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1.  Quantitative Imaging of Single Upconversion Nanoparticles in Biological Tissue 
PLoS ONE  2013;8(5):e63292.
The unique luminescent properties of new-generation synthetic nanomaterials, upconversion nanoparticles (UCNPs), enabled high-contrast optical biomedical imaging by suppressing the crowded background of biological tissue autofluorescence and evading high tissue absorption. This raised high expectations on the UCNP utilities for intracellular and deep tissue imaging, such as whole animal imaging. At the same time, the critical nonlinear dependence of the UCNP luminescence on the excitation intensity results in dramatic signal reduction at (∼1 cm) depth in biological tissue. Here, we report on the experimental and theoretical investigation of this trade-off aiming at the identification of optimal application niches of UCNPs e.g. biological liquids and subsurface tissue layers. As an example of such applications, we report on single UCNP imaging through a layer of hemolyzed blood. To extend this result towards in vivo applications, we quantified the optical properties of single UCNPs and theoretically analyzed the prospects of single-particle detectability in live scattering and absorbing bio-tissue using a human skin model. The model predicts that a single 70-nm UCNP would be detectable at skin depths up to 400 µm, unlike a hardly detectable single fluorescent (fluorescein) dye molecule. UCNP-assisted imaging in the ballistic regime thus allows for excellent applications niches, where high sensitivity is the key requirement.
doi:10.1371/journal.pone.0063292
PMCID: PMC3653952  PMID: 23691012
3.  New Zealand supereruption provides time marker for the Last Glacial Maximum in Antarctica 
Scientific Reports  2017;7:12238.
Multiple, independent time markers are essential to correlate sediment and ice cores from the terrestrial, marine and glacial realms. These records constrain global paleoclimate reconstructions and inform future climate change scenarios. In the Northern Hemisphere, sub-visible layers of volcanic ash (cryptotephra) are valuable time markers due to their widespread dispersal and unique geochemical fingerprints. However, cryptotephra are not as widely identified in the Southern Hemisphere, leaving a gap in the climate record, particularly during the Last Glacial Maximum (LGM). Here we report the first identification of New Zealand volcanic ash in Antarctic ice. The Oruanui supereruption from Taupo volcano (25,580  ±  258 cal. a BP) provides a key time marker for the LGM in the New Zealand sector of the SW Pacific. This finding provides a high-precision chronological link to mid-latitude terrestrial and marine sites, and sheds light on the long-distance transport of tephra in the Southern Hemisphere. As occurred after identification of the Alaskan White River Ash in northern Europe, recognition of ash from the Oruanui eruption in Antarctica dramatically increases the reach and value of tephrochronology, providing links among climate records in widely different geographic areas and depositional environments.
doi:10.1038/s41598-017-11758-0
PMCID: PMC5613013  PMID: 28947829
4.  Tumor p38MAPK signaling enhances breast carcinoma vascularization and growth by promoting expression and deposition of pro-tumorigenic factors 
Oncotarget  2017;8(37):61969-61981.
The breast carcinoma microenvironment strikingly influences cancer progression and response to therapy. Various cell types in the carcinoma microenvironment show significant activity of p38 mitogen-activated protein kinase (MAPK), although the role of p38MAPK in breast cancer progression is still poorly understood. The present study examined the contribution of tumor p38MAPK to breast carcinoma microenvironment and metastatic capacity. Inactivation of p38MAPK signaling in metastatic breast carcinoma cells was achieved by forced expression of the kinase-inactive mutant of p38/MAPK14 (a dominant-negative p38, dn-p38). Disruption of tumor p38MAPK signaling reduced growth and metastases of breast carcinoma xenografts. Importantly, dn-p38 markedly decreased tumor blood-vessel density and lumen sizes. Mechanistic studies revealed that p38 controls expression of pro-angiogenic extracellular factors such as matrix protein Fibronectin and cytokines VEGFA, IL8, and HBEGF. Tumor-associated fibroblasts enhanced tumor growth and vasculature as well as increased expression of the pro-angiogenic factors. These effects were blunted by dn-p38. Metadata analysis showed elevated expression of p38 target genes in breast cancers and this was an unfavorable marker of disease recurrence and poor-outcome. Thus, our study demonstrates that tumor p38MAPK signaling promotes breast carcinoma growth, invasive and metastatic capacities. Importantly, p38 enhances carcinoma vascularization by facilitating expression and deposition of pro-angiogenic factors. These results argue that p38MAPK is a valuable target for anticancer therapy affecting tumor vasculature. Anti-p38 drugs may provide new therapeutic strategies against breast cancer, including metastatic disease.
doi:10.18632/oncotarget.18755
PMCID: PMC5617479
tumor microenvironment; breast cancer; p38MAPK; angiogenesis; fibronectin
5.  The value of transesophageal echocardiography for embolic strokes of undetermined source 
Neurology  2016;87(10):988-995.
