In this study we tested our previous hypothesis that ischemia is a multifactorial injurious event involving all components of the myocyte simultaneously. This hypothesis was based on ultrastructural ...findings and was now tested again by protein analysis of sarcolemmal structural proteins and of markers of transcriptional and translational activities. This knowledge may help to clarify the cellular mechanisms involved in progression of acute ischemic myocardial injury and reperfusion. Therefore, we investigated all three intracellular/extracellular linkage systems of the sarcolemma using antibodies against dystrophin, beta-dystroglycan, gamma-sarcoglycan, vinculin, beta1-integrin, laminin, and spectrin. In addition, antibodies were used to evaluate membrane permeability (albumin), transcriptional efficacy (non-snRNP splicing factor SC-35), and translational capacity (phosphorylated p70 ribosomal protein S6 kinase). Tissue samples were obtained from a canine model of regional myocardial ischemia (90 min or 4.5 h) with or without reperfusion. Immunoconfocal microscopy and Western blotting revealed that the rank order of sensitivity was the following: dystrophin, beta-dystroglycan, gamma-sarcoglycan, vinculin, spectrin, integrin and laminin. Different levels of dystrophin loss indicate reversible/irreversible injury as established by albumin uptake and electron microscopy. Dystrophin depletion closely coincided with generally depressed transcription and translation. These changes occurred simultaneously in a time-dependent manner and persisted during reperfusion. In conclusion, damage of the different structural proteins results in membrane destabilization and disruption of the contractile apparatus from the sarcolemma. These changes, concomitantly associated with disturbances in transcription and translation, are major mechanisms determining the transition to irreversibility of myocardial ischemic injury and confirm our hypothesis that ischemia is a multifactorial injurious event involving all components of the cardiac myocyte.
Objective
This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sjögren ...Syndrome (cCRESS) and candidate Sjögren Tool for Assessing Response (STAR) composite endpoints.
Methods
Longitudinal analysis of peripheral blood and SG biopsies was performed pre‐ and post‐treatment from the Trial of Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing.
Results
Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class‐switched memory B cells within the SG. Furthermore, rituximab significantly down‐regulated genes involved in immune‐cell recruitment, lymphoid organization alongside antigen presentation, and T cell co‐stimulatory pathways. In the peripheral compartment, rituximab down‐regulated immunoglobulins and auto‐antibodies together with pro‐inflammatory cytokines and chemokines. Interestingly, patients classified as responders according to STAR displayed significantly higher baseline levels of C‐X‐C motif chemokine ligand‐13 (CXCL13), interleukin (IL)‐22, IL‐17A, IL‐17F, and tumor necrosis factor‐α (TNF‐α), whereas a longitudinal analysis of serum T cell–related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS‐responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ‐receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration.
Conclusion
Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification.
The investigation of the energy frontier in physics requires novel concepts for future colliders. The idea of a muon collider is very appealing since it would allow to study particle collisions at up ...to tens of TeV energy, while offering a cleaner experimental environment with respect to hadronic colliders. One key element in the muon collider design is the low-emittance muon production. Recently, the Low EMittance Muon Accelerator (LEMMA) collaboration has explored the muon pair production close to its kinematic threshold by annihilating 45 GeV positrons with electrons in a low Z material target. In this configuration, muons are emerging from the target with a naturally low-emittance. In this paper we describe the performance of a system, to study this production mechanism, that consists in several segmented absorbers with alternating active layers composed of fast Cherenkov detectors together with a muon identification technique based on this detector. Passive layers were made of tungsten. We collected data corresponding to muon and electron beams produced at the H2 line in the North Area of the European Organization for Nuclear Research (CERN) in September 2018.
