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The High Luminosity LHC (HL-LHC) Project is planning to install 16 cold-masses made with Nb3Sn quadrupole magnets in the LHC Interaction Regions to significantly increase its luminosity. Half of these cold masses are fabricated at BNL, FNAL, and LBNL under the US Accelerator Research Program (AUP). Each cold mass includes two identical Nb3Sn quadrupole magnets, called MQXFA with a magnetic length of 4.2 m. Currently, the AUP project has completed the fabrication and test of the first 5 pre-series magnets, and is working on the following 16 magnets for the series production. The brittleness and strain sensitivity of the Nb3Sn superconducting material requires a careful definition of the allowable maximum stress in the windings during magnet assembly and pre-load, and a tight control of their variation within the whole coil length. Therefore, a series of assembly and pre-load specifications have been defined with the goals of minimizing the risk of conductor degradation and providing the mechanical support required to reach the nominal current during powering. In this paper we present the specifications defined for the MQXFA magnets and applied during the different assembly phases and during the pre-load process of the first 5 pre-series magnets.

The U.S. High-Luminosity LHC Accelerator Upgrade Project (HL-LHC AUP) is developing MQXFA magnets, a series of 4.5 m long 150 mm aperture high-field Nb$_{3}$Sn quadrupole magnets for the HL-LHC upgrade at CERN. Five pre-series magnets, MQXFA03 through MQXFA07, have been developed. During the magnet assembly stage, we perform magnetic measurements on the coil-pack sub-assembly and magnets after loading to track the field quality for two purposes. First, it serves as a quality assurance tool to check if the magnet field quality is on track to meet the acceptance criteria. Magnetic measurements are used to understand if magnetic shims are needed to compensate low-order field errors and to meet the field quality targets. Second, the measurements during the assembly stage can also help understand the field quality, especially the geometric field errors, for Nb$_{3}$Sn accelerator magnets. Here we summarize the measurement results of the pre-series MQXFA magnets, including the magnetic axis and twist angle. The results will provide useful feedback for the series production of Nb$_{3}$Sn magnets and on the optimization of field quality of accelerator magnets based on the wind-and-react Nb$_{3}$Sn technology.

The Nb3Sn quadrupole MQXF is being developed as a part of the large hadron collide (LHC) High Luminosity upgrade. The magnet design was tested on 1.5-m-long short models, sharing the same cross section with the full-length magnets. Various azimuthal and longitudinal preloads were applied, studying the impact on the magnet training and on its mechanical performances. The experiments demonstrated the possibility to control the magnet prestress. However, various factors, coil size among the others, may affect the stress variation between and within each winding. This variation could prevent the magnets from reaching the magnet performances, as for example as a result of the critical current reduction of the Nb3Sn strands. This paper analyzes the mechanical performances of the short models, studying in particular the stress variation on different coils. The measured coil size was used as input in the numerical simulations, and the results were then compared with the strain gauge measurements. Finally, the short model experience was used to evaluate the feasibility of a loading operation that does not rely on the strain measurements.

HD3 is the latest magnet of a series of block-type Nb3Sn dipole model magnets developed by the Superconducting Magnet Program at Lawrence Berkeley National Laboratory. The magnet is 1 m long with a clear aperture of 43 mm. As a model magnet designed with accelerator-quality features, each coil has flared ends to provide a clear bore for a beam tube. The magnet design was also optimized to minimize the geometric and saturation field errors. In 2013, HD3b reached a peak dipole field of 13.4 T at 4.4 K. As part of the magnet test, we measured field quality using rotating coils with lengths of 26 and 130 mm developed by Fermi National Accelerator Laboratory. Here, we report and analyze the measured static and dynamic field errors. We discuss the insight provided by the field quality study of HD3, which can be useful for the development of high-field block-type dipole magnets for next-generation circular colliders.

The high luminosity large hadron collider (LHC) upgrade requires new quadrupoles, MQXF, to replace the present LHC inner triplet magnets. The MQXFA magnet is the first prototype that has a 150-mm aperture and uses Nb3Sn superconducting technology in a 4.2-m magnetic length structure. The support structure design of the MQXFA magnet is based on the bladder-and-key technology, where a relatively low pre-stress at room temperature is increased to the final preload targets during the cool-down by the differential thermal contraction of the various components. The magnet support structure components experience different load levels from pre-load to cool-down and excitation. Consequently, a few parts experience high stresses that may cause localized plastic deformations or internal fracture development. The concept presented in this paper for the failure assessment of support structures integrates nonlinear finite-element (FE) analysis with detailed sub-models and fracture mechanics into an advanced engineering tool. The nonlinear FE solutions enable estimations of the structural response to the given loads, and the advanced fracture analysis with failure assessment diagram assesses the structure safety index of results obtained from the FE model. The paper describes how the MQXFA end-shell segments are being optimized based on the failure analyses.

Among the components to be upgraded in LHC interaction regions for the HiLumi-LHC projects are the inner triplet (or low-β) quadrupole magnets, denoted as Q1, Q2a, Q2b, and Q3. The new quadrupole magnets, called MQXF, are based on Nb3Sn superconducting magnet technology and operate at a gradient of 132.6 T/m, with a conductor peak field of 11.4 T. Q1 and Q3 are composed of magnets (called MQXFA) fabricated by the U.S. Accelerator Upgrade Project (AUP), with a magnetic length of 4.2 m. Q2a and Q2b consist of magnets (called MQXFB) fabricated by CERN, with a magnetic length of 7.15 m. After a series of short models, constructed in close collaboration by the US and CERN, the development program is now entering in the prototyping phase, with CERN on one side and BNL, FNAL, and LBNL on the other side assembling and testing their first long magnets We provide in this paper a description of the status of the MQXF program, with a summary of the short model test results, including quench performance, and mechanics, and an update on the fabrication, assembly, and test of the long prototypes.

The U.S. High-Luminosity LHC Accelerator Upgrade Project, in collaboration with CERN, is developing Nb 3 Sn quadrupole magnets (MQXFA) to be installed at the interaction region of the LHC. The project will deliver 20 MQXFA magnets in 10 cold masses. These magnets need to meet the stringent requirements on field quality at the nominal operating current. Compared to the mature NbTi accelerator magnet technology, achieving excellent field quality can be challenging for Nb 3 Sn magnets. To help track, understand, and allow effective correction of geometric field errors, field quality measurements at room temperature during the MQXFA assembly stage was planned for the project. The measurements also intend to evaluate the magnetic axis and twist angle along the magnet aperture. We report the first measurement on a prototype MQXFA magnet using a recently developed measurement system. The magnetic axis and twist angle met the acceptance criteria. Further development needs for the room-temperature measurements were discussed. We expect that statistics obtained from such measurements throughout the project will provide insight into future applications of high-performance Nb 3 Sn accelerator magnets.