Objective:
Our aim was to evaluate the diagnostic yield of transesophageal echocardiography (TEE) in consecutive patients with ischemic stroke (IS) fulfilling the diagnostic criteria of embolic strokes of undetermined source (ESUS).
Methods:
We prospectively evaluated consecutive patients with acute IS satisfying ESUS criteria who underwent in-hospital TEE examination in 3 tertiary care stroke centers during a 12-month period. We also performed a systematic review and meta-analysis estimating the cumulative effect of TEE findings on therapeutic management for secondary stroke prevention among different IS subgroups.
Results:
We identified 61 patients with ESUS who underwent investigation with TEE (mean age 44 ± 12 years, 49% men, median NIH Stroke Scale score = 5 points [interquartile range: 3–8]). TEE revealed additional findings in 52% (95% confidence interval [CI]: 40%–65%) of the study population. TEE findings changed management (initiation of anticoagulation therapy, administration of IV antibiotic therapy, and patent foramen ovale closure) in 10 (16% [95% CI: 9%–28%]) patients. The pooled rate of reported anticoagulation therapy attributed to abnormal TEE findings among 3,562 acute IS patients included in the meta-analysis (12 studies) was 8.7% (95% CI: 7.3%–10.4%). In subgroup analysis, the rates of initiation of anticoagulation therapy on the basis of TEE investigation did not differ (p = 0.315) among patients with cryptogenic stroke (6.9% [95% CI: 4.9%–9.6%]), ESUS (8.1% [95% CI: 3.4%–18.1%]), and IS (9.4% [95% CI: 7.5%–11.8%]).
Conclusions:
Abnormal TEE findings may decisively affect the selection of appropriate therapeutic strategy in approximately 1 of 7 patients with ESUS.
doi:10.1212/WNL.0000000000003063
PMCID: PMC5027807  PMID: 27488602
6.  Three-Dimensional Geometric Morphometric Analysis of Fossil Canid Mandibles and Skulls 
Scientific Reports  2017;7:9508.
Much of the fossil record for dogs consists of mandibles. However, can fossil canid mandibles be reliably identified as dogs or wolves? 3D geometric morphometric analysis correctly classifies 99.5% of the modern dog and wolf mandibles. However, only 4 of 26 Ust’-Polui fossil mandibles, a Russian Arctic site occupied from 250BCE to 150CE, were identified as dogs and none of the 20 Ivolgin mandibles, an Iron Age site in southern Russia, were identified as dogs. Three of the Ust’-Polui mandibles and 8 of the Ivolgin mandibles were identified as wolves. In contrast, all 12 Ivolgin skulls and 5 Ust’-Polui skulls were clearly identified as dogs. Only the classification of the UP6571 skull as a dog (Dog Posterior Probability = 1.0) was not supported by the typical probability. Other evidence indicates these canids were domesticated: they were located within human dwellings, remains at both sites have butchery marks indicating that they were consumed, and isotope analysis of canid and human remains from Ust’-Polui demonstrate that both were consuming freshwater protein; indicating that the humans were feeding the canids. Our results demonstrate that the mandible may not evolve as rapidly as the cranium and the mandible is not reliable for identifying early dog fossils.
doi:10.1038/s41598-017-10232-1
PMCID: PMC5573390  PMID: 28842717
7.  Theoretical and NMR-based Conformational Analysis of Phosphodiester-linked Disaccharides 
Scientific Reports  2017;7:8934.
The conformational behaviour of three phosphate-bridged dimannosides was studied by means of NMR and computational molecular modelling. First, the conformations of the phosphodiester linker were determined by quantum chemistry methods using dimethyl phosphate as a model. Then, a series of conformations was constructed for each of the studied molecules. Preliminary molecular dynamics (MD) simulations revealed that the inclusion of a cation had a drastic influence on the obtained results. Additionally, triethylammonium had the same effect as sodium as the counter-ion. After that, another series of MD simulations was run. The resulting MD trajectories were used to define the conformations responsible for the observed nuclear Overhauser effects and inter-nuclear coupling.
doi:10.1038/s41598-017-09055-x
PMCID: PMC5566550  PMID: 28827544
8.  Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma 
Science translational medicine  2017;9(396):eaak9969.
Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as EZH2. Using a focused genetic screen, we identified SESTRIN1 as a relevant target of the 6q deletion and demonstrate tumor suppression by SESTRIN1 in vivo. Moreover, SESTRIN1 is a direct target of the lymphoma-specific EZH2 gain-of-function mutation (EZH2Y641X). SESTRIN1 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. SESTRIN1 loss represents an alternative to RRAGC mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, EZH2Y641X mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies.
doi:10.1126/scitranslmed.aak9969
PMCID: PMC5559734  PMID: 28659443
9.  Megafauna of the UKSRL exploration contract area and eastern Clarion-Clipperton Zone in the Pacific Ocean: Annelida, Arthropoda, Bryozoa, Chordata, Ctenophora, Mollusca 
Background
There is growing interest in mining polymetallic nodules from the abyssal Clarion-Clipperton Zone (CCZ) in the tropical Pacific Ocean. Despite having been the focus of environmental studies for decades, the benthic megafauna of the CCZ remain poorly known. To predict and manage the environmental impacts of mining in the CCZ, baseline knowledge of the megafauna is essential. The ABYSSLINE Project has conducted benthic biological baseline surveys in the UK Seabed Resources Ltd polymetallic-nodule exploration contract area (UK-1). Prior to ABYSSLINE research cruises in 2013 and 2015, no biological studies had been done in this area of the eastern CCZ.
New information
Using a Remotely Operated Vehicle and Autonomous Underwater Vehicle (as well as several other pieces of equipment), the megafauna within the UK Seabed Resources Ltd exploration contract area (UK-1) and at a site ~250 km east of the UK-1 area were surveyed, allowing us to make the first estimates of megafaunal morphospecies richness from the imagery collected. Here, we present an atlas of the abyssal annelid, arthropod, bryozoan, chordate, ctenophore and molluscan megafauna observed and collected during the ABYSSLINE cruises to the UK-1 polymetallic-nodule exploration contract area in the CCZ. There appear to be at least 55 distinct morphospecies (8 Annelida, 12 Arthropoda, 4 Bryozoa, 22 Chordata, 5 Ctenophora, and 4 Mollusca) identified mostly by morphology but also using molecular barcoding for a limited number of animals that were collected. This atlas will aid the synthesis of megafaunal presence/absence data collected by contractors, scientists and other stakeholders undertaking work in the CCZ, ultimately helping to decipher the biogeography of the megafauna in this threatened habitat.
doi:10.3897/BDJ.5.e14598
PMCID: PMC5565845
deep-sea mining; polymetallic nodule; Clarion-Clipperton Zone; megafauna; atlas
10.  Fiducial, total and differential cross-section measurements of t-channel single top-quark production in pp collisions at 8 TeV using data collected by the ATLAS detector 
Aaboud, M. | Aad, G. | Abbott, B. | Abdallah, J. | Abdinov, O. | Abeloos, B. | AbouZeid, O. S. | Abraham, N. L. | Abramowicz, H. | Abreu, H. | Abreu, R. | Abulaiti, Y. | Acharya, B. S. | Adachi, S. | Adamczyk, L. | Adams, D. L. | Adelman, J. | Adomeit, S. | Adye, T. | Affolder, A. A. | Agatonovic-Jovin, T. | Aguilar-Saavedra, J. A. | Ahlen, S. P. | Ahmadov, F. | Aielli, G. | Akerstedt, H. | Åkesson, T. P. A. | Akimov, A. V. | Alberghi, G. L. | Albert, J. | Albrand, S. | Verzini, M. J. Alconada | Aleksa, M. | Aleksandrov, I. N. | Alexa, C. | Alexander, G. | Alexopoulos, T. | Alhroob, M. | Ali, B. | Aliev, M. | Alimonti, G. | Alison, J. | Alkire, S. P. | Allbrooke, B. M. M. | Allen, B. W. | Allport, P. P. | Aloisio, A. | Alonso, A. | Alonso, F. | Alpigiani, C. | Alshehri, A. A. | Alstaty, M. | Gonzalez, B. Alvarez | Piqueras, D. Álvarez | Alviggi, M. G. | Amadio, B. T. | Coutinho, Y. Amaral | Amelung, C. | Amidei, D. | Santos, S. P. 