bluuebunny/crossref_metadata_2025_split huggingface dataset:
MyD88 in Macrophages Is Critical for Abscess Resolution in Staphylococcal Skin Infection
Authors: Feuerstein Reinhild , Seidl Maximilian , Prinz Marco , Henneke Philipp 
Published: February 2015

Abstract
When Staphylococcus aureus penetrates the epidermis and reaches the dermis, polymorphonuclear leukocytes (PMLs) accumulate and an abscess is formed. However, the molecular mechanisms that orchestrate initiation and termination of inflammation in skin infection are incompletely understood. In human myeloid differentiation primary response gene 88 (MyD88) deficiency, staphylococcal skin and soft tissue infections are a leading and potentially life-threatening problem. In this study, we found that MyD88-dependent sensing of S. aureus by dermal macrophages (Mϕ) contributes to both timely escalation and termination of PML-mediated inflammation in a mouse model of staphylococcal skin infection. Mϕs were key to recruit PML within hours in response to staphylococci, irrespective of bacterial viability. In contrast with bone marrow–derived Mϕs, dermal Mϕs did not require UNC-93B or TLR2 for activation. Moreover, PMLs, once recruited, were highly activated in an MyD88-independent fashion, yet failed to clear the infection if Mϕs were missing or functionally impaired. In normal mice, clearance of the infection and contraction of the PML infiltrate were accompanied by expansion of resident Mϕs in a CCR2-dependent fashion. Thus, whereas monocytes were dispensable for the early immune response to staphylococci, they contributed to Mϕ renewal after the infection was overcome. Taken together, MyD88-dependent sensing of staphylococci by resident dermal Mϕs is key for a rapid and balanced immune response, and PMLs are dependent on intact Mϕ for full function. Renewal of resident Mϕs requires both local control of bacteria and inflammatory monocytes entering the skin.
Cutting Edge: NF-κB p65 and c-Rel Control Epidermal Development and Immune Homeostasis in the Skin
Authors: Grinberg-Bleyer Yenkel , Dainichi Teruki , Oh Hyunju , Heise Nicole , Klein Ulf , Schmid Roland M. , Hayden Matthew S. , Ghosh Sankar 
Published: February 2015

Abstract
Psoriasis is an inflammatory skin disease in which activated immune cells and the proinflammatory cytokine TNF are well-known mediators of pathogenesis. The transcription factor NF-κB is a key regulator of TNF production and TNF-induced proinflammatory gene expression, and both the psoriatic transcriptome and genetic susceptibility further implicate NF-κB in psoriasis etiopathology. However, the role of NF-κB in psoriasis remains controversial. We analyzed the function of canonical NF-κB in the epidermis using CRE-mediated deletion of p65 and c-Rel in keratinocytes. In contrast to animals lacking p65 or c-Rel alone, mice lacking both subunits developed severe dermatitis after birth. Consistent with its partial histological similarity to human psoriasis, this condition could be prevented by anti-TNF treatment. Moreover, regulatory T cells in lesional skin played an important role in disease remission. Our results demonstrate that canonical NF-κB in keratinocytes is essential for the maintenance of skin immune homeostasis and is protective against spontaneous dermatitis.
TRAF4-SMURF2–Mediated DAZAP2 Degradation Is Critical for IL-25 Signaling and Allergic Airway Inflammation
Authors: Zepp Jarod A. , Wu Ling , Qian Wen , Ouyang Wenjun , Aronica Mark , Erzurum Serpil , Li Xiaoxia 
Published: February 2015

Abstract
IL-25 promotes type 2 immunity by inducing the expression of Th2–associated cytokines. Although it is known that the IL-25R (IL-17RB) recruits the adaptor protein ACT1, the IL-25R signaling mechanism remains poorly understood. While screening for IL-25R components, we found that IL-25 responses were impaired in Traf4 −/− cells. Administering IL-25 to Traf4 −/− mice resulted in blunted airway eosinophilia and Th2 cytokine production. Notably, IL-25R recruitment of TRAF4 was required for the ACT1/IL-25R interaction. Mechanistically, TRAF4 recruited the E3-ligase SMURF2, to degrade the IL-25R–inhibitory molecule DAZAP2. Silencing Dazap2 increased ACT1/IL-25R interaction and IL-25 responsiveness. Moreover, a tyrosine within the IL-25R elicited DAZAP2 interference. This study indicates that TRAF4-SMURF2–mediated DAZAP2 degradation is a crucial initiating event for the IL-25 response.
High Diversity in the TCR Repertoire of GAD65 Autoantigen-Specific Human CD4+ T Cells
Authors: Eugster Anne , Lindner Annett , Catani Mara , Heninger Anne-Kristin , Dahl Andreas , Klemroth Sylvia , Kühn Denise , Dietz Sevina , Bickle Marc , Ziegler Anette-Gabrielle , Bonifacio Ezio 
Published: February 2015

