bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring Time-Resolved Characterization of the Heterogeneity and Dynamics of Ligand-Receptor Interactions on Living Cells
Authors: Pavel Barta  , Karl Andersson  , Frantisek Trejtnar  , Jos Buijs
Published: April 2014

The time-resolved interaction analysis was applied on living cells to extract detailed interaction characteristics of two therapeutic antibodies and natural ligand binding to the same receptor expressed on two different human carcinoma cell lines. The observed differences in the antibody binding characteristics and heterogeneity could be attributed both to differences in antibodies and cell lines. The stability of antibody binding to EGFR on cells is significantly higher than the binding stability to isolated EGFR. This higher stability can be of fundamental importance as it potentially shifts the drug-target residence time into a domain that is limiting in pharmacokinetics and hence is of importance for in vivodrug efficacy. EGF binding to its receptor was more heterogeneous and it was demonstrated for the first time that time-resolved interaction measurements in combination with Interaction Map analysis could be used to probe the dynamics of a ligand (protein) induced dimerization and/or oligomerization process.
The Influence of Family Factors on Smoking Behavior in Turkey
Authors: Oncel Sevgi Yurt , Aliev Fazil
Published: April 2014

Aim: The goal of this study is to specify the risks, family and environmental factors affecting smoking behavior and develop suggestions for Turkish individuals by considering sibling data.
Materials and Methods: The data was collected by voluntary senior year students attending Kırıkkale University, Department of Statistics. The sample of 751 families was selected from families with at least two children. Each sibling’s socio-demographic information and behavioral phenotypes were collected using a survey from both siblings. We selected one of siblings randomly as ‘sibling1’ and defined the other sibling as ‘sibling2’. Hypothesis testing and multivariable clustered logistic regression models were used to evaluate the data and find the optimum model by using dependent sibling data.
Results: Out of 1502 (751 pairs) siblings 843 (56.1%) were males, 659 (43.9%) were females. According to the survey results, 508 of the males (67.7%) and 242 of the females (32.3%) were smokers for a month or longer and smoked every day. The risk of smoking was 2.26 times higher in males than in females. Having a smoking sibling increased the risk of smoking 1.95 times, alcohol using increased the risk 2.11 times. We found that when the age difference between siblings is 0-7 years, having a same sex sibling who smokes increases one’s risk 4.7 times in females and 5 times in males; when the siblings are of different sexes, according to these age differences
Conclusion: The survey showed that the gender and sibling’s and parent’s smoking both play a significant role on smoking behavior. But children seem to learn smoking from their siblings more than from parents. Having same sex sibling who smokes plays significant role in smoking behavior for both males and females.
Adoption of Six Sigma’s DMAIC to Reduce Complications in IntraLase Surgeries
Authors: Åžahbaz Ibrahim , Taner Mehmet Tolga , Eliaçik Mustafa , Kagan Gamze , Erbas Engin
Published: April 2014

Purpose: To show how a private eye care center in Turkey initiated Six Sigma principles to reduce the number of complications encountered during and after femtosecond laser-assisted LASIK (IntraLase) surgeries.
Method: Data were collected for five years. To analyse the complications among 448 surgeries, main tools of Six Sigma’s Define-Measure-Analyze-Improve-Control (DMAIC) improvement cycle such as SIPOC table, Fishbone Diagram and, Failure, Mode and Effect Analysis were implemented. Sources and root causes of seventeen types of complications were identified and reported.
Results: For a successful IntraLase surgery, experience of the refractive surgeon, patient’s anatomy and calibration of laser power were determined to be the “critical few” factors whereas, patient’s psychology, sterilization and hygiene, and suction-ring’s pressure were found to be the “trivial many” factors. The most frequently occurring complication was found to be subconjunctival haemorrhage.
Conclusion: The process sigma level of the process was measured to be 3.3547. The surgical team concluded that sixteen complications (out of seventeen) should be significantly reduced by taking the necessary preventive measures.
Functional acuity contrast sensitivity assessment in young and middle age healthy persons at the day time with and without glare
Authors: Sidorova Jelena , Čiumbaraitė Rasa , Čebatorienė Džastina , Banevičius Mantas , Liutkevičienė Rasa
Published: April 2014

Background. As people age, their vision becomes less clear; they can clearly see big objects but experience problems discerning minor things and minor details. The functional acuity contrast test is a very sensitive method used for visual system evaluation which may help to detect the beginning of the disease in case the visual acuity is still normal.
Purpose. To determine functional acuity contrast sensitivity in young and in middle age healthy persons at the day time with and without glare.
Materials and methods. We examined 40–49 yrs (Group 1), and 50– 59 yrs (Group 2) healthy persons. The typical Snellen chart (the direc­tion of the gap in Landolt C) was used for the non-corrected and the bestcorrected visual acuity testing. Functional acuity contrast sensitivity was measured employing a Ginsburg Box, VSCR- CST-6500, at the day time with and without glare.
Results. Functional acuity contrast sensitivity remained very similar in the age groups of 40–49 years and 50–59 years. However, statistically, it significantly decreased at day time without glare (18 cycle / degree) spatial frequencies (p = 0.05). Results in Group 1 as compared to Group 2 decreased from 3.09% to 51.7% at the day time without glare and from 2.16% to 11.61% at the day time with glare.
Conclusion. The facts are that contrast sensitivity remained very similar in the age groups of 40–49 years and 50–59 years at the day time with and without glare.
Prevalence of lower urinary tract symptoms in Vilnius area children and adolescents
Authors: Jankauskienė Augustina , Vaičiūnienė Daiva , Stacevičienė Indrė
Published: April 2014

