Analysis of the mechanical performance of the 4.2 m long MQXFA magnets for the Hi-Lumi LHC Upgrade

Under the U.S. High Luminosity LHC Accelerator Upgrade Project (HL-LHC AUP), the 150 mm bore, high-field Nb3Sn low-\b{eta} MQXFA quadrupole magnets are being fabricated, assembled and tested, in the context of the CERN Hi-Luminosity LHC (HL-LHC) upgrade. These magnets have 4.2 m magnetic length and 4.56 m long iron yoke. To date, eight MQXFA magnets have been tested. One of the magnets additionally underwent a successful endurance test with 40 triggered quenches, and two magnets did not perform as expected. This work summarizes for the first time the available strain gauge data from eight identical Nb3Sn MQXFA tested magnets, focusing on the endurance test, and on a possible cause of underperformance of the two magnets that did not pass the vertical test. We applied methods to prevent this from happening in future MQXFA magnets, which shown to be effective for last two tested magnets

Connexin40 regulates platelet function

The presence of multiple connexins was recently demonstrated in platelets, with notable expression of Cx37. Studies with Cx37-deficient mice and connexin inhibitors established roles for hemichannels and gap junctions in platelet function. It was uncertain, however, whether Cx37 functions alone or in collaboration with other family members through heteromeric interactions in regulation of platelet function. Here we report the presence and functions of an additional platelet connexin, Cx40. Inhibition of Cx40 in human platelets or its deletion in mice reduces platelet aggregation, fibrinogen binding, granule secretion and clot retraction. The effects of the Cx37 inhibitor 37,43Gap27 on Cx40-/- mouse platelets and of the Cx40 inhibitor 40Gap27 on Cx37-/- mouse platelets revealed that each connexin is able to function independently. Inhibition or deletion of Cx40 reduces haemostatic responses in mice, indicating the physiological importance of this protein in platelets. We conclude that multiple connexins are involved in regulating platelet function, thereby contributing to haemostasis and thrombosis

A novel transport mechanism for MOMP in Chlamydophila pneumoniae and its putative role in immune-therapy

Major outer membrane proteins (MOMPs) of Gram negative bacteria are one of the most intensively studied membrane proteins. MOMPs are essential for maintaining the structural integrity of bacterial outer membranes and in adaptation of parasites to their hosts. There is evidence to suggest a role for purified MOMP from Chlamydophila pneumoniae and corresponding MOMP-derived peptides in immune-modulation, leading to a reduced atherosclerotic phenotype in apoE−/− mice via a characteristic dampening of MHC class II activity. The work reported herein tests this hypothesis by employing a combination of homology modelling and docking to examine the detailed molecular interactions that may be responsible. A three-dimensional homology model of the C. pneumoniae MOMP was constructed based on the 14 transmembrane β-barrel crystal structure of the fatty acid transporter from Escherichia coli, which provides a plausible transport mechanism for MOMP. Ligand docking experiments were used to provide details of the possible molecular interactions driving the binding of MOMP-derived peptides to MHC class II alleles known to be strongly associated with inflammation. The docking experiments were corroborated by predictions from conventional immuno-informatic algorithms. This work supports further the use of MOMP in C. pneumoniae as a possible vaccine target and the role of MOMP-derived peptides as vaccine candidates for immune-therapy in chronic inflammation that can result in cardiovascular events

Challenges and Lessons Learned from fabrication, testing and analysis of eight MQXFA Low Beta Quadrupole magnets for HL-LHC

