Extracellular Domain N-Glycosylation Controls Human Thrombopoietin Receptor Cell Surface Levels

The thrombopoietin receptor (TpoR) is a type I transmembrane protein that mediates the signaling functions of thrombopoietin (Tpo) in regulating megakaryocyte differentiation, platelet formation, and hematopoietic stem cell renewal. We probed the role of each of the four extracellular domain putative N-glycosylation sites for cell surface localization and function of the receptor. Single N-glycosylation mutants at any of the four sites were able to acquire the mature N-glycosylated pattern, but exhibited a decreased Tpo-dependent JAK2–STAT response in stably transduced Ba/F3 or Ba/F3-JAK2 cell lines. The ability of JAK2 to promote cell surface localization and stability of TpoR required the first N-glycosylation site (Asn117). In contrast, the third N-glycosylation site (Asn298) decreased receptor maturation and stability. TpoR mutants lacking three N-glycosylation sites were defective in maturation, but N-glycosylation on the single remaining site could be detected by sensitivity to PNGaseF. The TpoR mutant defective in all four N-glycosylation sites was severely impaired in plasma membrane localization and was degraded by the proteasome. N-glycosylation receptor mutants are not misfolded as, once localized on the cell surface in overexpression conditions, they can bind and respond to Tpo. Our data indicate that extracellular domain N-glycosylation sites regulate in a combinatorial manner cell surface localization of TpoR. We discuss how mutations around TpoR N-glycosylation sites might contribute to inefficient receptor traffic and disease

Translating radiological research into practice — from discovery to clinical impact

At the European Society of Radiology (ESR), we strive to provide evidence for radiological practices that improve patient outcomes and have a societal impact. Successful translation of radiological research into clinical practice requires multiple factors including tailored methodology, a multidisciplinary approach aiming beyond technical validation, and a focus on unmet clinical needs. Low levels of evidence are a threat to radiology, resulting in low visibility and credibility. Here, we provide the background and rationale for the thematic series Translating radiological research into practice—from discovery to clinical impact, inviting authors to describe their processes of achieving clinically impactful radiological research. We describe the challenges unique to radiological research. Additionally, a survey was sent to non-radiological clinical societies. The majority of respondents (6/11) were in the field of gastrointestinal/abdominal medicine. The implementation of CT/MRI techniques for disease characterisation, detection and staging of cancer, and treatment planning and radiological interventions were mentioned as the most important radiological developments in the past years. The perception was that patients are substantially unaware of the impact of these developments. Unmet clinical needs were mostly early diagnosis and staging of cancer, microstructural/functional assessment of tissues and organs, and implant assessment. All but one respondent considered radiology important for research in their discipline, but five indicated that radiology is currently not involved in their research. Radiology research holds the potential for being transformative to medical practice. It is our responsibility to take the lead in studies including radiology and strive towards the highest levels of evidence. Critical relevance statement For radiological research to make a clinical and societal impact, radiologists should take the lead in radiological studies, go beyond the assessment of technical feasibility and diagnostic accuracy, and—in a multidisciplinary approach—address clinical unmet needs. Key points • Multiple factors are essential for radiological research to make a clinical and societal impact. • Radiological research needs to go beyond diagnostic accuracy and address unmet clinical needs. • Radiologists should take the lead in radiological studies with a multidisciplinary approach.</p

Translating radiological research into practice — from discovery to clinical impact

At the European Society of Radiology (ESR), we strive to provide evidence for radiological practices that improve patient outcomes and have a societal impact. Successful translation of radiological research into clinical practice requires multiple factors including tailored methodology, a multidisciplinary approach aiming beyond technical validation, and a focus on unmet clinical needs. Low levels of evidence are a threat to radiology, resulting in low visibility and credibility. Here, we provide the background and rationale for the thematic series Translating radiological research into practice—from discovery to clinical impact, inviting authors to describe their processes of achieving clinically impactful radiological research. We describe the challenges unique to radiological research. Additionally, a survey was sent to non-radiological clinical societies. The majority of respondents (6/11) were in the field of gastrointestinal/abdominal medicine. The implementation of CT/MRI techniques for disease characterisation, detection and staging of cancer, and treatment planning and radiological interventions were mentioned as the most important radiological developments in the past years. The perception was that patients are substantially unaware of the impact of these developments. Unmet clinical needs were mostly early diagnosis and staging of cancer, microstructural/functional assessment of tissues and organs, and implant assessment. All but one respondent considered radiology important for research in their discipline, but five indicated that radiology is currently not involved in their research. Radiology research holds the potential for being transformative to medical practice. It is our responsibility to take the lead in studies including radiology and strive towards the highest levels of evidence. Critical relevance statement For radiological research to make a clinical and societal impact, radiologists should take the lead in radiological studies, go beyond the assessment of technical feasibility and diagnostic accuracy, and—in a multidisciplinary approach—address clinical unmet needs. Key points • Multiple factors are essential for radiological research to make a clinical and societal impact. • Radiological research needs to go beyond diagnostic accuracy and address unmet clinical needs. • Radiologists should take the lead in radiological studies with a multidisciplinary approach.</p