Background. Lower urinary tract symptoms are a common problem world­wide among children. The aim of the study was to evaluate how common lower urinary tract symptoms are among children and adolescents in the Vilnius area.
Materials and methods. A cross-sectional study comprised 360 children (5–11 years) and 388 adolescents (12–18 years) who were hospitalized at the Children’s Hospital or referred for consultation for different health reasons not related to urination problems. Data were obtained by using a self-administered anonymous questionnaire. The data were compared between gender (344 boys and 404 girls) and age groups (children and adolescents).
Results. Only a half (55.7%) of all questioned children and adolescents had no lower urinary tract symptoms. Nocturnal enuresis (NE) was found in 8.7%, urgency in 34.0% and daytime wetting in 24.6% of the questioned children and adolescents. Monosymptomatic NE accounted for 20.0% of NE. Secondary NE was seen in a quarter (24.5%) of children with NE. Lower urinary tract symptoms were more prevalent in children compared to adolescents (56.1% vs 38.1%, p = 0.000). There were no significant differences between genders except urgency, which was more frequent in girls (29.4% vs 37.9%, p = 0.014).
Conclusion. Lower urinary tract symptoms are frequent in children and adolescents in the Vilnius area, so they need greater attention by healthcare providers.
Head-to-tail interactions of the coiled-coil domains regulate ClpB activity and cooperation with Hsp70 in protein disaggregation
Authors: Carroni Marta , Kummer Eva , Oguchi Yuki , Wendler Petra , Clare Daniel K , Sinning Irmgard , Kopp Jürgen , Mogk Axel , Bukau Bernd , Saibil Helen R
Published: April 2014

The hexameric AAA+ chaperone ClpB reactivates aggregated proteins in cooperation with the Hsp70 system. Essential for disaggregation, the ClpB middle domain (MD) is a coiled-coil propeller that binds Hsp70. Although the ClpB subunit structure is known, positioning of the MD in the hexamer and its mechanism of action are unclear. We obtained electron microscopy (EM) structures of the BAP variant of ClpB that binds the protease ClpP, clearly revealing MD density on the surface of the ClpB ring. Mutant analysis and asymmetric reconstructions show that MDs adopt diverse positions in a single ClpB hexamer. Adjacent, horizontally oriented MDs form head-to-tail contacts and repress ClpB activity by preventing Hsp70 interaction. Tilting of the MD breaks this contact, allowing Hsp70 binding, and releasing the contact in adjacent subunits. Our data suggest a wavelike activation of ClpB subunits around the ring.
Monosynaptic premotor circuit tracing reveals neural substrates for oro-motor coordination
Authors: Stanek Edward , Cheng Steven , Takatoh Jun , Han Bao-Xia , Wang Fan
Published: April 2014

Feeding behaviors require intricately coordinated activation among the muscles of the jaw, tongue, and face, but the neural anatomical substrates underlying such coordination remain unclear. In this study, we investigate whether the premotor circuitry of jaw and tongue motoneurons contain elements for coordination. Using a modified monosynaptic rabies virus-based transsynaptic tracing strategy, we systematically mapped premotor neurons for the jaw-closing masseter muscle and the tongue-protruding genioglossus muscle. The maps revealed that the two groups of premotor neurons are distributed in regions implicated in rhythmogenesis, descending motor control, and sensory feedback. Importantly, we discovered several premotor connection configurations that are ideally suited for coordinating bilaterally symmetric jaw movements, and for enabling co-activation of specific jaw, tongue, and facial muscles. Our findings suggest that shared premotor neurons that form specific multi-target connections with selected motoneurons are a simple and general solution to the problem of orofacial coordination.
Confirmation of progressive plate motion during the Midcontinent Rift's early magmatic stage from the Osler Volcanic Group, Ontario, Canada
Authors: Swanson‐Hysell Nicholas L. , Vaughan Angus A. , Mustain Monica R. , Asp Kristofer E.
Published: April 2014

As the supercontinent Rodinia was assembling ca. 1.1 billion years ago, there was extensive magmatism on at least five Proterozoic continents including the development of the North American Midcontinent Rift. New paleomagnetic data from 84 lava flows of the Osler Volcanic Group of the Midcontinent Rift reveal that there was a significant and progressive decrease in inclination between the initiation of extrusive volcanism in the region (ca. 1110 Ma) and ca. 1105 ± 2 Ma (during the “early stage” of rift development). Paleomagnetic poles can be calculated for the lower portion of the reversed Osler Volcanic Group (40.9°N, 218.6°E, A95 = 4.8°, N = 30) and the upper portion of the reversed Osler Volcanic Group (42.5°N, 201.6°E, A95 = 3.7°, N = 59; this pole can be assigned the age of ca. 1105 ± 2 Ma). This result is a positive test of the hypothesis that there was significant plate motion during the early stage of rift development. In addition to being a time of widespread volcanism on Laurentia and other continents, this interval of the late Mesoproterozoic was characterized by rapid paleogeographic change.
The contribution of the Weddell Gyre to the lower limb of the Global Overturning Circulation
Authors: Jullion Loïc , Garabato Alberto C. Naveira , Bacon Sheldon , Meredith Michael P. , Brown Pete J. , Torres‐Valdés Sinhue , Speer Kevin G. , Holland Paul R. , Dong Jun , Bakker Dorothée , Hoppema Mario , Loose Brice , Venables Hugh J. , Jenkins William J. , Messias Marie‐José , Fahrbach Eberhard
Published: May 2014