Abstract
Autoreactive CD4+ T cells are an essential feature of type 1 diabetes mellitus. We applied single-cell TCR α- and β-chain sequencing to peripheral blood GAD65-specific CD4+ T cells, and TCR α-chain next-generation sequencing to bulk memory CD4+ T cells to provide insight into TCR diversity in autoimmune diabetes mellitus. TCRs obtained for 1650 GAD65-specific CD4+ T cells isolated from GAD65 proliferation assays and/or GAD65 557I tetramer staining in 6 patients and 10 islet autoantibody-positive children showed large diversity with 1003 different TCRs identified. TRAV and TRBV gene usage was broad, and the TRBV5.1 gene was most prominent within the GAD65 557I tetramer+ cells. Limited overlap (&lt;5%) was observed between TCRs of GAD65-proliferating and GAD65 557I tetramer+ CD4+ T cells. Few TCRs were repeatedly found in GAD65-specific cells at different time points from individual patients, and none was seen in more than one subject. However, single chains were often shared between patients and used in combination with different second chains. Next-generation sequencing revealed a wide frequency range (&lt;0.00001–1.62%) of TCR α-chains corresponding to GAD65-specific T cells. The findings support minor selection of genes and TCRs for GAD65-specific T cells, but fail to provide strong support for TCR-targeted therapies.
Function-theoretic Properties for the Gauss Maps of Various Classes of Surfaces
Authors: Kawakami Yu 
Published: February 2015

AbstractWe elucidate the geometric background of function-theoretic properties for the Gauss maps of several classes of immersed surfaces in three-dimensional space forms, for example, minimal surfaces in Euclidean three-space, improper affine spheres in the affine three-space, and constant mean curvature one surfaces and flat surfaces in hyperbolic three-space. To achieve this purpose, we prove an optimal curvature bound for a specified conformal metric on an open Riemann surface and give some applications. We also provide unicity theorems for the Gauss maps of these classes of surfaces.
Dust deposition in the eastern Indian Ocean: The ocean perspective from Antarctica to the Bay of Bengal
Authors: Grand Maxime M. , Measures Christopher I. , Hatta Mariko , Hiscock William T. , Buck Clifton S. , Landing William M. 
Published: February 2015

AbstractAtmospheric deposition is an important but still poorly constrained source of trace micronutrients to the open ocean because of the dearth of in situ measurements of total deposition (i.e., wet + dry deposition) in remote regions. In this work, we discuss the upper ocean distribution of dissolved Fe and Al in the eastern Indian Ocean along a 95°E meridional transect spanning the Antarctic margin to the Bay of Bengal. We use the mixed layer concentration of dissolved Al in conjunction with empirical data in a simple steady state model to produce 75 estimates of total dust deposition that we compare with historical observations and atmospheric model estimates. Except in the northern Bay of Bengal where the Ganges‐Brahmaputra river plume contributes to the inventory of dissolved Al, the surface distribution of dissolved Al along 95°E is remarkably consistent with the large‐scale gradients in mineral dust deposition and multiple‐source regions impacting the eastern Indian Ocean. The lowest total dust deposition fluxes are calculated for the Southern Ocean (66 ± 60 mg m−2 yr−1) and the highest for the northern end of the south Indian subtropical gyre (up to 940 mg m−2 yr−1 at 18°S) and in the southern Bay of Bengal (2500 ± 570 mg m−2 yr−1). Our total deposition fluxes, which have an uncertainty on the order of a factor of 3.5, are comparable with the composite atmospheric model data of Mahowald et al. (2005), except in the south Indian subtropical gyre where models may underestimate total deposition. Using available measurements of the solubility of Fe in aerosols, we confirm that dust deposition is a minor source of dissolved Fe to the Southern Ocean and show that aeolian deposition of dissolved Fe in the southern Bay of Bengal may be comparable to that observed underneath the Saharan dust plume in the Atlantic Ocean.
Baroclinic energy flux at the continental shelf edge modified by wind‐mixing
Authors: R. Stephenson Gordon , Hopkins Joanne E. , Mattias Green J. A. , Inall Mark E. , Palmer Matthew R. 
Published: February 2015