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M. | Brock, I. | Brock, R. | Brooijmans, G. | Brooks, T. | Brooks, W. K. | Brosamer, J. | Brost, E. | Broughton, J. H | de Renstrom, P. A. Bruckman | Bruncko, D. | Bruneliere, R. | Bruni, A. | Bruni, G. | Bruni, L. S. | Brunt, BH | Bruschi, M. | Bruscino, N. | Bryant, P. | Bryngemark, L. | Buanes, T. | Buat, Q. | Buchholz, P. | Buckley, A. G. | Budagov, I. A. | Buehrer, F. | Bugge, M. K. | Bulekov, O. | Bullock, D. | Burckhart, H. | Burdin, S. | Burgard, C. D. | Burger, A. M. | Burghgrave, B. | Burka, K. | Burke, S. | Burmeister, I. | Burr, J. T. P. | Busato, E. | Büscher, D. | Büscher, V. | Bussey, P. | Butler, J. M. | Buttar, C. M. | Butterworth, J. M. | Butti, P. | Buttinger, W. | Buzatu, A. | Buzykaev, A. R. | Urbán, S. Cabrera | Caforio, D. | Cairo, V. M. | Cakir, O. | Calace, N. | Calafiura, P. | Calandri, A. | Calderini, G. | Calfayan, P. | Callea, G. | Caloba, L. P. | Lopez, S. Calvente | Calvet, D. | Calvet, S. | Calvet, T. P. | Toro, R. 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Detailed measurements of t-channel single top-quark production are presented. They use 20.2 fb\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{-1}$$\end{document}-1 of data collected by the ATLAS experiment in proton–proton collisions at a centre-of-mass energy of 8 TeV at the LHC. Total, fiducial and differential cross-sections are measured for both top-quark and top-antiquark production. The fiducial cross-section is measured with a precision of 5.8% (top quark) and 7.8% (top antiquark), respectively. The total cross-sections are measured to be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sigma _{\text {tot}} (tq) = 56.7^{+4.3}_{-3.8}\;\mathrm{pb}$$\end{document}σtot(tq)=56.7-3.8+4.3pb for top-quark production and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sigma _{\text {tot}} (\bar{t} q) = 32.9^{+3.0}_{-2.7}\;\mathrm{pb}$$\end{document}σtot(t¯q)=32.9-2.7+3.0pb for top-antiquark production, in agreement with the Standard Model prediction. In addition, the ratio of top-quark to top-antiquark production cross-sections is determined to be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R_t=1.72 \pm 0.09$$\end{document}Rt=1.72±0.09. The differential cross-sections as a function of the transverse momentum and rapidity of both the top quark and the top antiquark are measured at both the parton and particle levels. The transverse momentum and rapidity differential cross-sections of the accompanying jet from the t-channel scattering are measured at particle level. All measurements are compared to various Monte Carlo predictions as well as to fixed-order QCD calculations where available.
doi:10.1140/epjc/s10052-017-5061-9
PMCID: PMC5589447
11.  p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli 
Aging (Albany NY)  2017;9(8):1867-1884.
Constitutive p16Ink4a expression, along with senescence-associated β-galactosidase (SAβG), are commonly accepted biomarkers of senescent cells (SCs). Recent reports attributed improvement of the healthspan of aged mice following p16Ink4a-positive cell killing to the eradication of accumulated SCs. However, detection of p16Ink4a/SAβG-positive macrophages in the adipose tissue of old mice and in the peritoneal cavity of young animals following injection of alginate-encapsulated SCs has raised concerns about the exclusivity of these markers for SCs. Here we report that expression of p16Ink4a and SAβG in macrophages is acquired as part of a physiological response to immune stimuli rather than through senescence, consistent with reports that p16Ink4a plays a role in macrophage polarization and response. Unlike SCs, p16Ink4a/SAβG-positive macrophages can be induced in p53-null mice. Macrophages, but not mesenchymal SCs, lose both markers in response to M1- [LPS, IFN-α, Poly(I:C)] and increase their expression in response to M2-inducing stimuli (IL-4, IL-13). Moreover, interferon-inducing agent Poly(I:C) dramatically reduced p16Ink4a expression in vivo in our alginate bead model and in the adipose tissue of aged mice. These observations suggest that the antiaging effects following eradication of p16Ink4a-positive cells may not be solely attributed to SCs but also to non-senescent p16Ink4a/SAβG-positive macrophages.
doi:10.18632/aging.101268
PMCID: PMC5611982  PMID: 28768895
aging; macrophage; senescent cell; p16(Ink4a); beta-galactosidase
12.  Early sleep apnea screening on a stroke unit is feasible in patients with acute cerebral ischemia 
Journal of neurology  2012;260(5):1343-1350.