The horizontal and vertical circulation of the Weddell Gyre is diagnosed using a box inverse model constructed with recent hydrographic sections and including mobile sea ice and eddy transports. The gyre is found to convey 42 ± 8 Sv (1 Sv = 106 m3 s–1) across the central Weddell Sea and to intensify to 54 ± 15 Sv further offshore. This circulation injects 36 ± 13 TW of heat from the Antarctic Circumpolar Current to the gyre, and exports 51 ± 23 mSv of freshwater, including 13 ± 1 mSv as sea ice to the midlatitude Southern Ocean. The gyre's overturning circulation has an asymmetric double‐cell structure, in which 13 ± 4 Sv of Circumpolar Deep Water (CDW) and relatively light Antarctic Bottom Water (AABW) are transformed into upper‐ocean water masses by midgyre upwelling (at a rate of 2 ± 2 Sv) and into denser AABW by downwelling focussed at the western boundary (8 ± 2 Sv). The gyre circulation exhibits a substantial throughflow component, by which CDW and AABW enter the gyre from the Indian sector, undergo ventilation and densification within the gyre, and are exported to the South Atlantic across the gyre's northern rim. The relatively modest net production of AABW in the Weddell Gyre (6 ± 2 Sv) suggests that the gyre's prominence in the closure of the lower limb of global oceanic overturning stems largely from the recycling and equatorward export of Indian‐sourced AABW.
Using the natural spatial pattern of marine productivity in the Subarctic North Pacific to evaluate paleoproductivity proxies
Authors: Serno Sascha , Winckler Gisela , Anderson Robert F. , Hayes Christopher T. , Ren Haojia , Gersonde Rainer , Haug Gerald H.
Published: April 2014

Sedimentary proxies used to reconstruct marine productivity suffer from variable preservation and are sensitive to factors other than productivity. Therefore, proxy calibration is warranted. Here we map the spatial patterns of two paleoproductivity proxies, biogenic opal and barium fluxes, from a set of core‐top sediments recovered in the Subarctic North Pacific. Comparisons of the proxy data with independent estimates of primary and export production, surface water macronutrient concentrations, and biological pCO2 drawdown indicate that neither proxy shows a significant correlation with primary or export productivity for the entire region. Biogenic opal fluxes, when corrected for preservation using 230Th‐normalized accumulation rates, show a good correlation with primary productivity along the volcanic arcs (τ = 0.71, p = 0.0024) and with export productivity throughout the western Subarctic North Pacific (τ = 0.71, p = 0.0107). Moderate and good correlations of biogenic barium flux with export production (τ = 0.57, p = 0.0022) and with surface water silicate concentrations (τ = 0.70, p = 0.0002) are observed for the central and eastern Subarctic North Pacific. For reasons unknown, however, no correlation is found in the western Subarctic North Pacific between biogenic barium flux and the reference data. Nonetheless, we show that barite saturation, uncertainty in the lithogenic barium corrections, and problems with the reference data sets are not responsible for the lack of a significant correlation between biogenic barium flux and the reference data. Further studies evaluating the factors controlling the variability of the biogenic constituents in the sediments are desirable in this region.
Hydrology and pore water chemistry in a permafrost wetland, Ilulissat, Greenland
Authors: Jessen Søren , Holmslykke Hanne D. , Rasmussen Kristine , Richardt Niels , Holm Peter E.
Published: May 2014

Hydrological and geochemical processes controlling the pore water chemistry in a permafrost wetland, with loam overlain by sphagnum peat, were investigated. The vertical distributions of dissolved Cl, and of pore water δ18O, appeared unrelated to ion freeze‐out and isotope ice‐water fractionation processes, respectively, dismissing solute freeze‐out as a main control on the water chemistry. However, concentrations of major ions, others than Cl, generally increased with depth into the active layer. A conceptual model for water and solute movement in the active layer was derived. The model indicates upward diffusive transport of elements, released in the loam layer by mineral weathering, to the peat layer, in which lateral advective transport dominates. Active layer pore water and water of melted core sections of permafrost were of Ca‐Mg‐HCO3 type (1:1:4 stoichiometry) and were subsaturated for calcite and dolomite. The results are consistent with an annual cycling of inorganic carbon species, Ca and Mg, via cryogenic carbonate precipitation during fall freeze‐up and their redissolution following spring thaw. Similarly, elevated Fe2+ concentrations appear to be related to cryogenic siderite formation. Pore water in the active layer showed high partial pressures of CO2, indicating the feasibility of bubble ebullition as a greenhouse gas emission pathway from permafrost wetlands. Elevated concentrations of geogenic trace elements (Ni, Al, and As) were observed, and the controlling geochemical processes are discussed. The conceptual model for water and solute movement was applied to quantify the contribution of released trace elements to a downstream lake in the permafrost catchment.
On the predictability limit of convection models of the Earth's mantle
Authors: Bello Léa , Coltice Nicolas , Rolf Tobias , Tackley Paul J.
Published: April 2014