AbstractTemperature and current measurements from two moorings onshore of the Celtic Sea shelf break, a well‐known hot spot for tidal energy conversion, show the impact of passing summer storms on the baroclinic wavefield. Wind‐driven vertical mixing changed stratification to permit an increased on‐shelf energy transport, and baroclinic energy in the semidiurnal band appeared at the moorings 1–4 days after the storm mixed the upper 50 m of the water column. The timing of the maximum in the baroclinic energy flux is consistent with the propagation of the semidiurnal internal tide from generation sites at the shelf break to the moorings 40 km away. Also, the ∼3 day duration of the peak in M2 baroclinic energy flux at the moorings corresponds to the restratification time scale following the first storm.
Ion beta dependence on the development of Alfvénic fluctuations in reconnection jets
Authors: Higashimori Katsuaki , Hoshino Masahiro 
Published: February 2015

AbstractThe generation of magneto‐hydro‐dynamic (MHD) to ion‐scale fluctuations in collisionless magnetic reconnection is discussed using a two‐dimensional electromagnetic hybrid code. It is shown that reconnection jets become turbulent specifically in low beta conditions, βi0<0.1–0.2 (where βi0 is the ion plasma beta in initial inflow regions). The fluctuations observed in reconnection jets consist of outgoing Alfvénic fluctuations. As probable candidates for the origin of Alfvénic fluctuations, this study focused on the dynamics in the plasma sheet boundary layer (PSBL) and a current sheet. We suggest that PSBL ion dynamics play an important part in excitation and suppression of waves. PSBL beam ions drive Alfvén waves in MHD to ion scale, kλi<0.5 (λi is ion inertial length), independent of βi0. On the other hand, because the beam temperature is highly correlated with that of inflowing ions, the waves decay by cyclotron damping as the value of the inflow ion beta increases. Local linear analysis suggests that this damping signature changes in βi0∼0.1–0.2 and suppresses the wave activity of Alfvén modes in high beta reconnection jets.
Interpreting Ulysses data using inverse scattering theory: Oblique Alfvén waves
Authors: Wheeler Harry R. , Reynolds M. A. , Hamilton R. L. 
Published: February 2015

AbstractSolitary wave structures observed by the Ulysses spacecraft in the solar wind were analyzed using both inverse scattering theory and direct numerical integration of the derivative nonlinear Schrödinger (DNLS) equation. Several of these structures were found to be consistent with soliton solutions of the DNLS equation. Such solitary structures have been commonly observed in the space plasma environment and may, in fact, be long‐lived solitons. While the generation of these solitons may be due to an instability mechanism, e.g., the mirror instability, they may be observable far from the source region due to their coherent nature.
The global context of the 14 November 2012 storm event
Authors: Hwang K.‐J. , Sibeck D. G. , Fok M.‐C. H. , Zheng Y. , Nishimura Y. , Lee J.‐J. , Glocer A. , Partamies N. , Singer H. J. , Reeves G. D. , Mitchell D. G. , Kletzing C. A. , Onsager T. 
Published: February 2015