The introduction of flathead catfish (Pylodictis olivaris) into Lake Mitchell presented a unique opportunity to study the population dynamics of this species in a South Dakota impoundment. We ...collected flathead catfish using daytime, low-frequency electrofishing during June 2013, 2014, and 2015 and July, August and October of 2014 to examine population characteristics including abundance, recruitment, mortality, growth, condition, and diet. The flathead catfish population in Lake Mitchell was estimated at 1348 individuals (95% CI = 459-1455; density = 4.97/ha) in 2014 and 1197 individuals (95% CI = 931-1461; density = 4.42/ha) in 2015. Individuals from 11 year classes ranging from 1 to 13 years old were present. The population exhibited consistent recruitment, and annual mortality was estimated at 39%. Flathead catfish grew quickly exceeding stock length at age 3 and quality length at age 5; however, growth slowed in 2015. Similarly, condition of substock and stock-quality length fish declined in 2014 and 2015, respectively. The decline in growth and condition coincided with the recruitment of a large 2012 year class and may be an early indicator of intraspecific competition. Diets of Lake Mitchell flathead catfish primarily consisted of crayfish (Orconectes spp.) and fish with flathead catfish shifting to piscivory at approximately 400 mm. The high percentage of centrarchids in flathead catfish diets along with an increase in flathead catfish abundance coinciding with a decrease in bluegill abundance may indicate that flathead catfish are negatively impacting the bluegill population in Lake Mitchell.
On the dynamics of viscous masonry beams Lucchesi, M.; Pintucchi, B.; Šilhavý, M. ...
Continuum mechanics and thermodynamics,
05/2015, Letnik:
27, Številka:
3
Journal Article
Recenzirano
In this paper, we consider the longitudinal and transversal vibrations of the masonry beams and arches. The basic motivation is the seismic vulnerability analysis of masonry structures that can be ...modeled as monodimensional elements. The Euler–Bernoulli hypothesis is employed for the system of forces in the beam. The axial force and the bending moment are assumed to consist of the elastic and viscous parts. The elastic part is described by the no-tension material, i.e., the material with no resistance to tension and which accounts for the cases of limitless, as well as bounded compressive strength. The adaptation of this material to beams has been developed in Orlandi (Analisi non lineare di strutture ad arco in muratura. Thesis,
1999
) and Zani (Eur J Mech A/Solids 23:467–484,
2004
). The viscous part amounts to the Kelvin–Voigt damping depending linearly on the time derivatives of the linearized strain and curvature. The dynamical equations are formulated, and a mathematical analysis of them is presented. Specifically, following Gajewski et al. (Nichtlineare Operatorgleichungen und Operatordifferentialgleichungen. Akademie-Verlag, Berlin,
1974
), the theorems of existence, uniqueness and regularity of the solution of the dynamical equations are recapitulated and specialized for our purposes, to support the numerical analysis applied previously in Lucchesi and Pintucchi (Eur J Mech A/Solids 26:88–105,
2007
). As usual, for that the Galerkin method has been used. As an illustration, two numerical examples (slender masonry tower and masonry arch) are presented in this paper with the applied forces corresponding to the acceleration in the earthquake in Emilia Romagna in May 29, 2012.
Giant planets helped to shape the conditions we see in the Solar System today and they account for more than 99% of the mass of the Sun’s planetary system. They can be subdivided into the Ice Giants ...(Uranus and Neptune) and the Gas Giants (Jupiter and Saturn), which differ from each other in a number of fundamental ways. Uranus, in particular is the most challenging to our understanding of planetary formation and evolution, with its large obliquity, low self-luminosity, highly asymmetrical internal field, and puzzling internal structure. Uranus also has a rich planetary system consisting of a system of inner natural satellites and complex ring system, five major natural icy satellites, a system of irregular moons with varied dynamical histories, and a highly asymmetrical magnetosphere. Voyager 2 is the only spacecraft to have explored Uranus, with a flyby in 1986, and no mission is currently planned to this enigmatic system. However, a mission to the uranian system would open a new window on the origin and evolution of the Solar System and would provide crucial information on a wide variety of physicochemical processes in our Solar System. These have clear implications for understanding exoplanetary systems. In this paper we describe the science case for an orbital mission to Uranus with an atmospheric entry probe to sample the composition and atmospheric physics in Uranus’ atmosphere. The characteristics of such an orbiter and a strawman scientific payload are described and we discuss the technical challenges for such a mission. This paper is based on a white paper submitted to the European Space Agency’s call for science themes for its large-class mission programme in 2013.
•Describe the science case for an orbital mission to Uranus, its planetary system and magnetosphere.•Present an outline configuration for a Uranus orbiter and atmospheric entry probe.•Present a strawman scientific payload.
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