Reconstructing convective flow in the Earth's mantle is a crucial issue for a diversity of disciplines, from seismology to sedimentology. The common and fundamental limitation of these reconstructions based on geodynamic modeling is the unknown initial conditions. Because of the chaotic nature of convection in the Earth's mantle, errors in initial conditions grow exponentially with time and limit forecasting and hindcasting abilities. In this work, we estimate for the first time the limit of predictability of Earth's mantle convection. Following the twin experiment method, we compute the Lyapunov time (i.e., e‐folding time) for state of the art 3‐D spherical convection models, varying rheology, and Rayleigh number. Our most Earth‐like and optimistic solution gives a Lyapunov time of 136 ± 13 Myr. Rough estimates of the uncertainties in best guessed initial conditions are around 5%, leading to a limit of predictability for mantle convection of 95 Myr. Our results suggest that error growth could produce unrealistic convective structures over time scales shorter than that of Pangea dispersal.
Helium isotopic textures in Earth's upper mantle
Authors: Graham David W. , Hanan Barry B. , Hémond Christophe , Blichert‐Toft Janne , Albarède Francis
Published: April 2014

We report 3He/4He for 150 mid‐ocean ridge basalt (MORB) glasses from the Southeast Indian Ridge (SEIR). Between 81°E and 101°E 3He/4He varies from 7.5 to 10.2 RA, encompassing more than half the MORB range away from ocean island hot spots. Abrupt transitions are present and in one case the full range occurs over ∼10 km. Melting of lithologically heterogeneous mantle containing a few percent garnet pyroxenite or eclogite leads to lower 3He/4He, while 3He/4He above ∼9 RA likely indicates melting of pyroxenite‐free or eclogite‐free mantle. Patterns in the length scales of variability represent a description of helium isotopic texture. We utilize four complementary methods of spectral analysis to evaluate this texture, including periodogram, redfit, multitaper method, and continuous wavelet transform. Long‐wavelength lobes with prominent power at 1000 and 500 km are present in all treatments, similar to hot spot‐type spectra in Atlantic periodograms. The densely sampled region of the SEIR considered separately shows significant power at ∼100 and ∼30–40 km, the latter scale resembling heterogeneity in the bimodal distribution of Hf and Pb isotopes in the same sample suite. Wavelet transform coherence reveals that 3He/4He varies in‐phase with axial depth along the SEIR at ∼1000 km length scale, suggesting a coupling between melt production, 3He/4He and regional variations in mantle temperature. Collectively, our results show that the length scales of MORB 3He/4He variability are dominantly controlled by folding and stretching of heterogeneities during regional (∼1000 km) and mesoscale (∼100 km) mantle flow, and by sampling during the partial melting process (∼30 km).
Effects of the core‐shell structure on the magnetic properties of partially oxidized magnetite grains: Experimental and micromagnetic investigations
Authors: Ge Kunpeng , Williams Wyn , Liu Qingsong , Yu Yongjae
Published: April 2014

The relationship between magnetic hysteresis parameters and the degree of oxidation of ultrafine magnetite particles is examined by both experimental measurements (distributed particle assemblage with median grain size of ∼80 nm and standard deviation 0.43) and micromagnetic simulations (single particles from 40 nm to 140 nm). Experimental results show that both coercivity (Bc) and the ratio of saturation remanence to saturation magnetization (Mrs/Ms) increase slowly, as the oxidation parameter z increases from 0 to ∼0.9. Thereafter, both parameters decrease sharply as magnetite becomes completely oxidized to maghemite. Numerical simulations of hysteresis loop and microstructure using a micromagnetic model with a core‐shell geometry (a stoichiometric core surrounded by an oxidized shell) show three categories of behavior for magnetic grains during oxidation. First, the coercivity of SD particles decreases as oxidation proceeds, but their remanence magnetization remains in a uniform state. Second, for PSD sized particles near the critical SD boundary (80 nm to 100 nm), the initial vortex domain structure changes to a SD as oxidation occurs and returns to a vortex state upon complete maghemitization, resulting in an initial rise and then fall of Bc and Mrs. Finally, larger PSD grains remain a vortex state throughout the maghemitization, with less variations of Bc and Mrs. The predicted magnetic properties exhibit good agreement with experimental observations and suggest that the domain arrangement is likely to be dominated by a core‐shell structure with strong exchange coupling at their interface. Overall, the partially oxidized magnetite in SD‐PSD range can reliably record palaeomagnetic signals.
Twentieth century sea‐ice trends in the Ross Sea from a high‐resolution, coastal ice‐core record
Authors: Sinclair Kate E. , Bertler Nancy A. N. , Bowen Melissa M. , Arrigo Kevin R.
Published: April 2014

We present the first proxy record of sea‐ice area (SIA) in the Ross Sea, Antarctica, from a 130 year coastal ice‐core record. High‐resolution deuterium excess data show prevailing stable SIA from the 1880s until the 1950s, a 2–5% reduction from the mid‐1950s to the early‐1990s, and a 5% increase after 1993. Additional support for this reconstruction is derived from ice‐core methanesulphonic acid concentrations and whaling records. While SIA has continued to decline around much of the West Antarctic coastline since the 1950s, concurrent with increasing air and ocean temperatures, the underlying trend is masked in the Ross Sea by a switch to positive SIA anomalies since the early‐1990s. This increase is associated with a strengthening of southerly winds and the enhanced northward advection of sea ice.
tFISH/RAPiD: Rapid improvement of near‐field tsunami forecasting based on offshore tsunami data by incorporating onshore GNSS data
Authors: Tsushima Hiroaki , Hino Ryota , Ohta Yusaku , Iinuma Takeshi , Miura Satoshi
Published: April 2014

