeutic efficacy, and pathological relevance of multiple soluble factors released by a therapeutically remodeled TME remains largely unexplored. Here we show that the secreted frizzled-related protein 2 (SFRP2), a Wnt pathway modulator, is produced by human primary fibroblasts after genotoxic treatments. SFRP2 induction is remarkable in tumor stroma, with transcription mainly modulated by the nuclear factor-κB (NF-κB) complex, a property shared by several effectors of the DNA damage secretory program. Instead of directly altering canonical Wnt signaling, SFRP2 augments β-catenin activities initiated by WNT16B, another soluble factor from DNA-damaged stroma. WNT16B recognizes cancer cell surface receptors including frizzled (FZD) 3/4/6, a process enhanced by SFRP2, coordinated by the co-receptor LRP6 but subject to abrogation by DKK1. Importantly, we found WNT16B plays a central role in promoting advanced malignancies particularly acquired resistance by counteracting cell death, an effect that can be minimized by a neutralizing antibody co-administered with classical chemotherapy. Furthermore, DNA damage-triggered expression of WNT16B is systemic, imaged by significant induction among diverse solid organs and circulation in peripheral blood, thereby holding promise as not only a TME-derived anticancer target but also a novel biomarker for clinical evaluation of treatment efficacy. Overall, our study substantiates the biological complexity and pathological implication of a therapy-activated TME, and provides the proof of principle of co-targeting tumor and the TME to prevent acquired resistance, with the aim of improving intervention outcome in an era of precision medicine.
doi:10.1038/onc.2015.494
PMCID: PMC4994019  PMID: 26751775
9.  MIMIC-III, a freely accessible critical care database 
Scientific Data  2016;3:160035.
MIMIC-III (‘Medical Information Mart for Intensive Care’) is a large, single-center database comprising information relating to patients admitted to critical care units at a large tertiary care hospital. Data includes vital signs, medications, laboratory measurements, observations and notes charted by care providers, fluid balance, procedure codes, diagnostic codes, imaging reports, hospital length of stay, survival data, and more. The database supports applications including academic and industrial research, quality improvement initiatives, and higher education coursework.
doi:10.1038/sdata.2016.35
PMCID: PMC4878278  PMID: 27219127
Outcomes research; Health care; Prognosis; Diagnosis; Medical research
10.  Event generator tunes obtained from underlying event and multiparton scattering measurements 
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A. | Janssen, X. | Knutsson, A. | Lauwers, J. | Luyckx, S. | Van De Klundert, M. | Van Haevermaet, H. | Van Mechelen, P. | Van Remortel, N. | Van Spilbeeck, A. | Abu Zeid, S. | Blekman, F. | D’Hondt, J. | Daci, N. | De Bruyn, I. | Deroover, K. | Heracleous, N. | Keaveney, J. | Lowette, S. | Moreels, L. | Olbrechts, A. | Python, Q. | Strom, D. | Tavernier, S. | Van Doninck, W. | Van Mulders, P. | Van Onsem, G. P. | Van Parijs, I. | Barria, P. | Brun, H. | Caillol, C. | Clerbaux, B. | De Lentdecker, G. | Fasanella, G. | Favart, L. | Grebenyuk, A. | Karapostoli, G. | Lenzi, T. | Léonard, A. | Maerschalk, T. | Marinov, A. | Perniè, L. | Randle-conde, A. | Seva, T. | Vander Velde, C. | Yonamine, R. | Vanlaer, P. | Yonamine, R. | Zenoni, F. | Zhang, F. | Adler, V. | Beernaert, K. | Benucci, L. | Cimmino, A. | Crucy, S. | Dobur, D. | Fagot, A. | Garcia, G. | Gul, M. | Mccartin, J. | Ocampo Rios, A. 