The Nb 3 Sn low-β quadrupole MQXF is being developed as a part of the High-Luminosity large hadron collider (LHC) upgrade project. The magnet will be produced in two different configurations, sharing the same cross section but with different lengths. A 7.2-m mechanical model of MQXFB was recently assembled at european organization for nuclear research (CERN) with one copper coil, two low-grade coils, and one rejected coil. Coil dimensions were measured with a portable coordinate measurement machine. The coil pack shimming was designed in order to optimize the field quality and the contacts between the coils and the collars. The azimuthal preload target was defined using the short models experience. The mechanical behavior during loading was monitored by means of strain gauges. The results demonstrated that the structure can provide the required prestress to the coils.

As part of the High-Luminosity Large Hadron Collider (LHC) Project, a set of Nb3Snquadrupoles are being developed, aiming to enhance the performance of the inner triplets. The new magnets, identified as MQXFA and MQXFB, will share the same cross section with two different lengths, 4.2 and 7.2 m, respectively. During the magnet development, three short models were tested, along with a number of mechanical models, demonstrating the capability of the magnet cross section to achieve the specified performances. The same performances are now required for the full-length magnets. To ensure this, the authors studied the impact of the magnet length on the capability of the structure to provide an adequate support to the coils. Finite element and simplified analytical models were used to evaluate the impact of the magnet length on the stresses in the magnet ends and coil elongation during powering. The models were calibrated using the results from the short model tests, and used to provide an indication on the required prestress and its foreseen impact on the magnet performance.

During the development of MQXF, the new Nb3Sn quadrupole to be used in the large hadron collider (LHC) inner triplets for the High Luminosity upgrade, three short models were tested: MQXFS1, MQXFS3, and MQXFS5. These models differ in the use of thin or thick laminations for the iron components, in the coil design, and in the superconductive strands, rod restack process (RRP) or powder in tube (PIT). In the MQXF design, the azimuthal prestress is provided at room temperature by means of the bladder-key technology, and it is further increased during the cooldown by the differential thermal contraction of the various components. Four aluminum rods provide the longitudinal prestress. Both systems allow for a flexible control of the amount of prestress applied. As a consequence, it was possible to test the models exploring different azimuthal and longitudinal prestress conditions, in an attempt to understand their impact on the magnet performances. This paper studies the mechanical behavior of these short models, also providing the strain and stresses measured by means of strain gauges installed on the aluminum shell, on the winding poles and on the rods. Finally, the paper compares the measures with the results from finite element (FE) models.

The LHC accelerator research program (LARP), in collaboration with CERN and under the scope of the high luminosity upgrade of the Large Hadron Collider, is in the prototyping stage in the development of a 150 mm aperture high-field Nb3Sn quadrupole magnet called MQXF. This magnet is mechanically supported using a shell-based support structure, which has been extensively demonstrated on several R&D models within LARP, as well as in the more recent short (1.2 m magnetic length) MQXF model program. The MQXFA magnets are each 4.2 m magnetic length, and the first mechanical long model, MQXFA1M (using aluminum surrogate coils), and MQXFAP1 prototype magnet (the first prototype with Nb3Sn coils) have been assembled at the LBNL. In this paper, we summarize the tooling and the assembly processes, and discuss the mechanical performance of these first two assemblies, comparing strain gauge data with finite element model analysis, as well as the near-term plans for the long MQXF magnet program.

In the framework of the High-Luminosity Large Hadron Collider, the installation of a new generation of quadrupole magnets is foreseen on each side of ATLAS and CMS experiments. The new magnets are based on Nb3Sn technology and shall be able to reach an ultimate current of 17.9 kA with a peak field of 12.3 T in the coil. In 2016 and 2017, the first two short models, called MQXFS3 and MQXFS5, have been tested at 4.2 and 1.9 K in the two new test benches at the European Organization for Nuclear Research. This paper presents the result of the quench performance of the two models; the first magnet reached nominal but failed to reach ultimate, showing detraining in one coil. MQXFS5 reached ultimate performance without any detraining phenomena, validating the PIT conductor used for the first time in this magnet program.

During the development of MQXF, the new Nb3Sn quadrupole to be used in the large hadron collider (LHC) inner triplets for the High Luminosity upgrade, three short models were tested: MQXFS1, MQXFS3, and MQXFS5. These models differ in the use of thin or thick laminations for the iron components, in the coil design, and in the superconductive strands, rod restack process (RRP) or powder in tube (PIT). In the MQXF design, the azimuthal prestress is provided at room temperature by means of the bladder-key technology, and it is further increased during the cooldown by the differential thermal contraction of the various components. Four aluminum rods provide the longitudinal prestress. Both systems allow for a flexible control of the amount of prestress applied. As a consequence, it was possible to test the models exploring different azimuthal and longitudinal prestress conditions, in an attempt to understand their impact on the magnet performances. This paper studies the mechanical behavior of these short models, also providing the strain and stresses measured by means of strain gauges installed on the aluminum shell, on the winding poles and on the rods. Finally, the paper compares the measures with the results from finite element (FE) models.

The U.S. LHC Accelerator Research Program (LARP) and CERN combined their efforts in developing Nb3Sn magnets for the high-luminosity LHC upgrade. The ultimate goal of this collaboration is to fabricate large aperture Nb 3Sn quadrupoles for the LHC interaction regions. These magnets will replace the present 70-mm-Aperture NbTi quadrupole triplets for expected increase of the LHC peak luminosity up to 5 × 1034 cm-2s-1 or more. Over the past decade, LARP successfully fabricated and tested short and long models of 90 and 120-mm-Aperture Nb3Sn quadrupoles. Recently, the first short model of 150-mm-diameter quadrupole MQXFS was built with coils fabricated both by LARP and CERN. The magnet performance was tested at Fermilab's vertical magnet test facility. This paper reports the test results, including the quench training at 1.9 K, ramp rate and temperature dependence, as well as protection heater studies.