Early screening for sleep apnea (SA) is rarely considered in patients with acute cerebral ischemia. We aimed to evaluate the feasibility of early SA screening on a stroke unit, its impact on post-discharge SA care and the relation of SA to clinical features. Patients with acute ischemic stroke (AIS) and transient ischemic attack (TIA) prospectively underwent overnight cardiorespiratory polygraphy within 3 ± 2 days of symptom-onset. Feasibility was defined as analyzable polygraphy in 90 % of studied patients. We enrolled 61 patients (84 % AIS, 16 % TIA): mean age 66 ± 8 years, 44 % men, median NIHSS 1 (0–15), median ESS 5 (0–13). Analyzability was given in 56/61 (91.8 %; one-sided 95 % CI, lower-bound 86.0 %) patients indicating excellent feasibility of early SA screening with no significant differences in stroke severity (100 % in TIA, 91 % minor stroke, 83 % major stroke, p = 0.474). Ninety-one percent (51/56) had an apnea–hypopnea index ≥5/h (median: 20/h [0–79]); 32 % (18/ 56) mild, 30 % (17/56) moderate, and 29 % (16/56) severe SA. When comparing sleep-related ischemic stroke (SIS) and non-SIS patients, no differences were found regarding the presence (95 vs. 89 %, p = 0.49) or severity (e.g., severe SA: 32 vs. 27 %, p = 0.69) of SA. After 12 months, 27/38 (71 %) patients given specific recommendations completed in-laboratory sleep work-up and 7/27 (25 %) were prescribed for non-invasive ventilatory correction. In conclusion, early SA screening is feasible in patients with acute cerebral ischemia and may have a positive impact on post-discharge SA care. Given the high frequency and atypical presentation of SA, early screening for SA should be considered in all acute cerebral ischemia patients.
doi:10.1007/s00415-012-6803-0
PMCID: PMC5535074  PMID: 23263538
Stroke; Sleep apnea; Secondary prevention
13.  Explicit Consideration of Baseline Factors to Assess Recombinant Tissue-Type Plasminogen Activator Response With Respect to Race and Sex 
Stroke  2013;44(6):1525-1531.
Background and Purpose
Sex and race reportedly influence outcome after recombinant tissue-type plasminogen activator (rtPA). It is, however, unclear whether baseline imbalances (eg, stroke severity) or lack of response to thrombolysis is responsible. We applied balancing methods to test the hypothesis that race and sex influence outcome after rtPA independent of baseline conditions.
Methods
We mapped group outcomes from the National Institute of Neurological Disorders and Stroke (NINDS) dataset based on race and sex onto a surrogate-control function to assess differences from expected outcomes at their respective National Institutes of Health Stroke Scale and age. Outcomes were also compared for subjects matched individually on key baseline factors using NINDS and 2 recent datasets from southeastern United States.
Results
At similar National Institutes of Health Stroke Scale and age, 90-day good outcomes (modified Rankin Score, 0–2) in NINDS were similarly improved after rtPA for white men and women. There was a strong trend for improvement in black men. Conversely, black women treated with rtPA showed response rates no different from the controls. After baseline matching, there were nonsignificant trends in outcomes except for significantly fewer good outcomes in black versus matched white women (37% versus 63%; P=0.027). Pooling the 3 datasets showed a similar trend for poorer short-term outcome for black women (P=0.054; modified Rankin Score, 0–1).
Conclusions
Matching for key baseline factors indicated that race and sex influence outcome most strikingly in black women who demonstrated poorest outcomes after rtPA. This finding supports the hypothesis that poor response to rtPA, rather than differences in baseline conditions, contributes to the worse outcome. This finding requires prospective confirmation.
doi:10.1161/STROKEAHA.113.001116
PMCID: PMC5535075  PMID: 23674524
alteplase; race; recombinant tissue-type plasminogen activator; sex; stroke; thrombolysis
14.  Association of sleep apnea with clinically silent microvascular brain tissue changes in acute cerebral ischemia 
Journal of neurology  2013;261(2):343-349.
The aim of this study was to determine the importance of sleep apnea in relation to clinically silent microvascular brain tissue changes in patients with acute cerebral ischemia. Patients with acute cerebral ischemia prospectively underwent nocturnal respiratory polygraphy within 5 days from symptom-onset. Sleep apnea was defined as apnea-hypopnea-index (AHI) ≥5/h. Experienced readers blinded to clinical and sleep-related data reviewed brain computed tomography and magnetic resonance imaging scans for leukoaraiosis and chronic lacunar infarctions. Ischemic lesions were considered clinically silent when patients did not recall associated stroke-like symptoms. Functional outcome was assessed with modified Rankin Scale at discharge, 6 and 12 months. Fifty-one of 56 (91 %) patients had sleep apnea of any degree. Patients with moderate-to-severe leukoaraiosis (Wahlund score ≥5) were found to have higher mean AHI than those with none or mild leukoaraiosis (34.4 vs. 12.8/h, p < 0.001). Moderate-to-severe sleep apnea (AHI >15/h) was found to be an independent predictor of moderate-to-severe leukoaraiosis (adjusted OR 6.03, 95 % CI 1.76-20.6, p = 0.0042) and of moderate-to-severe leukoaraiosis associated with clinically silent chronic lacunar infarctions (adjusted OR 10.5, 95 % CI 2.19-50.6, p = 0.003). The higher the Wahlund score and the AHI, the more likely unfavorable functional outcome resulted over time (p = 0.0373). In acute cerebral ischemia, sleep apnea is associated with clinically silent microvascular brain tissue changes and may negatively influence functional outcome. Routine sleep apnea screening and further investigation of possible long-term effects of non-invasive ventilatory treatment of sleep apnea appear warranted in this at-risk population.
doi:10.1007/s00415-013-7200-z
PMCID: PMC5523685  PMID: 24292644
Acute stroke; Silent brain infarction; Sleep apnea; Leukoaraiosis
15.  Patient Selection for Drip and Ship Thrombolysis in Acute Ischemic Stroke 
Southern medical journal  2015;108(7):393-398.