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M. | Antunovic, Z. | Kovac, M. | Brigljevic, V. | Kadija, K. | Luetic, J. | Micanovic, S. | Sudic, L. | Attikis, A. | Mavromanolakis, G. | Mousa, J. | Nicolaou, C. | Ptochos, F. | Razis, P. A. | Rykaczewski, H. | Bodlak, M. | Finger, M. | Finger, M. | Abdelalim, A. A. | Awad, A. | Mahrous, A. | Mohammed, Y. | Radi, A. | Calpas, B. | Kadastik, M. | Murumaa, M. | Raidal, M. | Tiko, A. | Veelken, C. | Eerola, P. | Pekkanen, J. | Voutilainen, M. | Härkönen, J. | Karimäki, V. | Kinnunen, R. | Lampén, T. | Lassila-Perini, K. | Lehti, S. | Lindén, T. | Luukka, P. | Mäenpää, T. | Peltola, T. | Tuominen, E. | Tuominiemi, J. | Tuovinen, E. | Wendland, L. | Talvitie, J. | Tuuva, T. | Besancon, M. | Couderc, F. | Dejardin, M. | Denegri, D. | Fabbro, B. | Faure, J. L. | Favaro, C. | Ferri, F. | Ganjour, S. | Givernaud, A. | Gras, P. | Hamel de Monchenault, G. | Jarry, P. | Locci, E. | Machet, M. | Malcles, J. | Rander, J. | Rosowsky, A. | Titov, M. | Zghiche, A. | Antropov, I. | Baffioni, S. | Beaudette, F. | Busson, P. | Cadamuro, L. | Chapon, E. | Charlot, C. | Dahms, T. | Davignon, O. | Filipovic, N. | Granier de Cassagnac, R. | Jo, M. | Lisniak, S. | Mastrolorenzo, L. | Miné, P. | Naranjo, I. N. | Nguyen, M. | Ochando, C. | Ortona, G. | Paganini, P. | Pigard, P. | Regnard, S. | Salerno, R. | Sauvan, J. B. | Sirois, Y. | Strebler, T. | Yilmaz, Y. | Zabi, A. | Agram, J.-L. | Andrea, J. | Aubin, A. | Bloch, D. | Brom, J.-M. | Buttignol, M. | Chabert, E. C. | Chanon, N. | Collard, C. | Conte, E. | Coubez, X. | Fontaine, J.-C. | Gelé, D. | Goerlach, U. | Goetzmann, C. | Le Bihan, A.-C. | Merlin, J. A. | Skovpen, K. | Van Hove, P. | Gadrat, S. | Beauceron, S. | Bernet, C. | Boudoul, G. | Bouvier, E. | Carrillo Montoya, C. A. | Chierici, R. | Contardo, D. | Courbon, B. | Depasse, P. | El Mamouni, H. | Fan, J. | Fay, J. | Gascon, S. | Gouzevitch, M. | Ille, B. | Lagarde, F. | Laktineh, I. B. | Lethuillier, M. | Mirabito, L. | Pequegnot, A. L. | Perries, S. | Ruiz Alvarez, J. D. | Sabes, D. | Sgandurra, L. | Sordini, V. | Vander Donckt, M. | Verdier, P. | Viret, S. | Toriashvili, T. | Lomidze, D. | Autermann, C. | Beranek, S. | Edelhoff, M. | Feld, L. | Heister, A. | Kiesel, M. K. | Klein, K. | Lipinski, M. | Ostapchuk, A. | Preuten, M. | Raupach, F. | Schael, S. | Schulte, J. 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New sets of parameters (“tunes”) for the underlying-event (UE) modelling of the pythia8, pythia6 and herwig++ Monte Carlo event generators are constructed using different parton distribution functions. Combined fits to CMS UE proton–proton (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm {p}\mathrm {p}$$\end{document}pp) data at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s} = 7\,\text {TeV} $$\end{document}s=7TeV and to UE proton–antiproton (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm {p}\overline{\mathrm{p}} $$\end{document}pp¯) data from the CDF experiment at lower \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s}$$\end{document}s, are used to study the UE models and constrain their parameters, providing thereby improved predictions for proton–proton collisions at 13\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\text {TeV}$$\end{document}TeV. In addition, it is investigated whether the values of the parameters obtained from fits to UE observables are consistent with the values determined from fitting observables sensitive to double-parton scattering processes. Finally, comparisons are presented of the UE tunes to “minimum bias” (MB) events, multijet, and Drell–Yan (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \mathrm{q} \overline{\mathrm{q}} \rightarrow \mathrm{Z}/ \gamma ^* \rightarrow $$\end{document}qq¯→Z/γ∗→ lepton-antilepton+jets) observables at 7 and 8\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\text {TeV}$$\end{document}TeV, as well as predictions for MB and UE observables at 13\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\text {TeV}$$\end{document}TeV.