In the framework of the Hi-Lumi LHC Project, CERN and U.S. LARP are jointly developing MQXF, a 150-mm aperture high-field Nb3Sn quadrupole for the upgrade of the inner triplet of the low-beta interaction regions. The magnet is supported by a shell-based structure, providing the preload by means of bladder-key technology and differential thermal contraction of the various components. Two short models have been produced using the same cross section currently considered for the final magnet. The structures were preliminarily tested replacing the superconducting coils with blocks of aluminum. This procedure allows for model validation and calibration, and also to set performance goals for the real magnet. Strain gauges were used to monitor the behavior of the structure during assembly, cool down and also excitation in the case of the magnets. The various structures differ for the shell partitioning strategies adopted and for the presence of thick or thin laminations. This paper presents the results obtained and discusses the mechanical performance of all the short models produced up to now.

The Large Hadron Collider Luminosity upgrade (HiLumi) program requires new low-β triplet quadrupole magnets, called MQXF, in the interaction region to increase the LHC peak and integrated luminosity. The MQXF magnets, designed and fabricated in collaboration between CERN and the U.S. LARP, will all have the same cross section. The MQXF long model, referred as MQXFA, is a quadrupole using the Nb3Sn superconducting technology with 150 mm aperture and a 4.2 m magnetic length and is the first long prototype of the final MQXF design. The MQXFA magnet is based on the previous LARP HQ and MQXFS designs. In this paper, we present the baseline design of the MQXFA structure with detailed three-dimensional (3-D) numerical analysis. A detailed tolerance analysis of the baseline case has been performed by using a 3-D finite element model, which allows fast computation of structures modeled with actual tolerances. Tolerance sensitivity of each component is discussed to verify the actual tolerances to be achieved by vendors. Tolerance stack-up analysis is presented in the end of this paper.

Within the scope of the High-Luminosity LHC project, the collaboration between CERN and U.S. LARP is developing new low-$\beta$ quadrupoles using the Nb3Sn superconducting technology for the upgrade of the LHC interaction regions. The magnet support structure of the first short model was designed, and two units were fabricated and tested at CERN and at LBNL. The structure provides the preload to the collar-coil subassembly by an arrangement of outer aluminum shells pretensioned with water-pressurized bladders. For the mechanical qualification of the structure and the assembly procedure, superconducting coils were replaced with solid aluminum 'dummy coils,' and the structure was preloaded at room temperature and then cooled-down to 77 K. The mechanical behavior of the magnet structure was monitored with the use of strain gauges installed on the aluminum shells, the dummy coils, and the axial preload system. This paper reports on the outcome of the assembly and the cooldown tests with dummy coils, which were performed at CERN and at LBNL, and presents the strain gauge measurements compared with the 3-D finite-element model predictions.

Protection heaters are essential elements of a quench protection scheme for high-field accelerator magnets. Various heater designs fabricated by LARP and CERN have been already tested in the LARP high-field quadrupole HQ and presently being built into the coils of the high-field quadrupole MQXF. In order to compare the heat flow characteristics and thermal diffusion timescales of different heater designs, we powered heaters of two different geometries in ambient conditions and imaged the resulting thermal distributions using a high-sensitivity thermal video camera. We observed a peculiar spatial periodicity in the temperature distribution maps potentially linked to the structure of the underlying cable. Two-dimensional numerical simulation of heat diffusion and spatial heat distribution have been conducted, and the results of simulation and experiment have been compared. Imaging revealed hot spots due to a current concentration around high curvature points of heater strip of varying cross sections and visualized thermal effects of various interlayer structural defects. Thermal imaging can become a future quality control tool for the MQXF coil heaters.

The High Luminosity (HiLumi) Large Hadron Collider (LHC) project has, as the main objective, to increase the LHC peak luminosity by a factor five and the integrated luminosity by a factor ten. This goal will be achieved mainly with a new interaction region layout, which will allow a stronger focusing of the colliding beams. The target will be to reduce the beam size in the interaction points by a factor of two, which requires doubling the aperture of the low-β (or inner triplet) quadrupole magnets. The use of Nb3Sn superconducting material and, as a result, the possibility of operating at magnetic field levels in the windings higher than 11 T will limit the increase in length of these quadrupoles, called MQXF, to acceptable levels. After the initial design phase, where the key parameters were chosen and the magnet's conceptual design finalized, the MQXF project, a joint effort between the U.S. LHC Accelerator Research Program and the Conseil Europeén pour la Recherche Nucleaíre (CERN), has now entered the construction and test phase of the short models. Concurrently, the preparation for the development of the full-length prototypes has been initiated. This paper will provide an overview of the project status, describing and reporting on the performance of the superconducting material, the lessons learnt during the fabrication of superconducting coils and support structure, and the fine tuning of the magnet design in view of the start of the prototyping phase.

In preparation for the high-luminosity upgrade of the Large Hadron Collider (LHC), the LHC Accelerator Research Program (LARP) in collaboration with CERN is pursuing the development of MQXF: a 150-mm-aperture high-field Nb3Sn quadrupole magnet. The development phase starts with the fabrication and test of several short models (1.2-m magnetic length) and will continue with the development of several long prototypes. All of them are mechanically supported using a shell-based support structure, which has been extensively demonstrated on several RD models within LARP. The first short model MQXFS-AT has been assembled at LBNL with coils fabricated by LARP and CERN. In this paper, we summarize the assembly process and show how it relies strongly on experience acquired during the LARP 120-mm-aperture HQ magnet series. We present comparison between strain gauges data and finite-element model analysis. Finally, we present the implication of the MQXFS-AT experience on the design of the long prototype support structure.

The High Luminosity (HiLumi) Large Hadron Collider (LHC) project has, as the main objective, to increase the LHC peak luminosity by a factor five and the integrated luminosity by a factor ten. This goal will be achieved mainly with a new interaction region layout, which will allow a stronger focusing of the colliding beams. The target will be to reduce the beam size in the interaction points by a factor of two, which requires doubling the aperture of the low-β (or inner triplet) quadrupole magnets. The use of Nb3Sn superconducting material and, as a result, the possibility of operating at magnetic field levels in the windings higher than 11 T will limit the increase in length of these quadrupoles, called MQXF, to acceptable levels. After the initial design phase, where the key parameters were chosen and the magnet's conceptual design finalized, the MQXF project, a joint effort between the U.S. LHC Accelerator Research Program and the Conseil Europeén pour la Recherche Nucleaíre (CERN), has now entered the construction and test phase of the short models. Concurrently, the preparation for the development of the full-length prototypes has been initiated. This paper will provide an overview of the project status, describing and reporting on the performance of the superconducting material, the lessons learnt during the fabrication of superconducting coils and support structure, and the fine tuning of the magnet design in view of the start of the prototyping phase.

