Subsidence related to multiple natural and human-induced processes affects an increasing number of areas worldwide. Although this phenomenon may involve surface deformation with 3D displacement ...components, negative vertical movement, either progressive or episodic, tends to dominate. Over the last decades, differential SAR interferometry (DInSAR) has become a very useful remote sensing tool for accurately measuring the spatial and temporal evolution of surface displacements over broad areas. This work discusses the main advantages and limitations of addressing active subsidence phenomena by means of DInSAR techniques from an end-user point of view. Special attention is paid to the spatial and temporal resolution, the precision of the measurements, and the usefulness of the data. The presented analysis is focused on DInSAR results exploitation of various ground subsidence phenomena (groundwater withdrawal, soil compaction, mining subsidence, evaporite dissolution subsidence, and volcanic deformation) with different displacement patterns in a selection of subsidence areas in Spain. Finally, a cost comparative study is performed for the different techniques applied.
In the past few years, 3D electron microscopy (3DEM) has undergone a revolution in instrumentation and methodology. One of the central players in this wide-reaching change is the continuous ...development of image processing software. Here we present Scipion, a software framework for integrating several 3DEM software packages through a workflow-based approach. Scipion allows the execution of reusable, standardized, traceable and reproducible image-processing protocols. These protocols incorporate tools from different programs while providing full interoperability among them. Scipion is an open-source project that can be downloaded from http://scipion.cnb.csic.es.
Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known ...about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients.
Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied.
After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3.
In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone.
This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.
Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell ...neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.
Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO2) and decreased O2 intracellular perfusion. ...Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine-threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3'-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR's regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.
Aims.
This paper describes the Polarimetric and Helioseismic Imager on the Solar Orbiter mission (SO/PHI), the first magnetograph and helioseismology instrument to observe the Sun from outside the ...Sun-Earth line. It is the key instrument meant to address the top-level science question: How does the solar dynamo work and drive connections between the Sun and the heliosphere? SO/PHI will also play an important role in answering the other top-level science questions of Solar Orbiter, while hosting the potential of a rich return in further science.
Methods.
SO/PHI measures the Zeeman effect and the Doppler shift in the Fe
I
617.3 nm spectral line. To this end, the instrument carries out narrow-band imaging spectro-polarimetry using a tunable LiNbO
3
Fabry-Perot etalon, while the polarisation modulation is done with liquid crystal variable retarders. The line and the nearby continuum are sampled at six wavelength points and the data are recorded by a 2k × 2k CMOS detector. To save valuable telemetry, the raw data are reduced on board, including being inverted under the assumption of a Milne-Eddington atmosphere, although simpler reduction methods are also available on board. SO/PHI is composed of two telescopes; one, the Full Disc Telescope, covers the full solar disc at all phases of the orbit, while the other, the High Resolution Telescope, can resolve structures as small as 200 km on the Sun at closest perihelion. The high heat load generated through proximity to the Sun is greatly reduced by the multilayer-coated entrance windows to the two telescopes that allow less than 4% of the total sunlight to enter the instrument, most of it in a narrow wavelength band around the chosen spectral line.
Results.
SO/PHI was designed and built by a consortium having partners in Germany, Spain, and France. The flight model was delivered to Airbus Defence and Space, Stevenage, and successfully integrated into the Solar Orbiter spacecraft. A number of innovations were introduced compared with earlier space-based spectropolarimeters, thus allowing SO/PHI to fit into the tight mass, volume, power and telemetry budgets provided by the Solar Orbiter spacecraft and to meet the (e.g. thermal) challenges posed by the mission’s highly elliptical orbit.
We compared the effects of two resistance training (RT) programs only differing in the repetition velocity loss allowed in each set: 20% (VL20) vs 40% (VL40) on muscle structural and functional ...adaptations. Twenty‐two young males were randomly assigned to a VL20 (n = 12) or VL40 (n = 10) group. Subjects followed an 8‐week velocity‐based RT program using the squat exercise while monitoring repetition velocity. Pre‐ and post‐training assessments included: magnetic resonance imaging, vastus lateralis biopsies for muscle cross‐sectional area (CSA) and fiber type analyses, one‐repetition maximum strength and full load‐velocity squat profile, countermovement jump (CMJ), and 20‐m sprint running. VL20 resulted in similar squat strength gains than VL40 and greater improvements in CMJ (9.5% vs 3.5%, P < 0.05), despite VL20 performing 40% fewer repetitions. Although both groups increased mean fiber CSA and whole quadriceps muscle volume, VL40 training elicited a greater hypertrophy of vastus lateralis and intermedius than VL20. Training resulted in a reduction of myosin heavy chain IIX percentage in VL40, whereas it was preserved in VL20. In conclusion, the progressive accumulation of muscle fatigue as indicated by a more pronounced repetition velocity loss appears as an important variable in the configuration of the resistance exercise stimulus as it influences functional and structural neuromuscular adaptations.
Bax and Bak are members of the Bcl‐2 family and core regulators of the intrinsic pathway of apoptosis. Upon apoptotic stimuli, they are activated and oligomerize at the mitochondrial outer membrane ...(MOM) to mediate its permeabilization, which is considered a key step in apoptosis. However, the molecular mechanism underlying Bax and Bak function has remained a key question in the field. Here, we review recent structural and biophysical evidence that has changed our understanding of how Bax and Bak promote MOM permeabilization. We also discuss how the spatial regulation of Bcl‐2 family preference for binding partners contributes to regulate Bax and Bak activation. Finally, we consider the contribution of mitochondrial composition, dynamics and interaction with other organelles to apoptosis commitment. A new perspective is emerging, in which the control of apoptosis by Bax and Bak goes beyond them and is highly influenced by additional mitochondrial components.
Bax and Bak are members of the Bcl‐2 family and core regulators of the intrinsic pathway of apoptosis. Here, we review recent structural and biophysical evidence on how Bax and Bak mediate mitochondrial outer membrane permeabilization. We also discuss the regulation of Bax and Bak by the Bcl‐2 family and the contribution of mitochondrial composition and dynamics to apoptosis commitment.
Ion stopping in warm dense matter is a process of fundamental importance for the understanding of the properties of dense plasmas, the realization and the interpretation of experiments involving ...ion-beam-heated warm dense matter samples, and for inertial confinement fusion research. The theoretical description of the ion stopping power in warm dense matter is difficult notably due to electron coupling and degeneracy, and measurements are still largely missing. In particular, the low-velocity stopping range, that features the largest modelling uncertainties, remains virtually unexplored. Here, we report proton energy-loss measurements in warm dense plasma at unprecedented low projectile velocities. Our energy-loss data, combined with a precise target characterization based on plasma-emission measurements using two independent spectroscopy diagnostics, demonstrate a significant deviation of the stopping power from classical models in this regime. In particular, we show that our results are in closest agreement with recent first-principles simulations based on time-dependent density functional theory.