doi:10.1140/epjc/s10052-016-3988-x
PMCID: PMC4946872  PMID: 27471433
11.  Measurement of the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm{t}\overline{{\mathrm{t}}}$$\end{document}tt¯ production cross section in the all-jets final state in pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s}=8$$\end{document}s=8\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\text {TeV}$$\end{document}TeV 
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The cross section for \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm{t}\overline{{\mathrm{t}}}$$\end{document}tt¯ production in the all-jets final state is measured in pp collisions at a centre-of-mass energy of 8 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\text {TeV}$$\end{document}TeV at the LHC with the CMS detector, in data corresponding to an integrated luminosity of 18.4 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\text {fb}^{-1}$$\end{document}fb-1. The inclusive cross section is found to be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$275.6 \pm 6.1 \,\text {(stat)} \pm 37.8 \,\text {(syst)} \pm 7.2 \,\text {(lumi)} $$\end{document}275.6±6.1(stat)±37.8(syst)±7.2(lumi) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {\,pb}$$\end{document}\,pb. The normalized differential cross sections are measured as a function of the top quark transverse momenta, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p_{\mathrm {T}}$$\end{document}pT, and compared to predictions from quantum chromodynamics. The results are reported at detector, parton, and particle levels. In all cases, the measured top quark \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p_{\mathrm {T}}$$\end{document}pT spectra are significantly softer than theoretical predictions.
doi:10.1140/epjc/s10052-016-3956-5
PMCID: PMC4946853  PMID: 27471431
12.  Osteonecrosis of the femoral head: using CT, MRI and gross specimen to characterize the location, shape and size of the lesion 
The British Journal of Radiology  2015;88(1046):20140508.
Objective:
To investigate the accuracy of using CT and MRI to characterize lesions of osteonecrosis of the femoral head (ONFH).
Methods:
Coronal CT and MRI scans were performed on 30 femoral head specimens collected from 23 patients who had undertaken hip arthroplasty owing to ONFH. The results were compared with findings from coronal sectional gross specimens. Two radiologists independently measured the volume of necrotic lesions from CT and MR images using computer software, and the results were averaged. The volume of specimens' necrotic lesion was measured using the water displacement method.
Results:
There was a high degree of consistency between CT, MRI and the coronal sectional gross specimen on the location, shape and spatial structure of lesions. Differences of the lesion volume measured from CT and MR images were not statistically significant between two radiologists. The necrotic lesion volumes measured from CT and MR images and gross specimens were 22.07 ±5.35, 22.21 ± 5.15 and 21.12 ±4.96 cm3, respectively, and the differences were not statistically significant (F = 0.396; p = 0.674).
Conclusion:
For patients with ONFH in Association Research Circulation Osseous stage III or above, CT and MRI can accurately display the characterization of lesion.