Within the scope of the High-Luminosity LHC project, the collaboration between CERN and U.S. LARP is developing new low-$\beta$ quadrupoles using the Nb3Sn superconducting technology for the upgrade of the LHC interaction regions. The magnet support structure of the first short model was designed, and two units were fabricated and tested at CERN and at LBNL. The structure provides the preload to the collar-coil subassembly by an arrangement of outer aluminum shells pretensioned with water-pressurized bladders. For the mechanical qualification of the structure and the assembly procedure, superconducting coils were replaced with solid aluminum 'dummy coils,' and the structure was preloaded at room temperature and then cooled-down to 77 K. The mechanical behavior of the magnet structure was monitored with the use of strain gauges installed on the aluminum shells, the dummy coils, and the axial preload system. This paper reports on the outcome of the assembly and the cooldown tests with dummy coils, which were performed at CERN and at LBNL, and presents the strain gauge measurements compared with the 3-D finite-element model predictions.

Electrical insulation breakdown between conductor and coil parts and structures is a limiting factor in the performance of high-field magnets. We have evaluated various insulation coatings for possible application in both Nb3Sn and Bi-2212 coil fabrication. Such coatings must be robust to maintain structural integrity and provide adequate voltage standoff after the wind-and-react coil fabrication process. Such processes are characterized by reaction temperatures of 650°C in an inert atmosphere for Nb3Sn and 890°C in a pure oxygen atmosphere for Bi-2212, and down to cryogenic temperatures when coils are in service. We present a method of testing standardized samples and report the performance characteristics of oxide layers produced (or applied) by plasma-spray, surface conversion, and "paintable" coatings in common areas of voltage breakdown in coil parts. We also address material compatibility and durability during high-temperature heat treatment and cryogenic shock. Suitable coatings selected in the testing process will be instrumental in improving the performance of future wind-and-react coils. © 2014 AIP Publishing LLC.

We report test results for the one meter long dipol HD3b, a block-Type accelerator quality Nb3Sn magnet built a LBNL with operational bore fields in the range of 13-15 T. Th magnet is an upgrade of the previously reported HD2 and HD3 versions, with several modifications implemented to improve conducto positioning, reduce cable "hard-way" bending radius, an strengthen electrical insulation between cables and coil parts The magnet exhibited long training behavior, but showed a goo "memory" of the trained state upon thermal cycling. Ramp-rat dependence of the quench current, field quality performance characteristics and protection heater studies were conducted. Quenc propagation velocity and quench locations were determined base on the voltage signals; quench localization was further improve using inductive quench antenna and acoustic emission sensors Short-And long-Term acoustic precursors to quenching wer observed.

We report test results for the one meter long dipol HD3b, a block-Type accelerator quality Nb3Sn magnet built a LBNL with operational bore fields in the range of 13-15 T. Th magnet is an upgrade of the previously reported HD2 and HD3 versions, with several modifications implemented to improve conducto positioning, reduce cable "hard-way" bending radius, an strengthen electrical insulation between cables and coil parts The magnet exhibited long training behavior, but showed a goo "memory" of the trained state upon thermal cycling. Ramp-rat dependence of the quench current, field quality performance characteristics and protection heater studies were conducted. Quenc propagation velocity and quench locations were determined base on the voltage signals; quench localization was further improve using inductive quench antenna and acoustic emission sensors Short-And long-Term acoustic precursors to quenching wer observed.

As part of the development of very high field dipole magnets for particle accelerators, the Superconducting Magnet Program at Lawrence Berkeley National Laboratory is developing block-type dipole magnets. One of the main challenges of this geometry is to provide support to the coil in the aperture while maintaining an adequate clear bore. Through finite element method analysis, strain-gauge measurements, and test results, this paper reviews the design of HD3, a 1-m-long, 43-mm-bore Nb3Sn dipole magnet, presents the findings in terms of strain gauges monitoring, and summarizes their implications. © 2002-2011 IEEE.

As part of the development of very high field dipole magnets for particle accelerators, the Superconducting Magnet Program at Lawrence Berkeley National Laboratory is developing block-type dipole magnets. One of the main challenges of this geometry is to provide support to the coil in the aperture while maintaining an adequate clear bore. Through finite element method analysis, strain-gauge measurements, and test results, this paper reviews the design of HD3, a 1-m-long, 43-mm-bore Nb3Sn dipole magnet, presents the findings in terms of strain gauges monitoring, and summarizes their implications. © 2002-2011 IEEE.

For the last several years, the Lawrence Berkeley National Laboratory has been engaged in the development of Nb3Sn block-type accelerator quality dipoles with operational bore fields in the range of 13-15 T. The magnet design features two coil modules wound around a titanium-alloy pole with a clear aperture of 43 mm. The latest model, HD3, incorporates several new features to overcome the limitations observed in previous tests. Among the key objectives are improved conductor positioning at critical transitions between straight section and end regions, and a more robust fabrication process. To date, several coils have been fabricated and we describe their performance with respect to these design and process changes. Additionally, we present our experience in design and fabrication of a new generation of magnet coils that introduce a two-piece pole design that allows for cable growth during reaction. These experiences are intended to form the basis for scale-up to longer lengths and larger aperture magnets. © 2002-2011 IEEE.

For the last several years, the Lawrence Berkeley National Laboratory has been engaged in the development of Nb3Sn block-type accelerator quality dipoles with operational bore fields in the range of 13-15 T. The magnet design features two coil modules wound around a titanium-alloy pole with a clear aperture of 43 mm. The latest model, HD3, incorporates several new features to overcome the limitations observed in previous tests. Among the key objectives are improved conductor positioning at critical transitions between straight section and end regions, and a more robust fabrication process. To date, several coils have been fabricated and we describe their performance with respect to these design and process changes. Additionally, we present our experience in design and fabrication of a new generation of magnet coils that introduce a two-piece pole design that allows for cable growth during reaction. These experiences are intended to form the basis for scale-up to longer lengths and larger aperture magnets. © 2002-2011 IEEE.