We have developed a new algorithm that improves near‐field tsunami forecasting based on offshore tsunami data soon after an earthquake by incorporating real‐time onshore Global Navigation Satellite System (GNSS) data. In our algorithm, called tFISH/RAPiD (tsunami Forecasting based on Inversion for initial sea‐Surface Height/Real‐time Automatic detection method for Permanent Displacement), the initial sea surface height distribution estimated from rapidly acquired GNSS data provides robust finite source size information that is incorporated into an offshore tsunami data inversion for reliable tsunami predictions along the near‐field coast. Our algorithm can be applicable to arbitrary types of large tsunamigenic earthquakes when the static displacements are substantial enough to be detected at onshore GNSS stations. We retrospectively applied our algorithm to the 2011 Mw 9.0 Tohoku earthquake and demonstrated its ability to provide information about disastrous tsunamis approaching wide areas along the near‐field coast. Furthermore, arrival times and wave heights of large‐amplitude, short‐period tsunamis affecting specific near‐field coasts can be predicted at least 5 min before the actual tsunami arrivals.
Pressure solution creep of random packs of spheres
Authors: Bernabé Y. , Evans B.
Published: May 2014

We performed numerical calculations of compaction in aggregates of spherical grains, using Lehner and Leroy's (2004, hereinafter LL) constitutive model of pressure solution at grain contacts. That model is founded on a local definition of the thermodynamic driving force and leads to a fully coupled formulation of elastic deformation, dissolution, and diffusive transport along the grain boundaries. The initial geometry of the aggregate was generated by random packing of spheres with a small standard deviation of the diameters. During the simulations, isostatic loading was applied. The elastic displacements at the contacts were calculated according to Digby's (1981) nonlinear contact force model, and deformation by dissolution was evaluated using the LL formulation. The aggregate strain and porosity were tracked as a function of time for fixed temperature, applied effective pressure, and grain size. We also monitored values of the average and standard deviation of total load at each contact, the coordination number for packing, and the statistics of the contact dimensions. Because the simulations explicitly exclude processes such as fracturing, plastic flow, and transport owing to surface curvature, they can be used to test the influence of relative changes in the kinetics of dissolution and diffusion processes caused by contact growth and packing rearrangements. We found that the simulated strain data could be empirically fitted by two successive power laws of the form, εx ∝ tξ, where ξ was equal to 1 at very early times, but dropped to as low as 0.3 at longer times. The apparent sensitivity of strain rate to stress found in the simulations was much lower than predicted from constitutive laws that assume a single dominant process driven by average macroscopic loads. Likewise, the apparent activation enthalpy obtained from the simulated data was intermediate between that assumed for dissolution and diffusion, and, further, tended to decrease with time. These results are similar to the experimental observations of Visser et al.'s (2012), who used an aggregate geometry and physical conditions closely resembling the present numerical simulations.
Acute Lymphoblastic Leukaemia
Authors: Morsi Hisham , Jewell Andy
Published: May 2014

Lymphoblastic leukaemia is a heterogeneous disease of children and adults resulting from clonal expansion of progenitor cells. Treatment with intensive cytotoxic therapy is effective in the majority of children, but treatments for adults are less effective, probably because the disease originates from relatively drug‐resistant stem cells. However, treatment of young adults according to paediatric‐based regimens has produced superior results to adults‐based regimens. Current treatment of children aged between 1 and 10 years has produced a high cure rate of >85% and continues to improve. Not only has survival improved but there are also continuing improvements in reducing toxicity of treatment. This success currently serves as a model for other types of cancer where the cure rate is not yet optimised. The advances of identifying prognostic markers and genome profiling have been instrumental in such successes and will continue serving as landmarks for progress.

Key Concepts:

MRD is the most important prognostic factor in ALL patients receiving chemotherapy.

Paediatric‐based treatment regimens produce superior results to adults‐based regimens in treating teenagers and young adults.

Febrile neutropenia/susceptibility to infection is a life‐threatening complication of chemotherapy that is potentially treatable.

The variability in presentation and response to treatment reflects the heterogeneity of acute lymphoblastic leuakaemia.

The current success in minimising the morbidity of managing childhood leukaemia serves as a model for other oncological conditions.
State‐of‐the‐Art Analytical Methods for Assessing Dynamic Bonding Soft Matter Materials
Authors: Brandt Josef , Oehlenschlaeger Kim K. , Schmidt Friedrich Georg , Barner‐Kowollik Christopher , Lederer Albena
Published: April 2014

Dynamic bonding materials are of high interest in a variety of fields in material science. The reversible nature of certain reaction classes is frequently employed for introducing key material properties such as the capability to self‐heal. In addition to the synthetic effort required for designing such materials, their analysis is a highly complex—yet important—endeavor. Herein, we critically review the current state of the art analytical methods and their application in the context of reversible bonding on demand soft matter material characterization for an in‐depth performance assessment. The main analytical focus lies on the characterization at the molecular level.
A case of thalamic hemorrhage with takotsubo cardiomyopathy
Authors: Inoue Teruhiro , Yanagawa Youichi , Omori Kazuhiko , Osaka Hiromichi , Oode Yasumasa , Sugita Manabu , Okamoto Ken
Published: April 2014

Case

A 76‐year‐old woman was found unconscious by her family. She had suffered a fall and was soaked in kerosene. On arrival at our emergency department, she was unconscious, normotensive, with right hemiplegia and chemical burns. A computed tomographic scan of her head indicated left thalamic hemorrhage. An electrocardiogram showed ST elevation at the precardial leads. An echocardiogram revealed characteristic of takotsubo cardiomyopathy.

Outcome

The patient was intubated and treated conservatively. She was transferred to another hospital for rehabilitation after complete epithelization of the chemical burn. This is the second reported case of thalamic hemorrhage with takotsubo cardiomyopathy. The thalamic hemorrhage might have induced autonomic disturbances and caused the takotsubo cardiomyopathy in this case.