Advances in knowledge:
The size and location of necrotic lesions are major factors associated with femoral head collapse. CT is superior to MRI in identifying subchondral fracture. CT can help diagnose and predict the prognosis of ONFH.
doi:10.1259/bjr.20140508
PMCID: PMC4614234  PMID: 25496444
13.  Measurement of differential cross sections for Higgs boson production in the diphoton decay channel in pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s}=8\,\text {TeV} $$\end{document}s=8TeV 
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A measurement is presented of differential cross sections for Higgs boson (H) production in pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s}=8$$\end{document}s=8\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\text {TeV}$$\end{document}TeV. The analysis exploits the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${H} \rightarrow {\gamma }{\gamma }$$\end{document}H→γγ decay in data corresponding to an integrated luminosity of 19.7\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\,\text {fb}^\text {-1}$$\end{document}fb-1 collected by the CMS experiment at the LHC. The cross section is measured as a function of the kinematic properties of the diphoton system and of the associated jets. Results corrected for detector effects are compared with predictions at next-to-leading order and next-to-next-to-leading order in perturbative quantum chromodynamics, as well as with predictions beyond the standard model. For isolated photons with pseudorapidities \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$|\eta |<2.5$$\end{document}|η|<2.5, and with the photon of largest and next-to-largest transverse momentum (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p_{\mathrm {T}} ^{\gamma }$$\end{document}pTγ) divided by the diphoton mass \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$m_{\gamma \gamma }$$\end{document}mγγ satisfying the respective conditions of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p_{\mathrm {T}} ^{\gamma }/m_{\gamma \gamma }> 1/3$$\end{document}pTγ/mγγ>1/3 and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${>}1/4$$\end{document}>1/4, the total fiducial cross section is \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$32 \pm 10$$\end{document}32±10\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {\,fb}$$\end{document}\,fb.
doi:10.1140/epjc/s10052-015-3853-3
PMCID: PMC4732665  PMID: 26855607
14.  Evolution of solidification texture during additive manufacturing 
Scientific Reports  2015;5:16446.
Striking differences in the solidification textures of a nickel based alloy owing to changes in laser scanning pattern during additive manufacturing are examined based on theory and experimental data. Understanding and controlling texture are important because it affects mechanical and chemical properties. Solidification texture depends on the local heat flow directions and competitive grain growth in one of the six <100> preferred growth directions in face centered cubic alloys. Therefore, the heat flow directions are examined for various laser beam scanning patterns based on numerical modeling of heat transfer and fluid flow in three dimensions. Here we show that numerical modeling can not only provide a deeper understanding of the solidification growth patterns during the additive manufacturing, it also serves as a basis for customizing solidification textures which are important for properties and performance of components.
doi:10.1038/srep16446
PMCID: PMC4639736  PMID: 26553246
15.  A Physiological Time Series Dynamics-Based Approach to Patient Monitoring and Outcome Prediction 
Cardiovascular variables such as heart rate (HR) and blood pressure (BP) are regulated by an underlying control system, and therefore, the time series of these vital signs exhibit rich dynamical patterns of interaction in response to external perturbations (e.g., drug administration), as well as pathological states (e.g., onset of sepsis and hypotension). A question of interest is whether “similar” dynamical patterns can be identified across a heterogeneous patient cohort, and be used for prognosis of patients’ health and progress. In this paper, we used a switching vector autoregressive framework to systematically learn and identify a collection of vital sign time series dynamics, which are possibly recurrent within the same patient and may be shared across the entire cohort. We show that these dynamical behaviors can be used to characterize the physiological “state” of a patient. We validate our technique using simulated time series of the cardiovascular system, and human recordings of HR and BP time series from an orthostatic stress study with known postural states. Using the HR and BP dynamics of an intensive care unit (ICU) cohort of over 450 patients from the MIMIC II database, we demonstrate that the discovered cardiovascular dynamics are significantly associated with hospital mortality (dynamic modes 3 and 9, p = 0.001, p = 0.006 from logistic regression after adjusting for the APACHE scores). Combining the dynamics of BP time series and SAPS-I or APACHE-III provided a more accurate assessment of patient survival/mortality in the hospital than using SAPS-I and APACHE-III alone (p = 0.005 and p = 0.045). Our results suggest that the discovered dynamics of vital sign time series may contain additional prognostic value beyond that of the baseline acuity measures, and can potentially be used as an independent predictor of outcomes in the ICU.