Lawrence Berkeley National Laboratory (LBNL) is developing Wind-and-React (W&R) Bi2sr2cacu2o8+δ (Bi-2212) accelerator magnet technology for insert coils, to surpass the intrinsic limitations of Nb-based magnets, and eventually develop hybrid systems that can approach 20 T dipole fields. The Bi-2212 technology is being developed in close collaboration with industry, and has been partly supported by the US Very High Field Superconducting Magnet Collaboration (VHFSMC). Steady improvements were made over the last several years, with coil HTS-SC08 reaching 2636 A, or about 85% of its witness sample critical current (Ic). Though this is still a factor 3 to 4 too low to be competitive with Nb-based materials, it is expected that the required Ic can be achieved through further conductor optimizations. Recent developments include the commissioning of infrastructure for the reaction of coils at LBNL. Earlier coils were fabricated and tested at LBNL, but were reacted at the wire manufacturer. We describe in detail the furnace calibrations and heat treatment optimizations that enable coil reactions at temperatures approaching 890 °C with a homogeneity of ± 1 °C in a pure oxygen flow. We reacted two new coils at LBNL, and tested the performance of coil HTS-SC10 at 4.2 K in self-field using a superconducting transformer system. We find that its performance is consistent with witness samples, and comparable to coil HTS-SC08, which is an identical coil that was reacted at Oxford Instruments Superconductor Technology (OST), thereby validating the in-house reaction process.

BACKGROUND: Retrograde double-balloon enteroscopy (rDBE) is technically a different procedure from its antegrade counterpart. Its unique indications, success rate, and learning curve have not been specifically reported. OBJECTIVE: To examine technical issues specific to the rDBE approach. DESIGN: Retrospective review. SETTING: Single tertiary-care center. PATIENTS: All patients referred for rDBE. MAIN OUTCOME MEASUREMENTS: Procedure duration, technical success, learning curve, and complications related to rDBE. RESULTS: A total of 59 rDBEs were performed on 56 patients for obscure GI bleeding (46.4%), metastatic carcinoids (23.2%), Crohn's disease (14.3%), and other indications. rDBE enabled a diagnosis in 47.5% of procedures and had a 38% diagnostic rate in finding primary small-bowel lesions that were responsible for metastatic carcinoids. The mean (standard deviation) total procedure time was 111.3 +/- 39.9 minutes. Procedure failure occurred in 12 cases (21%), which is significantly more than reported with antegrade procedures (2%). Failure was more common among patients with a prior abdominal or pelvic surgery (P = .001), and the time to achieve a stable ileal intubation was prolonged in these patients (13.9 vs 38.1 minutes; P = .0006). A trend was noted toward successful small-bowel access and increased lengths of small bowel examined after 20 procedures were performed. LIMITATIONS: Small retrospective study. CONCLUSIONS: rDBE is effective for the evaluation and the treatment of lower small-intestinal lesions; however, maintaining access through the ileocecal valve may be difficult. Prior surgery may be an important factor associated with failure. A minimum of 20 rDBE procedures was needed to minimize procedure failure, examine a substantial segment of the small-bowel, and shorten procedure duration. [ABSTRACT FROM AUTHOR]

Single molecules bridging two metallic electrodes can emit light through electroluminescence when subjected to a bias voltage. Typically, light emission in such devices results from transitions between molecular states, although in the presence of light-matter coupling, the emission can result from a transition between hybrid light-matter states. Here, we create single metal-molecule-metal junctions and simultaneously collect conductance and electroluminescence data using a scanning tunneling microscope (STM) equipped with a custom spectrometer. Through experimental analysis and electronic structure calculations, we provide evidence for a molecule-electrode interfacial exciton coupled to a junction cavity plasmon. Importantly, we find that close to resonant transport conditions, the molecular junction functions as a single emitter that is strongly coupled to the junction cavity mode, leading to characteristic Rabi splitting of the emission spectrum and providing the first example of an electroluminescence-driven single-molecule system in the regime of strong light-matter coupling.

Objective To evaluate the effects of total intravenous anesthesia on the circadian rhythms in the patients undergoing cardiac transcatheter closure. Methods Thirty patients undergoing cardiac transcatheter closure under elective intravenous anesthesia were included in this study.Paired t -tests were performed to compare the mRNA levels of the genes encoding circadian locomotor output cycles kaput(CLOCK),brain and muscle ARNT-1 like protein-1(BMAL1),cryptochrome 1(CRY1),and period circadian clock 2(PER2),the Munich Chronotype Questionnaire(MCTQ)score,and the Pittsburgh Sleep Quality Index(PSQI)score before and after anesthesia.Multiple stepwise regression analysis was performed to screen the factors influencing sleep chronotype and PSQI total score one week after surgery. Results The postoperative mRNA level of CLOCK was higher [1.38±1.23 vs .1.90±1.47; MD (95% CI ):0.52(0.20-0.84), t =3.327, P =0.002] and the postoperative mRNA levels of CRY1 [1.56±1.50 vs .1.13±0.98; MD (95% CI ):-0.43(-0.81--0.05), t =-2.319, P =0.028] and PER2 [0.82±0.63 vs .0.50±0.31; MD (95% CI ):-0.33(-0.53--0.12), t =-3.202, P =0.003] were lower than the preoperative levels.One week after surgery,the patients presented advanced sleep chronotype [3:03±0:59 vs .2:42±0:37; MD (95% CI ):-21(-40--1), t =-2.172, P =0.038],shortened sleep latency [(67±64)min vs .(37±21)min; MD (95% CI ):-30.33(-55.28--5.39), t =-2.487, P =0.019],lengthened sleep duration [(436±83)min vs .(499±83)min; MD (95% CI ):62.80(26.93-98.67), t =3.581, P =0.001],increased sleep efficiency [(87.59±10.35)% vs .(92.98±4.27)%; MD (95% CI ):5.39(1.21-9.58), t =2.636, P =0.013],decreased sleep quality score [1.13±0.78 vs .0.80±0.71; MD (95% CI ):-0.33(-0.62--0.05), t =-2.408, P =0.023],and declined PSQI total score [6.60±3.17 vs .4.03±2.58; MD (95% CI ):-2.57(-3.87--1.27), t =-4.039, P <0.001].Body mass index(BMI)( B =-227.460, SE =95.475, t =-2.382, P =0.025),anesthesia duration( B =-47.079, SE =18.506, t =-2.544, P =0.017),and mRNA level of PER2( B =2815.804, SE =1080.183, t =2.607, P =0.015)collectively influenced the sleep chronotype,and the amount of anesthesia medicine( B =0.067, SE =0.028, t =2.385, P =0.024)independently influenced the PSQI one week after surgery. Conclusion Total intravenous anesthesia can improve sleep habits by advancing sleep chronotype.BMI,anesthesia duration,and mRNA level of PER2 collectively influence sleep chronotype one week after surgery.The amount of anesthesia medicine independently influences the PSQI total score one week after surgery.