Conclusion

Physicians should pay attention to the potential complication of takotsubo cardiomyopathy, which may affect cardiopulmonary function even when patients are being treated for intracerebral hemorrhage.
Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity
Authors: Breuer Johanna , Schwab Nicholas , Schneider‐Hohendorf Tilman , Marziniak Martin , Mohan Hema , Bhatia Urvashi , Gross Catharina C. , Clausen Björn E. , Weishaupt Carsten , Luger Thomas A. , Meuth Sven G. , Loser Karin , Wiendl Heinz
Published: April 2014

Objective

Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity.

Methods

Effects of UVB light were analyzed in a murine model of CNS autoimmunity (experimental autoimmune encephalomyelitis). Additionally, patients with relapsing–remitting MS were treated with narrowband UVB phototherapy. Immunomodulatory effects were examined in skin biopsies, serum samples, and immune cells of the peripheral blood.

Results

Regulatory T cells (Tregs), which are induced locally in the skin‐draining lymph nodes in response to UVB exposure, connect the cutaneous immune response to CNS immunity by migration to the sites of inflammation (blood, spleen, CNS). Here, they attenuate the inflammatory response and ameliorate disease symptoms. Treg‐inducing tolerogenic dendritic cells (DCs) were further necessary for induction of this systemic immune regulation by UVB radiation, because ablation of Langerhans cells abolished the UVB‐induced phenotype. MS patients treated with UVB phototherapy showed an increase in induced Tregs and tolerogenic DCs accompanied by the downregulation of the T‐cell effector cytokine interleukin 21. The treatment further induced elevated serum levels of vitamin D.

Interpretation

Local UVB radiation of the skin influences systemic immune reactions and attenuates systemic autoimmunity via the induction of skin‐derived tolerogenic DCs and Tregs. Our data could have implications for the understanding or therapeutic modulation of environmental factors that influence immune tolerance. Ann Neurol 2014;75:739–758
Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome
Authors: Claassen Jan , Albers David , Schmidt J. Michael , De Marchis Gian Marco , Pugin Deborah , Falo Christina Maria , Mayer Stephan A. , Cremers Serge , Agarwal Sachin , Elkind Mitchell S. V. , Connolly E. Sander , Dukic Vanja , Hripcsak George , Badjatia Neeraj
Published: April 2014

Objective

Nonconvulsive seizures (NCSz) are frequent following acute brain injury and have been implicated as a cause of secondary brain injury, but mechanisms that cause NCSz are controversial. Proinflammatory states are common after many brain injuries, and inflammation‐mediated changes in blood–brain barrier permeability have been experimentally linked to seizures.

Methods

In this prospective observational study of aneurysmal subarachnoid hemorrhage (SAH) patients, we explored the link between the inflammatory response following SAH and in‐hospital NCSz studying clinical (systemic inflammatory response syndrome [SIRS]) and laboratory (tumor necrosis factor receptor 1 [TNF‐R1], high‐sensitivity C‐reactive protein [hsCRP]) markers of inflammation. Logistic regression, Cox proportional hazards regression, and mediation analyses were performed to investigate temporal and causal relationships.

Results

Among 479 SAH patients, 53 (11%) had in‐hospital NCSz. Patients with in‐hospital NCSz had a more pronounced SIRS response (odds ratio [OR] = 1.9 per point increase in SIRS, 95% confidence interval [CI] = 1.3–2.9), inflammatory surges were more likely immediately preceding NCSz onset, and the negative impact of SIRS on functional outcome at 3 months was mediated in part through in‐hospital NCSz. In a subset with inflammatory serum biomarkers, we confirmed these findings linking higher serum TNF‐R1 and hsCRP to in‐hospital NCSz (OR = 1.2 per 20‐point hsCRP increase, 95% CI = 1.1–1.4; OR = 2.5 per 100‐point TNF‐R1 increase, 95% CI = 2.1–2.9). The association of inflammatory biomarkers with poor outcome was mediated in part through NCSz.

Interpretation

In‐hospital NCSz were independently associated with a proinflammatory state following SAH as reflected in clinical symptoms and serum biomarkers of inflammation. Our findings suggest that inflammation following SAH is associated with poor outcome and that this effect is at least in part mediated through in‐hospital NCSz. Ann Neurol 2014;75:771–781
Elementary‐Siphon‐Based Control Policy for Flexible Manufacturing Systems with Partial Observability and Controllability of Transitions
Authors: Qin Meng , Li ZhiWu , Al‐Ahmari Abdulrahman M.
Published: May 2014

Elementary siphons have been extensively studied to solve deadlock problems in Petri nets. However, most of the existing approaches based on elementary siphons can deal with the Petri nets in which all the transitions are supposed to be controllable and observable. This paper develops an elementary‐siphon‐based deadlock control policy for flexible manufacturing systems with uncontrollable and unobservable transitions. For elementary siphons, their complementary sets are successively expanded by considering unobservability and uncontrollability of transitions. Monitors are designed for the expanded complementary sets. The proposed method permits that there are arcs from monitors to a set of special uncontrollable transitions. Moreover, we show that the dependent siphons are always marked in the controlled system that is derived from the proposed method when there exist uncontrollable and unobservable transitions.
Bemessungsdiagramme zur Ermittlung der Durchstanztragfähigkeit von Einzelfundamenten
Authors: Kueres Dominik , Siburg Carsten , Wieneke Katrin , Hegger Josef
Published: May 2014

Die gesteigerte Komplexität, die sich infolge der iterativen Bestimmung des Durchstanzwiderstands nach DIN EN 1992‐1‐1+NA(D) bei gedrungenen Einzelfundamenten ergibt, verursacht sowohl bei Tragwerksplanern als auch bei Prüfingenieuren einen erheblichen Mehraufwand. Aufgrund fehlender Erfahrungswerte ist eine überschlägliche Bemessung kaum möglich und die Verwendung rechnergestützter Verfahren oft unvermeidbar.