doi:10.1109/JBHI.2014.2330827
PMCID: PMC4346516  PMID: 25014976
Intensive care unit; physiological control systems; switching linear dynamical systems
16.  Enhanced immunoPET of ALCAM-positive colorectal carcinoma using site-specific 64Cu-DOTA conjugation 
Activated leukocyte cell adhesion molecule (ALCAM) is an immunoglobulin superfamily cell adhesion molecule that is aberrantly expressed in a wide variety of human tumors, including melanoma, prostate cancer, breast cancer, colorectal carcinoma, bladder cancer and pancreatic adenocarcinoma. This wide spectrum of human malignancies makes ALCAM a prospective pan-cancer immunoPET target to aid in detection and diagnosis in multiple malignancies. In this study, we assess site-specific versus non-site-specific conjugation strategies for 64Cu-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) immunoPET imaging of a fully human ALCAM cys-diabody (cDb) with a reduced linker length that retains its bivalent binding ability. ALCAM constructs with linker lengths of eight, five and three amino acids were produced to make true non-covalent site-specifically modified cDbs. Characterization by gel electrophoresis, size exclusion chromatography, flow cytometry and mass spectrometry of the various constructs was performed. To demonstrate the increased utility of targeting multiple malignancies expressing ALCAM, we compare the targeting of the site-specific versus non-site-specific conjugated cDbs to the human colorectal cancer xenograft LS174T. Interestingly, the conjugation strategy not only affects tumor targeting but also hepatic and renal uptake/clearance.
doi:10.1093/protein/gzu030
PMCID: PMC4191443  PMID: 25095796
ALCAM; Cu-64; DOTA; immunoPET; site-specific conjugation
17.  Controlling spin-dependent tunneling by bandgap tuning in epitaxial rocksalt MgZnO films 
Scientific Reports  2014;4:7277.
Widespread application of magnetic tunnel junctions (MTJs) for information storage has so far been limited by the complicated interplay between tunnel magnetoresistance (TMR) ratio and the product of resistance and junction area (RA). An intricate connection exists between TMR ratio, RA value and the bandgap and crystal structure of the barrier, a connection that must be unravelled to optimise device performance and enable further applications to be developed. Here, we demonstrate a novel method to tailor the bandgap of an ultrathin, epitaxial Zn-doped MgO tunnel barrier with rocksalt structure. This structure is attractive due to its good Δ1 spin filtering effect, and we show that MTJs based on tunable MgZnO barriers allow effective balancing of TMR ratio and RA value. In this way spin-dependent transport properties can be controlled, a key challenge for the development of spintronic devices.
doi:10.1038/srep07277
PMCID: PMC4250913  PMID: 25451163
18.  Ca2+ signaling in human induced pluripotent stem cell-derived cardiomyocytes (iPS-CM) from normal and catecholaminergic polymorphic ventricular tachycardia (CPVT)-afflicted subjects 
Cell calcium  2013;54(2):57-70.
Derivation of cardiomyocytes from induced pluripotent stem cells (iPS-CMs) allowed us to probe the Ca2+-signaling parameters of human iPS-CMs from healthy- and catecholaminergic polymorphic ventricular tachycardia (CPVT1)-afflicted individuals carrying a novel point mutation p.F2483I in ryanodine receptors (RyR2). iPS-CMs were dissociated on day 30–40 of differentiation and patch-clamped within 3–6 days. Calcium currents (ICa) averaged ~8 pA/pF in control and mutant iPS-CMs. ICa-induced Ca2+-transients in control and mutant cells had bell-shaped voltage-dependence similar to that of ICa, consistent with Ca2+-induced Ca2+-release (CICR) mechanism. The ratio of ICa-activated to caffeine-triggered Ca2+-transients was ~0.3 in both cell types. Caffeine-induced Ca2+-transients generated significantly smaller Na+–Ca2+ exchanger current (INCX) in mutant cells, reflecting their smaller Ca2+-stores. The gain of CICR was voltage-dependent as in adult cardiomyocytes. Adrenergic agonists enhanced ICa, but differentially altered the CICR gain, diastolic Ca2+, and Ca2+-sparks in mutant cells. The mutant cells, when Ca2+-overloaded, showed longer and wandering Ca2+-sparks that activated adjoining release sites, had larger CICR gain at −30 mV yet smaller Ca2+-stores. We conclude that control and mutant iPS-CMs express the adult cardiomyocyte Ca2+-signaling phenotype. RyR2 F2483I mutant myocytes have aberrant unitary Ca2+-signaling, smaller Ca2+-stores, higher CICR gains, and sensitized adrenergic regulation, consistent with functionally altered Ca2+-release profile of CPVT syndrome.