AbstractFrom 2 to 5 UT on 14 November 2012, the Van Allen Probes observed repeated particle flux dropouts during the main phase of a geomagnetic storm as the satellites traversed the post‐midnight to dawnside inner magnetosphere. Each flux dropout corresponded to an abrupt change in the magnetic topology, i.e., from a more dipolar configuration to a configuration with magnetic field lines stretched in the dawn‐dusk direction. Geosynchronous GOES spacecraft located in the dusk and near‐midnight sectors and the LANL constellation with wide local time coverage also observed repeated flux dropouts and stretched field lines with similar occurrence patterns to those of the Van Allen Probe events. THEMIS recorded multiple transient abrupt expansions of the evening‐side magnetopause ∼20–30 min prior to the sequential Van Allen Probes observations. Ground‐based magnetograms and all sky images demonstrate repeatable features in conjunction with the dropouts. We combine the various in situ and ground‐based measurements to define and understand the global spatiotemporal features associated with the dropouts observed by the Van Allen Probes. We discuss various proposed hypotheses for the mechanism that plausibly caused this storm‐time dropout event as well as formulate a new hypothesis that explains the combined in situ and ground‐based observations: the earthward motion of magnetic flux ropes containing lobe plasmas that form along an extended magnetotail reconnection line in the near‐Earth plasma sheet.
Multiscale seismic reflectivity of shallow thermoclines
Authors: Ker S. , Le Gonidec Y. , Marié L. , Thomas Y. , Gibert D. 
Published: February 2015

AbstractSeismic oceanography is coming of age as an established technique of observation of the thermohaline structure of the ocean. The present paper deals with the seismic reflectivity of the Armorican Shelf seasonal thermocline, west of France, based on two seismic experiments performed with a sparker source. The peak frequency was 500 Hz for the ASPEX experiment, where the thermocline was located at 27 m water depth, and reduced to 400 Hz associated to a higher source level for the IFOSISMO experiment, where the thermocline was 12 m deeper. Despite these settings, only the first experiment could clearly highlight the thermocline reflector, providing the first seismic observation of a shallow oceanic structure. To better understand the limitation of high‐resolution seismic devices in detecting weak oceanic features, we develop a wavelet‐based seismic analysis and consider, as a first approximation, a simple thermocline modeled by a Gauss error function, allowing an analytical expression for the associated seismic reflectivity. We show that the acoustic impedance profile of the thermocline is mainly controlled by a sound velocity proportional to the temperature. We show that the seismic reflectivity is controlled by the reflection coefficient of the large‐scale structure of the thermocline and by an attenuation factor which depends on the ratio between the seismic wavelength and the characteristic size of the thermocline. Depending on this ratio, the strength of the thermocline‐related reflection may be too weak to be detected by seismic measurement.
Updated PMC trends derived from SBUV data
Authors: DeLand Matthew T. , Thomas Gary E. 
Published: February 2015

AbstractPrevious analysis of polar mesospheric clouds (PMCs) observed by Solar Backscatter Ultraviolet (SBUV) instruments found that long‐term variations in PMC brightness and occurrence frequency were anticorrelated with solar activity and that an increasing secular trend was present at most latitudes. In this paper, long‐term PMC variations are presented in terms of ice water content (IWC), a physically based variable which is easier to interpret than previously reported UV albedo values. This model‐based conversion from albedo to IWC removes most scattering angle effects. The derived long‐term PMC variations in the SBUV data set are qualitatively the same using either an empirically derived adjustment for local time effects or no adjustment (i.e., assuming cancelation of interannual variations in tidally induced amplitude and/or phase). When we use stratospheric ozone variations as a proxy for mesospheric temperature changes, as suggested by recent model studies, we can explain more of the long‐term IWC variability than if we use a linear trend. These results show that PMC ice water content in bright clouds increased rapidly from 1979 through the late 1990s and has been approximately constant from the late 1990s through 2013. The numerical value and sign of this trend during the last 15 years depend on the choice of end points and latitude band. Simultaneously, the solar response of IWC observed by SBUV has weakened during the most recent cycle in the Northern Hemisphere, but increased in the Southern Hemisphere.
An accurate and fast forward model of three‐dimensional electromagnetic wave scattering in a layered structure with multilayer rough interfaces
Authors: Wu Chao , Zhang Xiaojuan , Fang Guangyou , Shi Jiancheng , Liu Shiyin 
Published: February 2015