Objectives
The drip and ship model is a method used to deliver thrombolysis to acute stroke patients in facilities lacking onsite neurology coverage. We sought to determine whether our drip and ship population differs from patients treated directly at our stroke center (direct presenters).
Methods
We retrospectively reviewed consecutive patients who received thrombolysis at an outside facility with subsequent transfer to our center between 2009 and 2011. Patients received thrombolysis after telephone consultation with a stroke specialist. We examined demographics, vascular risk factors, laboratory values, and stroke severity in drip and ship patients compared with direct presenters.
Results
Ninety-six patients were identified who received thrombolysis by drip and ship compared with 212 direct presenters. The two groups did not differ with respect to sex, ethnicity, vascular risk factors, or admission glucose. The odds ratio (OR) of arriving at our hospital as a drip and ship for someone 80 years or older was 0.31 (95% confidence interval [CI] 0.15–0.61, P < 0.001). Only 21% of drip and ship patients were black versus 38% of direct presenters (OR 0.434, 95% CI 0.25–0.76, P = 0.004). Even after stratifying by age (<80 vs ≥80), a smaller proportion of drip and ship patients were black (OR 0.44, 95% CI 0.24–0.81, P = 0.008). Furthermore, we found that fewer black patients with severe strokes arrived by drip and ship (OR 0.33, 95% CI 0.11–0.98, P = 0.0028).
Conclusions
Our study showed that a smaller proportion of blacks and older adults arrived at our center by the drip and ship model. This may reflect differences in how patients are selected for thrombolysis and transfer to a higher level of care.
doi:10.14423/SMJ.0000000000000306
PMCID: PMC5523805  PMID: 26192934
ischemic stroke; thrombolysis; race
16.  Topological cell clustering in the ATLAS calorimeters and its performance in LHC Run 1 
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The reconstruction of the signal from hadrons and jets emerging from the proton–proton collisions at the Large Hadron Collider (LHC) and entering the ATLAS calorimeters is based on a three-dimensional topological clustering of individual calorimeter cell signals. The cluster formation follows cell signal-significance patterns generated by electromagnetic and hadronic showers. In this, the clustering algorithm implicitly performs a topological noise suppression by removing cells with insignificant signals which are not in close proximity to cells with significant signals. The resulting topological cell clusters have shape and location information, which is exploited to apply a local energy calibration and corrections depending on the nature of the cluster. Topological cell clustering is established as a well-performing calorimeter signal definition for jet and missing transverse momentum reconstruction in ATLAS.
doi:10.1140/epjc/s10052-017-5004-5
PMCID: PMC5586976
17.  Solving Kinetic Equations for the Laser Flash Photolysis Experiment on Nitric Oxide Synthases: Effect of Conformational Dynamics on the Interdomain Electron Transfer 
The journal of physical chemistry. A  2015;119(45):11066-11075.
The production of nitric oxide by the nitric oxide synthase (NOS) enzyme depends on the interdomain electron transfer (IET) between the flavin mononucleotide (FMN) and heme domains. Although the rate of this IET has been measured by laser flash photolysis (LFP) for various NOS proteins, no rigorous analysis of the relevant kinetic equations was performed so far. In this work, we provide an analytical solution of the kinetic equations underlying the LFP approach. The derived expressions reveal that the bulk IET rate is significantly affected by the conformational dynamics that determines the formation and dissociation rates of the docking complex between the FMN and heme domains. We show that in order to informatively study the electron transfer across the NOS enzyme, LFP should be used in combination with other spectroscopic methods that could directly probe the conformational rate constants. The implications of the obtained analytical expressions for the interpretation of the LFP results from various native and modified NOS proteins are discussed. The mathematical formulae derived in this work should also be applicable for interpreting the IET kinetics in other modular redox enzymes.