doi:10.1016/j.ceca.2013.04.004
PMCID: PMC3781932  PMID: 23684427
Mutation in RyR2 gene; Pluripotent stem cells; CPVT; Calcium signaling; CICR gain
19.  Deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis 
Oncotarget  2014;5(16):6976-6982.
PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly, heterozygous loss of Ptprd was sufficient to promote tumorigenesis in our model, suggesting that Ptprd may be a haploinsufficient tumor suppressor. The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.
PMCID: PMC4196177  PMID: 25138050
PTPRD; CDKN2A
20.  A century of variation in the dependence of Greenland iceberg calving on ice sheet surface mass balance and regional climate change 
Iceberg calving is a major component of the total mass balance of the Greenland ice sheet (GrIS). A century-long record of Greenland icebergs comes from the International Ice Patrol's record of icebergs (I48N) passing latitude 48° N, off Newfoundland. I48N exhibits strong interannual variability, with a significant increase in amplitude over recent decades. In this study, we show, through a combination of nonlinear system identification and coupled ocean–iceberg modelling, that I48N's variability is predominantly caused by fluctuation in GrIS calving discharge rather than open ocean iceberg melting. We also demonstrate that the episodic variation in iceberg discharge is strongly linked to a nonlinear combination of recent changes in the surface mass balance (SMB) of the GrIS and regional atmospheric and oceanic climate variability, on the scale of the previous 1–3 years, with the dominant causal mechanism shifting between glaciological (SMB) and climatic (ocean temperature) over time. We suggest that this is a change in whether glacial run-off or under-ice melting is dominant, respectively. We also suggest that GrIS calving discharge is episodic on at least a regional scale and has recently been increasing significantly, largely as a result of west Greenland sources.
doi:10.1098/rspa.2013.0662
PMCID: PMC4042714  PMID: 24910517
nonlinear auto-regressive moving average with exogenous modelling; Greenland icebergs; coupled ocean–iceberg model; twentieth century climate variation
21.  Tracking Progression of Patient State of Health in Critical Care Using Inferred Shared Dynamics in Physiological Time Series 
Physiologic systems generate complex dynamics in their output signals that reflect the changing state of the underlying control systems. In this work, we used a switching vector autoregressive (switching VAR) framework to systematically learn and identify a collection of vital sign dynamics, which can possibly be recurrent within the same patient and shared across the entire cohort. We show that these dynamical behaviors can be used to characterize and elucidate the progression of patients’ states of health over time. Using the mean arterial blood pressure time series of 337 ICU patients during the first 24 hours of their ICU stays, we demonstrated that the learned dynamics from as early as the first 8 hours of patients’ ICU stays can achieve similar hospital mortality prediction performance as the well-known SAPS-I acuity scores, suggesting that the discovered latent dynamics structure may yield more timely insights into the progression of a patient’s state of health than the traditional snapshot-based acuity scores.
doi:10.1109/EMBC.2013.6611187
PMCID: PMC4030703  PMID: 24111374
22.  Patient-specific fibre-based models of muscle wrapping 
Interface Focus  2013;3(2):20120062.