AbstractWe develop an accurate and fast forward model for calculating the compact closed‐form high‐order perturbative solutions of the problem of three‐dimensional (3‐D) radiation and propagation electromagnetic fields in a layered structure with multilayer rough interfaces. The proposed method for the fast forward model is first demonstrated by strictly theoretical formulas derivation in the framework of classical small perturbation method (SPM) without other else approximation and equivalent process. The kernel functions of high order are proposed for calculating the radar cross sections with more efficiency and clear physical meanings for better use in practice. What is more, we give the clear physical interpretation of the first‐order fully polarimetric electromagnetic wave scattering mechanism in the layered structure with multilayer rough interfaces. The proposed forward model is necessary to insure a successful inversion process. Furthermore, the high‐order SPM solutions derived by employing the proposed method are validated with existing methods and numerical results. Finally, we study the performance of the high‐order fully polarimetric electromagnetic wave scattering according to the numerical results and analyze the scattering enhancement phenomena.
Porphyrias
Authors: Besur Siddesh , Bonkovsky Herbert L 
Published: February 2015

AbstractThe porphyrias are a group of eight disorders of haem biosynthesis characterised by overproduction of haem precursors secondary to partial enzyme deficiencies or, in one porphyria, gain of function of the rate‐controlling enzyme of the pathway in erythroid cells. Patients suffer from acute neurovisceral attacks, always associated with overproduction of porphyrin precursors, skin lesions caused by photosensitisation by porphyrins or both together. All are inherited, apart from sporadic porphyria cutanea tarda. The three porphyrias in which acute attacks occur (acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) and familial porphyria cutanea tarda are low penetrance autosomal dominant disorders and one is an X‐linked disorder. All others are autosomal recessive. Enzyme activities in the autosomal recessive porphyrias and in the homozygous variants of other porphyrias are usually less than 20% of normal.Key ConceptsThe porphyrias are disorders of haem biosynthesis.Each of the eight porphyrias is caused by an abnormality of a different enzyme of haem biosynthesis.Each enzyme abnormality leads to overproduction of haem precursors in a specific pattern that defines the disorder.Overproduction of porphyrin precursors leads to acute neurovisceral attacks that characterise the three autosomal dominant acute porphyrias and one rare recessive porphyria.Overproduction of porphyrins leads to photosensitisation of the skin with either skin fragility and blisters or, when only protoporphyrin accumulates, acute painful photosensitivity.All autosomal dominant porphyrias have low clinical penetrance.Most patients with the commonest inherited cutaneous porphyria, erythropoietic protoporphyria, have inherited a low expression ferrochelatase allele trans to a deleterious ferrochelatase mutation.The prevalence of erythropoietic protoporphyria and the proportion of families showing pseudo‐dominant inheritance are determined by the population frequency of the low expression allele.
Protein Kinases in the Era of Precision Medicine
Authors: Moiani Davide , Tabaian Amir , Suto Robert K , Doyle David M , Sowadski Janusz M 
Published: February 2015

Abstract

Precision medicine signals the beginning of an era in which each patient is a distinct individual from a diagnostic, treatment and health management perspective. In this article, we present a description of a methodology to develop a therapy, based on kinase inhibitors, and a strategy to retarget a therapy in rapid response to a patient's relapse. The idea is to translate the genomic data of an evolving cancer into a three‐dimensional structure to enable a better understanding of the mechanism of resistance, and to then control it with a specific and precise drug targeting therapy based on the
SNP
resistance mutation. In many cases, a combination of approved drug treatments can assist in controlling the disease. However, the clinical trials selection process is changing from randomised populations to selected populations so that genetic tests can more clearly define the presence of specific mutations in the relapsing patient. This knowledge of the subpopulation will also help identify new small molecules that target multiple kinases based on their specificity profiles. The tendency at present is to define an eligibility criteria based on the genetics of the patients.

Key Concepts

The crystallographic characterisation of kinase inhibitor complexes drove the approval of 27 drugs targeting kinome.

Organising the kinase three‐dimensional (3D) structures in a uniquely aligned library has enabled us to predict the functionality, in a 3D space, of any variants that are found in a patient's genome.

Accurate specificity profiles of approved kinase inhibitors inform a rational combination of inhibitors for a specific genetic subpopulation of patients.

Kinase inhibitor therapy can be matched to critical mutations in the kinase 3D structure and a companion diagnostics approach can then be used in specific clinical trial to more accurately select patients.

The targeting of both the kinase‐activating mutation and the drug‐resistant mutations can be optimised by the chemistry of the intermediate conformations of the DFG motif.

The drug resistance requires frequent genetic monitoring utilising a liquid biopsy.

Overcoming the drug resistance on the target is possible by combining approved drugs based on the enhanced knowledge of the highly accurate specificity profiles.