doi:10.1021/acs.jpca.5b08414
PMCID: PMC5518706  PMID: 26477677
18.  Measurements of electroweak \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$Wjj $$\end{document}Wjj production and constraints on anomalous gauge couplings with the ATLAS detector 
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Measurements of the electroweak production of a W boson in association with two jets at high dijet invariant mass are performed using \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= 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 proton–proton collision data produced by the Large Hadron Collider, corresponding respectively to 4.7 and 20.2 fb\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{-1}$$\end{document}-1 of integrated luminosity collected by the ATLAS detector. The measurements are sensitive to the production of a W boson via a triple-gauge-boson vertex and include both the fiducial and differential cross sections of the electroweak process.
doi:10.1140/epjc/s10052-017-5007-2
PMCID: PMC5586972
19.  Jet reconstruction and performance using particle flow with the ATLAS Detector 
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This paper describes the implementation and performance of a particle flow algorithm applied to 20.2 fb\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{-1}$$\end{document}-1 of ATLAS data from 8 TeV proton–proton collisions in Run 1 of the LHC. The algorithm removes calorimeter energy deposits due to charged hadrons from consideration during jet reconstruction, instead using measurements of their momenta from the inner tracker. This improves the accuracy of the charged-hadron measurement, while retaining the calorimeter measurements of neutral-particle energies. The paper places emphasis on how this is achieved, while minimising double-counting of charged-hadron signals between the inner tracker and calorimeter. The performance of particle flow jets, formed from the ensemble of signals from the calorimeter and the inner tracker, is compared to that of jets reconstructed from calorimeter energy deposits alone, demonstrating improvements in resolution and pile-up stability.
doi:10.1140/epjc/s10052-017-5031-2
PMCID: PMC5586971
20.  Synthetic glycosylphosphatidylinositol (GPI) anchors: how these complex molecules have been made† 
Natural product reports  2011;28(5):970-1020.
Glycosylphosphatidylinositols (GPIs) are a class of natural glycosylphospholipids that anchor proteins, glycoproteins and lipophosphoglycans to the membrane of eukaryotic cells. GPI anchors are widely present in parasitic protozoa, where GPI-anchored mucins and phosphoglycans are abundant and form a dense protective layer (glycocalyx) on the surface of the parasites. This type of anchor appears to be present in these organisms with a much higher frequency than in higher eukaryotes. Since the first full assignment of a GPI structure in 1988, more than 50 glycosylphosphatidylinositols have been structurally characterised. The functions of GPI anchors (in addition to the clear one of linking the above biopolymers to membranes) have been extensively discussed. The high lateral mobility of GPIs and GPI-anchored polymers seems to actively facilitate the selective release of molecules from the cell surface and the exchange of membrane proteins between cells. There is also evidence that GPIs and/or their metabolites can act as secondary messengers, modulating biological events including insulin production, insulin-mediated signal transduction, cellular proliferation and cell–cell recognition. Their discovered role as mediators of regulatory processes makes the chemical preparation of these compounds and their analogues of great interest. This comprehensive review highlights the progress in the chemical synthesis of GPI anchors and related glycoconjugate structures from protozoan parasites, yeast and mammals in the last two decades. The synthesis of a structurally related prokaryotic glycoconjugate of Mycobacterium tuberculosis is also discussed.
doi:10.1039/c0np00064g
PMCID: PMC5496678  PMID: 21448495
21.  Giant capsids from lattice self-assembly of cyclodextrin complexes 
Nature Communications  2017;8:15856.
Proteins can readily assemble into rigid, crystalline and functional structures such as viral capsids and bacterial compartments. Despite ongoing advances, it is still a fundamental challenge to design and synthesize protein-mimetic molecules to form crystalline structures. Here we report the lattice self-assembly of cyclodextrin complexes into a variety of capsid-like structures such as lamellae, helical tubes and hollow rhombic dodecahedra. The dodecahedral morphology has not hitherto been observed in self-assembly systems. The tubes can spontaneously encapsulate colloidal particles and liposomes. The dodecahedra and tubes are respectively comparable to and much larger than the largest known virus. In particular, the resemblance to protein assemblies is not limited to morphology but extends to structural rigidity and crystallinity—a well-defined, 2D rhombic lattice of molecular arrangement is strikingly universal for all the observed structures. We propose a simple design rule for the current lattice self-assembly, potentially opening doors for new protein-mimetic materials.
Designing and synthesizing protein mimetic molecules to form crystalline structures can be a challenge. Here the authors show lattice self-assembly of cyclodextrin complexes into a variety of capsid like structures, such as, lamellae, helical tubes and hollow rhombic dodecahedra.
doi:10.1038/ncomms15856
PMCID: PMC5481833  PMID: 28631756
22.  Study of male–mediated gene flow across a hybrid zone in the common shrew (Sorex araneus) using Y chromosome 
Comparative Cytogenetics  2017;11(2):421-430.