In many biomechanical problems, the availability of a suitable model for the wrapping of muscles when undergoing movement is essential for the estimation of forces produced on and by the body during motion. This is an important factor in the Osteoporotic Virtual Physiological Human project which is investigating the likelihood of fracture for osteoporotic patients undertaking a variety of movements. The weakening of their skeletons makes them particularly vulnerable to bone fracture caused by excessive loading being placed on the bones, even in simple everyday tasks. This paper provides an overview of a novel volumetric model that describes muscle wrapping around bones and other muscles during movement, and which includes a consideration of how the orientations of the muscle fibres change during the motion. The method can calculate the form of wrapping of a muscle of medium size and visualize the outcome within tenths of seconds on commodity hardware, while conserving muscle volume. This makes the method suitable not only for educational biomedical software, but also for clinical applications used to identify weak muscles that should be strengthened during rehabilitation or to identify bone stresses in order to estimate the risk of fractures.
doi:10.1098/rsfs.2012.0062
PMCID: PMC3638471  PMID: 24427519
musculoskeletal modelling; patient-specific model; motion fusion; muscle wrapping; Visualization Toolkit
23.  Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice 
Nutrition & Diabetes  2014;4(2):e108-.
Background:
Obesity is associated with reduced levels of circulating high-density lipoproteins (HDLs) and its major protein, apolipoprotein (apo) A-I. As a result of the role of HDL and apoA-I in cellular lipid transport, low HDL and apoA-I may contribute directly to establishing or maintaining the obese condition.
Methods:
To test this, male C57BL/6 wild-type (WT), apoA-I deficient (apoA-I−/−) and apoA-I transgenic (apoA-Itg/tg) mice were fed obesogenic diets (ODs) and monitored for several clinical parameters. We also performed cell culture studies.
Results:
ApoA-I−/− mice gained significantly more body weight and body fat than WT mice over 20 weeks despite their reduced food intake. During a caloric restriction regime imposed on OD-fed mice, apoA-I deficiency significantly inhibited the loss of body fat as compared with WT mice. Reduced body fat loss with caloric restriction in apoA-I−/− mice was associated with blunted stimulated adipose tissue lipolysis as verified by decreased levels of phosphorylated hormone-sensitive lipase (p-HSL) and lipolytic enzyme mRNA. In contrast to apoA-I−/− mice, apoA-Itg/tg mice gained relatively less weight than WT mice, consistent with other reports. ApoA-Itg/tg mice showed increased adipose tissue lipolysis, verified by increased levels of p-HSL and lipolytic enzyme mRNA. In cell culture studies, HDL and apoA-I specifically increased catecholamine-induced lipolysis possibly through modulating the adipocyte plasma membrane cholesterol content.
Conclusions:
Thus, apoA-I and HDL contribute to modulating body fat content by controlling the extent of lipolysis. ApoA-I and HDL are key components of lipid metabolism in adipose tissue and constitute new therapeutic targets in obesity.
doi:10.1038/nutd.2014.4
PMCID: PMC3940828  PMID: 24567123
HDL; caloric restriction; mice; obesity; hormone-sensitive lipase
25.  Discovering Shared Cardiovascular Dynamics within a Patient Cohort 
Cardiovascular variables such as heart rate (HR) and blood pressure (BP) are robustly regulated by an underlying control system. Time series of HR and BP exhibit distinct dynamical patterns of interaction in response to perturbations (e.g., drugs or exercise) as well as in pathological states (e.g., excessive sympathetic activation). A question of interest is whether “similar” dynamical patterns can be identified across a heterogeneous patient cohort. In this work, we present a technique based on switching linear dynamical systems for identification of shared dynamical patterns in the time series of HR and BP recorded from a patient cohort. The technique uses a mixture of linear dynamical systems, the components of which are shared across all patients, to capture both nonlinear dynamics and non-Gaussian perturbations. We present exploratory results based on a simulation study of the cardiovascular system, and real recordings from 10 healthy subjects undergoing a tilt-table test. These results demonstrate the ability of the proposed technique to identify similar dynamical patterns present across multiple time series.
doi:10.1109/EMBC.2012.6347489
PMCID: PMC3821961  PMID: 23367424
Cardiovascular control; switching linear dynamical systems; baroreflex

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