Mit dem Ziel, die Festlegung bzw. Kontrolle der Fundamentabmessungen in der Entwurfsphase wesentlich zu vereinfachen, wurden im Rahmen eines vom Deutschen Ausschuss für Stahlbeton e.V. geförderten Forschungsvorhabens Bemessungsdiagramme zur Bestimmung der Durchstanztragfähigkeit zentrisch und exzentrisch belasteter Einzelfundamente mit unterschiedlicher Stützen‐ und Fundamentgeometrie hergeleitet. Zur weiteren Vereinfachung wurden eine baupraktisch mindestens übliche Betondruckfestigkeit und ein Längsbewehrungsgrad festgelegt, um die aufnehmbare Stützenkraft direkt aus den Bemessungsdiagrammen ablesen zu können. In diesem Beitrag werden die Grundlagen der Berechnung sowie ausgewählte Diagramme als Ergebnis des Forschungsvorhabens präsentiert.

Dimensioning Diagrams for Determining the Punching Shear Resistance of Footings

According to DIN EN 1992‐1‐1+NA(D), the punching shear resistance of compact footings has to be determined iteratively. This increased complexity results in significant additional effort for structural designers and inspecting structural engineers. Due to the lack of experienced data, an estimated structural design is hardly possible and computational methods often unavoidable.

To simplify the determination of the footing's dimensions at design stage, dimensioning diagrams were derived to determine the punching shear resistance of centrically and eccentrically loaded compact footings with different column and footing dimensions. For further simplification a common concrete compressive strength and flexural reinforcement ratio were defined, thus the maximum column load can be determined directly from dimensioning diagrams. This article presents the results of this research project, which was funded by the German Commitee for Structural Concrete.
Ultrasound investigation of vastus medialis oblique muscle architecture: An in vivo study
Authors: Engelina S. , Antonios T. , Robertson C.J. , Killingback A. , Adds P.J.
Published: May 2014

There is thought to be a link between vastus medialis oblique (VMO) architecture and patellofemoral pain syndrome (PFPS). Historical data are largely derived from older populations, whereas PFPS commonly affects younger populations. The aim of this study was to gather data on VMO architecture in young asymptomatic adults, to provide baseline values for comparison with symptomatic sufferers. VMO maximum fiber angle and insertion ratio were measured with ultrasound. The insertion ratio represents the proportion (%) of the patella which has the muscle fibers attaching to its medial border. Eighty knees from 40 healthy young subjects (18 males, 22 females, and age 20–30) were assessed. Individual Tegner scores were recorded to assess participants' level of physical activity. Results were compared with data in the literature for PFPS sufferers and normal older individuals. Mean fiber angle and insertion ratio were 56.6° and 57.8%, respectively. There was no significant difference between age groups. The insertion ratio was higher among females (61.2% F:53.6% M). There was some evidence of increased fiber angle and decreased insertion ratio with increased Tegner score. There was some overlap in fiber angle between healthy knees in this study and values reported elsewhere for pathological knees. VMO fiber angle and insertion ratio are not age‐related. The overlap in fiber angle values between healthy and pathological knees suggests that the cause of PFPS is multifactorial. An individual's VMO architecture may be affected by their physical activity level, which could have important implications for PFPS. Clin. Anat. 27:1076–1084, 2014. © 2014 Wiley Periodicals, Inc.
Mesenchymal stem cell based therapy for osteo‐diseases
Authors: Ghasroldasht Mohammad Mousaei , Irfan‐Maqsood Muhammad , Matin Maryam M. , Bidkhori Hamid Reza , Naderi‐Meshkin Hojjat , Moradi Ali , Bahrami Ahmad Reza
Published: May 2014

Stem cell therapy in recent years has gained much attention as the modern therapeutic approach to treat diseases. Mesenchymal stem cells (MSCs) are seen as the most reliable cells applied in therapy over other stem cells because of their versatility. Bone and cartilage diseases (osteo‐diseases) are the major target of therapy using MSCs. In this perspective, we have statistically analyzed the data available on clinical trials registry databases regarding the mesenchymal stem cell based therapy for a number of mentioned diseases and paid attention towards the osteodiseases. We report that MSC therapy for osteo‐diseases needs optimization in its standards to achieve acceptable results so that we can apply it in daily routine clinical practice.
Superbasic Alkyl‐Substituted Bisphosphazene Proton Sponges: Synthesis, Structural Features, Thermodynamic and Kinetic Basicity, Nucleophilicity and Coordination Chemistry
Authors: Kögel Julius F. , Xie Xiulan , Baal Eduard , Gesevičius Donatas , Oelkers Benjamin , Kovačević Borislav , Sundermeyer Jörg
Published: May 2014