Despite many studies, the impact of chromosome rearrangements on gene flow between chromosome races of the common shrew (Sorex araneus Linnaeus, 1758) remains unclear. Interracial hybrids form meiotic chromosome complexes that are associated with reduced fertility. Nevertheless comprehensive investigations of autosomal and mitochondrial markers revealed weak or no barrier to gene flow between chromosomally divergent populations.
In a narrow zone of contact between the Novosibirsk and Tomsk races hybrids are produced with extraordinarily complex configurations at meiosis I. Microsatellite markers have not revealed any barrier to gene flow, but the phenotypic differentiation between races is greater than may be expected if gene flow was unrestricted. To explore this contradiction we analyzed the distribution of the Y chromosome SNP markers within this hybrid zone. The Y chromosome variants in combination with race specific autosome complements allow backcrosses to be distinguished and their proportion among individuals within the hybrid zone to be evaluated. The balanced ratio of the Y variants observed among the pure race individuals as well as backcrosses reveals no male mediated barrier to gene flow. The impact of reproductive unfitness of backcrosses on gene flow is discussed as a possible mechanism of the preservation of race-specific morphology within the hybrid zone.
doi:10.3897/CompCytogen.v11i2.13494
PMCID: PMC5596988  PMID: 28919973
Sorex araneus; phenotypic evolution; hybrid zone; gene flow; Y chromosome
23.  Enhancing Optical Forces in InP-Based Waveguides 
Scientific Reports  2017;7:3106.
Cantilever sensors are among the most important microelectromechanical systems (MEMS), which are usually actuated by electrostatic forces or piezoelectric elements. Although well-developed microfabrication technology has made silicon the prevailing material for MEMS, unique properties of other materials are overlooked in this context. Here we investigate optically induced forces exerted upon a semi-insulating InP waveguide suspended above a highly doped InP:Si substrate, in three different regimes: the epsilon-near-zero (ENZ), with excitation of surface plasmon polaritons (SPPs) and phonons excitation. An order of magnitude amplification of the force is observed when light is coupled to SPPs, and three orders of magnitude amplification is achieved in the phonon excitation regime. In the ENZ regime, the force is found to be repulsive and higher than that in a waveguide suspended above a dielectric substrate. Low losses in InP:Si result in a big propagation length. The induced deflection can be detected by measuring the phase change of the light when passing through the waveguide, which enables all-optical functioning, and paves the way towards integration and miniaturization of micro-cantilevers. In addition, tunability of the ENZ and the SPP excitation wavelength ranges, via adjusting the carrier concentration, provides an extra degree of freedom for designing MEMS devices.
doi:10.1038/s41598-017-03409-1
PMCID: PMC5465176  PMID: 28596522
24.  RESISTIVE RESPIRATORY TRAINING IMPROVES BLOOD PRESSURE REGULATION IN INDIVIDUALS WITH CHRONIC SPINAL CORD INJURY 
Objective
To investigate the effects of resistive Respiratory Motor Training (RMT) on pulmonary function and orthostatic stress-mediated cardiovascular and autonomic responses in individuals with chronic Spinal Cord Injury (SCI).
Design
Before-after intervention case-controlled clinical study.
Setting
Participants
Individuals with chronic C3-T2 SCI diagnosed with orthostatic hypotension (OH) (n=11) and healthy, non-injured (NI) controls (n=10).
Intervention
21 ± 2 (mean ± SD) sessions of resistive inspiratory-expiratory RMT performed 5 days a week during a one-month period.
Main Outcome Measures
Standard Pulmonary Function Test (PFT): Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), Maximal Inspiratory Pressure (PImax), and Maximal Expiratory Pressure (PEmax) and beat-to-beat arterial blood pressure (BP), heart rate (HR), and respiratory rate during orthostatic sit-up stress test acquired before and after RMT program.
Results
Completion of RMT intervention abolished OH in 7 out of 11 individuals. FVC, low-frequency component of power spectral density (LF PSD) of BP and HR oscillations, baroreflex effectiveness and cross correlations between BP, HR, and respiratory rate during orthostatic challenge were significantly improved, approaching levels observed in NI individuals. These findings indicate increased sympathetic activation and baroreflex effectiveness in association with improved respiratory-cardiovascular interactions in response to the sudden decrease in BP.
Conclusion
Resistive respiratory training increases respiratory capacity and improves orthostatically mediated respiratory, cardiovascular, and autonomic responses suggesting that this intervention can be an efficacious therapy for managing OH after SCI.
doi:10.1016/j.apmr.2015.11.018
PMCID: PMC4884550  PMID: 26718236
Spinal cord injury; Respiratory training; Respiratory function; Autonomic regulation; Blood pressure; Orthostatic hypotension