By the end of October 2022, the US HL-LHC Accelerator Upgrade Project (AUP) had completed fabrication of ten MQXFA magnets and tested eight of them. The MQXFA magnets are the low beta quadrupole magnets to be used in the Q1 and Q3 Inner Triplet elements of the High Luminosity LHC. This AUP effort is shared by BNL, Fermilab, and LBNL, with strand verification tests at NHMFL. An important step of the AUP QA plan is the testing of MQXFA magnets in a vertical cryostat at BNL. The acceptance criteria that could be tested at BNL were all met by the first four production magnets (MQXFA03-MQXFA06). Subsequently, two magnets (MQXFA07 and MQXFA08) did not meet some criteria and were disassembled. Lessons learned during the disassembly of MQXFA07 caused a revision to the assembly specifications that were used for MQXFA10 and subsequent magnets. In this paper, we present a summary of: 1) the fabrication and test data of all the MQXFA magnets; 2) the analysis of MQXFA07/A08 test results with characterization of the limiting mechanism; 3) the outcome of the investigation, including the lessons learned during MQXFA07 disassembly; and 4) the finite element analysis correlating observations with test performance

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

The role of the glucose regulated protein of 78kDa, Grp78/BiP, in the mammalian ER stress response.

Grp78/BiP is a 78kDa protein located within the lumen of the endoplasmic reticulum (ER), where it helps store Ca2+ and acts particularly as a chaperone assisting in the folding and assembly of membrane-bound or secretory proteins. Recent evidence has implicated the protein as a sensor of ER malfunction, regulating the initiation of a signalling pathway, known as the ER stress response or Unfolded Protein Response (UPR). The work undertaken for this thesis has addressed the role of Grp78/BiP in the mammalian UPR signalling pathway and the consequent effects upon cell survival, programmed cell death, and cell cycle regulation during ER stress. Novel Grp78/BiP fluorescent and bioluminescent chimeric proteins were generated in order to study dynamic changes of EGFP-tagged Grp78/BiP proteins located in the cell. This approach simplified and facilitated the generation of stable cell lines over-expressing Grp78/BiP and provided a powerful tool for single cell analysis to help determine its role in survival, apoptosis and cell cycle arrest under ER stress conditions. Use of these fluorescent molecular indicators showed that the apparent nuclear localisation of the Grp78/BiP is due to its presence in nuclear tubes, which are the results of invaginations of the normal ER strands into the nucleus from the nuclear envelope. This localisation was unaltered under ER stress, even at maximum doses of stressor, and so it appears that Grp78/BiP does not re-locate to the nucleus in order to fulfil its signalling functions. Under ER stress, levels of endogenous GRP78/BiP mRNA, as well as those for GRP94 and calreticulin, were induced, supporting previous evidence for their role as stress-inducible chaperones. Similar results were found for the transcription factor GADD153/CHOP. The induced expression of these mRNAs was attenuated in cells transiently over-expressing wild-type Grp78/BiP (wt-Grp78/BiP), indicating that the induction is triggered by a drop in the levels of free Grp78/BiP within the ER lumen. Such attenuation, however, did not occur in cells transiently expressing the Grp78/BiP chimeric proteins and the ramifications of these observations are discussed. To investigate the role of Grp78/BiP as an ER signalling molecule during ER stress, cells stably expressing Grp78/BiP fusion proteins at high levels, either EGFP-BiP or EGFP-BiP-AEQ, were selected using EGFP as an indicator of their expression. Under ER stress, these cells demonstrated increased cell survival and prevented apoptosis by directly attenuating the activation of UPR signalling pathways by modulating the activation of the ER sensors and increasing the ER folding capacity of the cells. Use of different chimeric proteins showed that, in order to do this, Grp78/BiP requires a free C-terminus. The results also demonstrated that Grp78/BiP over-expression attenuated cyclin D1 loss induced by tunicamycin. This slowed the S-phase of the cell cycle, possibly suggesting a novel role for this protein in cell division. These findings underline the role of Grp78/BiP as a key modulator of the UPR in mammalian cells and provide the basis for further investigation into its functions

Immunopeptidomics: Applications to dissect immune responses through proteomics-based approaches

The definitive guide to peptidomics- a hands-on lab reference The first truly comprehensive book about peptidomics for protein and peptide analysis, this ..