Herein we describe an easily accessible class of superbasic proton sponges based on the 1,8‐bisphosphazenylnaphthalene (PN) proton pincer motif and P‐alkyl substituents ranging from methyl (TMPN) ton‐butyl (TBPN), isopropyl (TiPrPN) and cyclopentyl (TcyPPN). These neutral bases with a pKBH+value (MeCN) of ∼30 were accessible via a Kirsanov condensation using commercially available 1,8‐diaminonaphthalene, and in case of TMPN and TBPN, simple one‐pot procedures starting from trisalkylphosphanes can be performed. Furthermore, the known pyrrolidinyl‐substituted superbase TPPN previously synthesized via a Staudinger reaction could also be prepared by the Kirsanov strategy allowing its preparation in a larger scale. The four alkyl‐substituted proton sponges were structurally characterized in their protonated form; molecular XRD structures were also obtained for unprotonated TiPrPN and TcyPPN. Moreover, we present a detailed description of spectroscopic features of chelating bisphosphazenes including TPPN and its hyperbasic homologue P2‐TPPN on which we reported recently. The four alkyl‐substituted superbases were investigated with respect to their basic features by computational means and by NMR titration experiments revealing unexpectedly high experimental pKBH+values in acetonitrile between 29.3 for TMPN and 30.9 for TBPN. Besides their thermodynamic basicity, we exemplarily studied the kinetic basicity of TMPN and TPPN by means of NMR‐spectroscopic methods. Furthermore, the competing nucleophilic versus basic properties were examined by reacting the proton sponges with ethyl iodide. Insight into the coordination chemistry of chelating superbases was provided by reacting TMPN with trimethylaluminum and trimethylgallium to give cationic complexes of Group XIII metal alkyls that were structurally characterized.
Synthesis of Purine and 7‐Deazapurine Nucleoside Analogues of 6‐N‐(4‐Nitrobenzyl)adenosine; Inhibition of Nucleoside Transport and Proliferation of Cancer Cells
Authors: Rayala Ramanjaneyulu , Theard Patricia , Ortiz Heysell , Yao Sylvia , Young James D. , Balzarini Jan , Robins Morris J. , Wnuk Stanislaw F.
Published: April 2014

Human equilibrative nucleoside transporter 1 (hENT1) is a prototypical nucleoside transporter protein ubiquitously expressed on the cell surface of almost all human tissue. Given the role of hENT1 in the transport of nucleoside drugs, an important class of therapeutics in the treatment of various cancers and viral infections, efforts have been made to better understand the mechanisms by which hENT1 modulates nucleoside transport. To that end, we report here the design and synthesis of novel tool compounds for the further study of hENT1. The 7‐deazapurine nucleoside antibiotic tubercidin was converted into its 4‐N‐benzyl and 4‐N‐(4‐nitrobenzyl) derivatives by alkylation at N3 followed by a Dimroth rearrangement to the 4‐N‐isomer or by fluoro‐diazotization followed by SNAr displacement of the 4‐fluoro group by a benzylamine. The 4‐N‐(4‐nitrobenzyl) derivatives of sangivamycin and toyocamycin antibiotics were prepared by the alkylation approach. Cross‐membrane transport of labeled uridine by hENT1 was inhibited to a weaker extent by the 4‐nitrobenzylated tubercidin and sangivamycin analogues than was observed with 6‐N‐(4‐nitrobenzyl)adenosine. Type‐specific inhibition of cancer cell proliferation was observed at micromolar concentrations with the 4‐N‐(4‐nitrobenzyl) derivatives of sangivamycin and toyocamycin, and also with 4‐N‐benzyltubercidin. Treatment of 2′,3′,5′‐O‐acetyladenosine with aryl isocyanates gave the 6‐ureido derivatives but none of them exhibited inhibitory activity against cancer cell proliferation or hENT1.
Induced neuronal reprogramming
Authors: Ang Cheen Euong , Wernig Marius
Published: April 2014

Cellular differentiation processes during normal embryonic development are guided by extracellular soluble factors such as morphogen gradients and cell contact signals, eventually resulting in induction of specific combinations of lineage‐determining transcription factors. The young field of epigenetic reprogramming takes advantage of this knowledge and uses cell fate determination factors to convert one lineage into another such as the conversion of fibroblasts into pluripotent stem cells or neurons. These induced cell fate conversions open up new avenues for studying disease processes, generating cell material for therapeutic intervention such as drug screening and potentially also for cell‐based therapies. However, there are still limitations that have to be overcome to fulfill these promises, centering on reprogramming efficiencies, cell identity, and maturation. In this review, we discuss the discovery of induced neuronal reprogramming, ways to improve the conversion process, and finally how to define properly the identity of those converted neuronal cells. J. Comp. Neurol. 522:2877–2886, 2014. © 2014 Wiley Periodicals, Inc.
A novel cell migratory zone in the developing hippocampal formation
Authors: Sugiyama Taku , Osumi Noriko , Katsuyama Yu
Published: April 2014

The hippocampal formation (HF) is a unique structure in the mammalian brain and is subdivided into the dentate gyrus, Ammon's horn, and subiculum by their functions and connectivity in the neuronal circuit. Because behaviors of the neural stem cells, neuronal progenitors, and the differentiating neurons are complex during hippocampal morphogenesis, the differentiation of these subdivisions has not been well understood. In this study, we investigated embryonic and postnatal expression of the proteins Prox1, Math2, and Ctip2, which clearly indicate principal cells of the dentate gyrus (Prox1 positive) and Ammon's horn (Math2 and Ctip2 positive). Expression patterns of Prox1 and Math2 were consistent with previously suggested localization of migratory pathways of the dentate granule cells and hippocampal pyramidal cells. Interestingly, we found intermingling of Prox1‐expressing cells and Math2‐expressing cells in a cell migratory stream, suggesting previously unknown behaviors of differentiating cells of the HF. J. Comp. Neurol. 522:3520–3538, 2014. © 2014 Wiley Periodicals, Inc.