Chronic pain reduces the quality of life and ability to function of individuals suffering from it, making it a common public health problem. Neuroinflammation which is mediated by the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in the spinal cord participates and modulates chronic pain. A chronic inflammatory pain mouse model was created in the current study by intraplantar injection of complete Freund's adjuvant (CFA) into C57BL/6J left foot of mice. Following CFA injection, the mice had enhanced pain sensitivities, decreased motor function, increased spinal inflammation and activated spinal astrocytes. Emodin (10 mg/kg) was administered intraperitoneally into the mice for 3 days. As a result, there were fewer spontaneous flinches, higher mechanical threshold values and greater latency to fall. Additionally, in the spinal cord, emodin administration reduced leukocyte infiltration level, downregulated protein level of IL-1β, lowered histone deacetylase (HDAC)6 and NLRP3 inflammasome activity and suppressed astrocytic activation. Emodin also binds to HDAC6 via four electrovalent bonds. In summary, emodin treatment blocked the HDAC6/NLRP3 inflammasome signaling, suppresses spinal inflammation and alleviates chronic inflammatory pain., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Cheng et al.)

The late embryonic mouse lens requires the transcription factor ATF4 for its survival although the underlying mechanisms were unknown. Here, RNAseq analysis revealed that E16.5 Atf4 null mouse lenses downregulate the mRNA levels of lens epithelial markers as well as known markers of late lens fiber cell differentiation. However, a comparison of this list of differentially expressed genes (DEGs) with other known transcriptional regulators of lens development indicated that ATF4 expression is not directly controlled by the previously described lens gene regulatory network. Pathway analysis revealed that the Atf4 DEG list was enriched in numerous genes involved in nutrient transport, amino acid biosynthesis, and tRNA charging. These changes in gene expression likely result in the observed reductions in lens free amino acid and glutathione levels, which would result in the observed low levels of extractable lens protein, finally leading to perinatal lens disintegration. These data demonstrate that ATF4, via its function in the integrated stress response, is likely to play a crucial role in mediating the adaption of the lens to the avascularity needed to maintain lens transparency.

Purpose: Increased inflammatory factor levels have been reported in the vitreous humor (VH) of diabetic retinopathy and neovascular age-related macular degeneration, ocular diseases generally associated with the formation of new retinal blood vessels and leakage. However, the levels of inflammatory mediators are less known in retinal degeneration without neovascularization. Human retinitis pigmentosa (RP) and animal models of light-induced retinal degeneration (LIRD) share several features, such as photoreceptor death and retinal inflammation. Here, we aimed to determine the levels of inflammatory factors in the VH of the LIRD mouse model., Methods: LIRD was induced by exposing BALB/c mice to white light (15,000 lx, 2 h), and the mice were recovered for 2 days before analysis (n = 50 mice). We assessed retinal morphology using optical coherence tomography and hematoxylin and eosin staining; retinal cell viability was determined using terminal deoxynucleotidyl transferase dUTP nick-end labeling, and retinal responses were measured based on electroretinogram signals. Total retinal RNAs were extracted and subjected to RNA sequencing analysis. VH samples from control (n = 4) and LIRD mice (n = 9) were assayed in triplicate for a panel of four inflammatory mediators using the Simple Plex Cartridge on an Ella System., Results: Retinal degeneration, photoreceptor death, infiltration of microglia/macrophages into the photoreceptor layer, and loss of a- and b-waves were obviously detected after LIRD. RNA sequencing revealed that light damage (LD) led to the significant upregulation of inflammatory factors in mouse retinas. In the VH, LD increased the total protein concentration. Dramatic induction of CCL2 (~3000 fold) and IL6 (~10 fold) was detected in VH in response to LD. Increased but not significant levels of TNFα and IL1β were also detected in light-exposed VH., Conclusions: Given that the LIRD model mimics RP pathogenesis in some aspects, these results suggest a causative link between retinal degeneration and VH inflammation in RP progression, and the increased CCL2 level in VH may reflect similar elevated CCL2 expression in the degenerative retina., (Copyright © 2023 Molecular Vision.)

Deleted in breast cancer 1 (DBC1) was initially identified from a homozygously deleted region in human chromosome 8p21. It has been well established that DBC1 plays a dual role during cancer development. Depending on the physiological context, it can promote or inhibit tumorigenesis. Whether it plays a role in lens pathogenesis remains elusive. In the present study, we demonstrated that DBC1 is highly expressed in lens epithelial cells from different vertebrates and in retina pigment epithelial cells as well. Moreover, DBC1 is SUMOylated through SUMO1 conjugation at K591 residue in human and mouse lens epithelial cells. The SUMOylated DBC1 is localized in the nucleus and plays an essential role in promoting stress-induced apoptosis. Silence of DBC1 attenuates oxidative stress-induced apoptosis. In contrast, overexpression of DBC1 enhances oxidative stress-induced apoptosis, and this process depends on p53. Mechanistically, DBC1 interacts with p53 to regulate its phosphorylation status at multiple sites and the SUMOylation of DBC1 enhances its interaction with p53. Together, our results identify that DBC1 is an important regulator mediating stress-induced apoptosis in lens, and thus participates in control of lens cataractogenesis.

Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90β (HSP90β) plays a fundamental role in suppressing cataractogenesis. HSP90β is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90β is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90β silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90β can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90β silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53/Bak-Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90β and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90β is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway.

Background: Chronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that act as key proinflammatory factors. We recently found the first-generation BET inhibitor JQ1 alleviated sodium iodate-induced retinal degeneration by suppressing cGAS-STING innate immunity. Here, we investigated the effects and mechanism of dBET6, a proteolysis‑targeting chimera (PROTAC) small molecule that selectively degrades BET by the ubiquitin‒proteasome system, in light-induced retinal degeneration., Methods: Mice were exposed to bright light to induce retinal degeneration, and the activation of cGAS-STING was determined by RNA-sequencing and molecular biology. Retinal function, morphology, photoreceptor viability and retinal inflammation were examined in the presence and absence of dBET6 treatment., Results: Intraperitoneal injection of dBET6 led to the rapid degradation of BET protein in the retina without detectable toxicity. dBET6 improved retinal responsiveness and visual acuity after light damage (LD). dBET6 also repressed LD-induced retinal macrophages/microglia activation, Müller cell gliosis, photoreceptor death and retinal degeneration. Analysis of single-cell RNA-sequencing results revealed cGAS-STING components were expressed in retinal microglia. LD led to dramatic activation of the cGAS-STING pathway, whereas dBET6 suppressed LD-induced STING expression in reactive macrophages/microglia and the related inflammatory response., Conclusions: This study indicates targeted degradation of BET by dBET6 exerts neuroprotective effects by inhibiting cGAS-STING in reactive retinal macrophages/microglia, and is expected to become a new strategy for treatment of retinal degeneration., (© 2023. The Author(s).)