Optical alignment and spinning of laser-trapped microscopic particles

Light-induced rotation of absorbing microscopic particles by transfer of angular momentum from light to the material raises the possibility of optically driven micromachines. The phenomenon has been observed using elliptically polarized laser beams or beams with helical phase structure. But it is difficult to develop high power in such experiments because of overheating and unwanted axial forces, limiting the achievable rotation rates to a few hertz. This problem can in principle be overcome by using transparent particles, transferring angular momentum by a mechanism first observed by Beth in 1936, when he reported a tiny torque developed in a quartz waveplate due to the change in polarization of transmitted light. Here we show that an optical torque can be induced on microscopic birefringent particles of calcite held by optical tweezers. Depending on the polarization of the incident beam, the particles either become aligned with the plane of polarization (and thus can be rotated through specified angles) or spin with constant rotation frequency. Because these microscopic particles are transparent, they can be held in three-dimensional optical traps at very high power without heating. We have observed rotation rates in excess of 350 Hz.Comment: 4 pages, 4 figure

Unstable states in QED of strong magnetic fields

We question the use of stable asymptotic scattering states in QED of strong magnetic fields. To correctly describe excited Landau states and photons above the pair creation threshold the asymptotic fields are chosen as generalized Licht fields. In this way the off-shell behavior of unstable particles is automatically taken into account, and the resonant divergences that occur in scattering cross sections in the presence of a strong external magnetic field are avoided. While in a limiting case the conventional electron propagator with Breit-Wigner form is obtained, in this formalism it is also possible to calculate $S$-matrix elements with external unstable particles.Comment: Revtex, 7 pages. To appear in Phys. Rev. D53(2

Constrained Statistical Modelling of Knee Flexion from Multi-Pose Magnetic Resonance Imaging

© 1982-2012 IEEE.Reconstruction of the anterior cruciate ligament (ACL) through arthroscopy is one of the most common procedures in orthopaedics. It requires accurate alignment and drilling of the tibial and femoral tunnels through which the ligament graft is attached. Although commercial computer-Assisted navigation systems exist to guide the placement of these tunnels, most of them are limited to a fixed pose without due consideration of dynamic factors involved in different knee flexion angles. This paper presents a new model for intraoperative guidance of arthroscopic ACL reconstruction with reduced error particularly in the ligament attachment area. The method uses 3D preoperative data at different flexion angles to build a subject-specific statistical model of knee pose. To circumvent the problem of limited training samples and ensure physically meaningful pose instantiation, homogeneous transformations between different poses and local-deformation finite element modelling are used to enlarge the training set. Subsequently, an anatomical geodesic flexion analysis is performed to extract the subject-specific flexion characteristics. The advantages of the method were also tested by detailed comparison to standard Principal Component Analysis (PCA), nonlinear PCA without training set enlargement, and other state-of-The-Art articulated joint modelling methods. The method yielded sub-millimetre accuracy, demonstrating its potential clinical value

Neurobiology of Vascular Dementia

Vascular dementia is, in its current conceptual form, a distinct type of dementia with a spectrum of specific clinical and pathophysiological features. However, in a very large majority of cases, these alterations occur in an already aged brain, characterized by a milieu of cellular and molecular events common for different neurodegenerative diseases. The cell signaling defects and molecular dyshomeostasis might lead to neuronal malfunction prior to the death of neurons and the alteration of neuronal networks. In the present paper, we explore some of the molecular mechanisms underlying brain malfunction triggered by cerebrovascular disease and risk factors. We suggest that, in the age of genetic investigation and molecular diagnosis, the concept of vascular dementia needs a new approach

SUSTAINABLE DEVELOPMENT THROUGH AGRO-TOURISM FOR THE CONSOLIDATION OF AGRICULTURE AND THE ENVIRONMENT

Designed as a necessary association between people and nature, as a new way of development that can support the human progress in time, sustainable development can be seen as a harmonization of interests between present and future generations.Therefore, in order to respond to present needs without compromising the capacity of future generations to meet their own needs, sustainable development planning must be understood as a process unfolding at three different levels: economical - by increasing the exploration and the exploitation of resources, environmental - by avoiding environmental degradation, and social - through jobs growth, traditional crafts, agro-tourism and by strengthening the cultural identity of local communities.These levels are closely linked with the different problems agriculture and environmental are facing; so, in order to have aproper development/performance, a soundmanagement and suitable solutions, we need a national legislative framework that is harmonized with international rules; this condition must be regarded as the first/prerequisite step to be takenfor a sustainable development in the future