The crystalline lens is a transparent and refractive biconvex structure formed by lens epithelial cells (LECs) and lens fibers. Lens opacity, also known as cataracts, is the leading cause of blindness in the world. LECs are the principal cells of lens throughout human life, exhibiting different physiological properties and functions. During the embryonic stage, LECs proliferate and differentiate into lens fibers, which form the crystalline lens. Genetics and environment are vital factors that influence normal lens development. During maturation, LECs help maintain lens homeostasis through material transport, synthesis and metabolism as well as mitosis and proliferation. If disturbed, this will result in loss of lens transparency. After cataract surgery, the repair potential of LECs is activated and the structure and transparency of the regenerative tissue depends on postoperative microenvironment. This review summarizes recent research advances on the role of LECs in lens development, homeostasis, and regeneration, with a particular focus on the role of cholesterol synthesis (eg., lanosterol synthase) in lens development and homeostasis maintenance, and how the regenerative potential of LECs can be harnessed to develop surgical strategies and improve the outcomes of cataract surgery (Fig. 1). These new insights suggest that LECs are a major determinant of the physiological and pathological state of the lens. Further studies on their molecular biology will offer possibility to explore new approaches for cataract prevention and treatment., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: To investigate the effect and comfort of using a distant-image screen for reading and learning. Methods: It was a prospective cross-over study. Thirty-nine volunteers, including 13 males and 26 females, aged (26.4±4.5) years (20 to 37 years), were recruited from Beijing Tongren Hospital Affiliated to Capital Medical University in July 2021. The volunteers read the digital correction table printed on paper and displayed on a distant-image screen in a random order and rest in an interval of 2 hours. Reading speed, efficiency and accuracy of using the two devices were recorded, and the changes of logMAR vision, diopter, flicker fusion frequency and visual fatigue score after reading were calculated. Comparison of the quantitative data was performed using the paired t -test. Results: The speed, accuracy and efficiency were (41.2±11.6) digit groups/min, 80.7%±13.3% and (32.4±7.4) digit groups/min in reading on paper, (41.7±11.1) digit groups/min, 76.4%±12.6% and (31.1±6.4) digit groups/min in reading from screen, respectively. There was no significant difference in reading speed ( t =-0.462, P =0.648) and reading efficiency ( t =1.954, P =0.058), but there was significant difference in reading accuracy ( t = 2.226, P =0.032). The logMAR visual acuity of right eye and left eye decreased by 0.014±0.032 and 0.013±0.050 after reading on paper, but increased by 0.007±0.033 and 0.007±0.036 after reading from screen, respectively. The difference was significant (right eye, t =2.592, P =0.013; left eye, t =2.154, P =0.038). The myopia degree of right eye and left eye increased by (0.07±0.29) D and (0.06±0.24) D after reading on paper, and increased by (0.01±0.29) D and (0.02±0.28) D after reading from screen, respectively. The flicker fusion frequency decreased by (0.1±1.0) Hz after reading on paper, but increased by (0.3±1.2) Hz after reading from screen. There was no significant difference ( P >0.05). The subjective scale score of visual fatigue increased in both groups, with no statistically significant difference ( t =1.165, P =0.251). Conclusion: The use of a distant-image screen for reading and learning does not affect the reading efficiency or increase the visual fatigue, and can avoid the decline of visual acuity caused by near viewing compared with using the printed matter.

Gilvimarinus sp. DA14, a putative new species isolated from mangrove sediment in the South China Sea (Beihai, Guangxi province), is an aerobic and heterotrophic agar degrading bacterium. Here, we present the complete genome sequence of strain DA14, which comprises 3.96 Mb sequences with 53.39% GC content. In total, 3391 CDSs, 6 rRNA genes and 44 tRNA genes were obtained. Genomic analysis of strain DA14 revealed that 218 CAZymes classes were identified and they were organized in 371 CAZymes in PULs involved in polysaccharides degradation, transport and regulation. Further, we performed the genome comparison among Gilvimarinus strains and analysis the diversity of CAZymes and PULs. Meanwhile, ability of agar and alginate degradation in strain DA14 were analyzed. This study represents a thorough genomic characterization of CAZymes repertoire of Gilvimarinus, provides insight into diversity of polysaccharide degrading enzymes existing in Gilvimarinus sp. DA14 and their biotechnological applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that can have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Atrophic ("dry") form of age-related macular degeneration (AMD) is a leading cause of vision loss characterized by macular retinal pigment epithelium (RPE) and the ensuing photoreceptor degeneration. cGAS-STING signaling is a key cytosolic DNA sensor system in innate immunity and have recently been shown promotes RPE degeneration. However, expression regulation and therapeutic potential of cGAS and STING are not explored in retina under dry AMD pathogenic conditions. Our analysis shows upregulated STING RNA and increased chromatin accessibility around cGAS and STING promoters in macular retinas from dry AMD patients. cGAS-STING activation was detected in oxidative stress-induced mouse retina degeneration, accompanied with cytosolic leakage of damaged DNA in photoreceptors. Pharmaceutical or genetic approaches indicates STING promotes retina inflammation and degeneration upon oxidative damage. Drug screening reveals that BRD4 inhibitor JQ1 reduces cGAS-STING activation, inflammation and photoreceptor degeneration in the injured retina. BRD4 inhibition epigenetically suppresses STING transcription, and promotes autophagy-dependent cytosolic DNA clearance. Together, our results show that activation of cGAS-STING in retina may present pivotal innate immunity response in GA pathogenesis, whereas inhibition of cGAS-STING signaling by JQ1 could serve as a potential therapeutic strategy., (© 2022. The Author(s).)

The male abnormal gene family 21 ( mab21 ), was initially identified in C. elegans . Since its identification, studies from different groups have shown that it regulates development of ocular tissues, brain, heart and liver. However, its functional mechanism remains largely unknown. Here, we demonstrate that Mab21L1 promotes survival of lens epithelial cells. Mechanistically, Mab21L1 upregulates expression of αB-crystallin. Moreover, our results show that αB-crystallin prevents stress-induced phosphorylation of p53 at S-20 and S-37 through abrogating the activation of the upstream kinases, ATR and CHK1. As a result of suppressing p53 activity by αB-crystallin, Mab21L1 downregulates expression of Bak but upregulates Mcl-1 during stress insult. Taken together, our results demonstrate that Mab21L1 promotes survival of lens epithelial cells through upregulation of αB-crystallin to suppress ATR/CHK1/p53 pathway.

Multinucleated retinal pigment epithelium (RPE) cells have been reported in humans and other mammals. Rodents have an extremely high percentage of multinucleated cells (more than 80%). Both mouse and human multinucleated RPE cells exhibit specific regional distributions that are potentially correlated with photoreceptor density. However, detailed investigations of multinucleated RPE in different species and their behavior after DNA damage are missing. Here, we compared the composition of multinucleated RPE cells in nocturnal and diurnal animals that possess distinct rod and cone proportions. We further investigated the reactive oxygen species (ROS) production and DNA damage response in mouse mononucleated and multinucleated RPE cells and determined the effect of p53 dosage on the DNA damage response in these cells. Our results revealed an unrealized association between multinucleated RPE cells and nocturnal vision. In addition, we found multinucleated RPE cells exhibited increased ROS production and DNA damage after X-ray irradiation. Furthermore, haploinsufficiency of p53 led to increased DNA damage frequency after irradiation, and mononucleated RPE cells were more sensitive to a change in p53 dosage. In conclusion, this study provides novel information on in vivo PRE topography and the DNA damage response, which may reflect specific requirements for vision adaption and macular function.

The methyltransferase EZH2 plays an important role in regulating chromatin conformation and gene transcription. Phosphorylation of EZH2 at S21 by AKT kinase suppresses its function. However, protein phosphatases responsible for the dephosphorylation of EZH2-S21 remain elusive. Here, it is demonstrated that EZH2 is highly expressed in the ocular lens, and AKT-EZH2 axis is important in TGFβ-induced epithelial-mesenchymal transition (EMT). More importantly, it is identified that MYPT1/PP1 dephosphorylates EZH2-S21 and thus modulates its functions. MYPT1 knockout accelerates EMT, but expression of the EZH2-S21A mutant suppresses EMT through control of multiple families of genes. Furthermore, the phosphorylation status and gene expression modulation of EZH2 are implicated in control of anterior subcapsular cataracts (ASC) in human and mouse eyes. Together, the results identify the specific phosphatase for EZH2-S21 and reveal EZH2 dephosphorylation control of several families of genes implicated in lens EMT and ASC pathogenesis. These results provide important novel information in EZH2 function and regulation., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Systemic infections from fungal organisms are becoming increasingly difficult to treat as drug resistance continues to emerge. To substantially expand the antifungal drug landscape new compounds must be identified and developed with novel modes of action against previously untested drug targets. Most drugs block the activity of their targets through reversible, noncovalent interactions. However, a significant number of drugs form irreversible, covalent bonds with their selected targets. While more challenging to develop, these irreversible inactivators offer some significant advantages as novel antifungal agents. Vinyl sulfones contain a potentially reactive functional group that could function as a selective enzyme inactivator, and members of this class of compounds are now being developed as inactivators against an antifungal drug target. The enzyme aspartate semialdehyde dehydrogenase (ASADH) catalyzes a key step in an essential microbial pathway and is essential for the survival of every microorganism examined. A series of vinyl sulfones have been designed, guided by molecular modeling and docking studies to enhance their affinity for fungal ASADHs. These newly synthesized compounds have been examined against this target enzyme from the pathogenic fungal organism Candida albicans. Vinyl sulfones containing complementary structural elements inhibit this enzyme with inhibition constants in the low-micromolar range. These inhibitors have also led to the rapid and irreversible inactivation of this enzyme, and show some initial selectivity when compared to the inactivation of a bacterial ASADH. The best inactivators will serve as lead compounds for the development of potent and selective antifungal agents., (© 2021 Wiley Periodicals LLC.)

Chronic pain is the predominant problem for rheumatoid arthritis patients, and negatively affects quality of life. Arthritis pain management remains largely inadequate, and developing new treatment strategies are urgently needed. Spinal inflammation and oxidative stress contribute to arthritis pain and represent ideal targets for the treatment of arthritis pain. In the present study, collagen-induced arthritis (CIA) mouse model was established by intradermally injection of type II collagen (CII) in complete Freund's adjuvant (CFA) solution, and exhibited as paw and ankle swelling, pain hypersensitivity and motor disability. In spinal cord, CIA inducement triggered spinal inflammatory reaction presenting with inflammatory cells infiltration, increased Interleukin-1β (IL-1β) expression, and up-regulated NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and cleaved caspase-1 levels, elevated spinal oxidative level presenting as decreased nuclear factor E2-related factor 2 (Nrf2) expression and Superoxide dismutase (SOD) activity. To explore potential therapeutic options for arthritis pain, emodin was intraperitoneally injected for 3 days on CIA mice. Emodin treatment statistically elevated mechanical pain sensitivity, suppressed spontaneous pain, recovered motor coordination, decreased spinal inflammation score and IL-1β expression, increased spinal Nrf2 expression and SOD activity. Further, AutoDock data showed that emodin bind to Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) through two electrovalent bonds. And emodin treatment increased the phosphorylated AMPK at threonine 172. In summary, emodin treatment activates AMPK, suppresses NLRP3 inflammasome response, elevates antioxidant response, inhibits spinal inflammatory reaction and alleviates arthritis pain.

Age-related macular degeneration (AMD) is a leading cause of blindness characterized by degeneration of retina pigment epithelium (RPE) and photoreceptors in the macular region. Activation of the innate immune cGAS-STING signaling has been detected in RPE of dry AMD patients, but the regulatory basis is largely unexplored. Heterochromatin is a highly compact, transcription inert chromatin status. We have recently shown that heterochromatin is required for RPE survival through epigenetically silencing p53-mediated apoptosis signaling. Here, we found that cGAS and STING were dose-dependently upregulated in mouse RPE and retina during oxidative injury, correlated with decreased chromatin compaction in their gene loci. Genetic or pharmaceutical disruption of heterochromatin leads to elevated cGAS and STING expression and enhanced inflammatory response in oxidative stress-induced RPE and retina degeneration. In contrast, application of methotrexate (MTX), a recently identified heterochromatin-promoting drug, inhibits cGAS and STING in both RPE and retina, attenuates RPE/retina degeneration and inflammation. Further, we show that intact heterochromatin is required for MTX to repress cGAS and STING. Together, we demonstrated an unrevealed regulatory function of heterochromatin on cGAS and STING expression and provide potential new therapeutic strategy for AMD treatment., (Copyright © 2021. Published by Elsevier Inc.)