High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity

Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present study our objective was to extend in vivo toxicogenomic screening from analyzing one or a few tissues to multiple organs, including heart, kidney, brain, liver and spleen. Nanocapillary quantitative real-time PCR (QRT-PCR) was used in the study, due to its higher throughput, sensitivity and reproducibility, and larger dynamic range compared to DNA microarray technologies. Based on previous data, 56 gene markers were selected coding for proteins with different functions, such as proteins for acute phase response, inflammation, oxidative stress, metabolic processes, heat-shock response, cell cycle/apoptosis regulation and enzymes which are involved in detoxification. Some of the marker genes are specific to certain organs, and some of them are general indicators of toxicity in multiple organs. Utility of the nanocapillary QRT-PCR platform was demonstrated by screening different references, as well as discovery of drug-like compounds for their gene expression profiles in different organs of treated mice in an acute experiment. For each compound, 896 QRT-PCR were done: four organs were used from each of the treated four animals to monitor the relative expression of 56 genes. Based on expression data of the discovery gene set of toxicology biomarkers the cardio- and nephrotoxicity of doxorubicin and sulfasalazin, the hepato- and nephrotoxicity of rotenone, dihydrocoumarin and aniline, and the liver toxicity of 2,4-diaminotoluene could be confirmed. The acute heart and kidney toxicity of the active metabolite SN-38 from its less toxic prodrug, irinotecan could be differentiated, and two novel gene markers for hormone replacement therapy were identified, namely fabp4 and pparg, which were down-regulated by estradiol treatment

Current Lead Design for the Accelerator Project for Upgrade of LHC

The Accelerator Project for Upgrade of LHC (APUL) is a U.S. project participating in and contributing to CERN's Large Hadron Collider (LHC) upgrade program. In collaboration with Brookhaven National Laboratory, Fermilab is developing sub-systems for an upgrade of the LHC final focus magnet systems. A concept of main and auxiliary helium flow was developed that allows the superconductor to remain cold while the lead body warms up to prevent upper section frosting. The auxiliary flow will subsequently cool the thermal shields of the feed box and the transmission line cryostats. A thermal analysis of the current lead central heat exchange section was performed using analytic and FEA techniques. A method of remote soldering was developed that allows the current leads to be field replaceable. The remote solder joint was designed to be made without flux or additional solder, and able to be remade up to ten full cycles. A method of upper section attachment was developed that allows high pressure sealing of the helium volume. Test fixtures for both remote soldering and upper section attachment for the 13 kA lead were produced. The cooling concept, thermal analyses, and test results from both remote soldering and upper section attachment fixtures are presented

Distinct patterns of serum and urine macrophage migration inhibitory factor kinetics predict death in sepsis: a prospective, observational clinical study

Abstract Macrophage migration inhibitory factor (MIF) has been considered as a biomarker in sepsis, however the predictive value of the pattern of its kinetics in the serum and in the urine has remained unclarified. It is also unclear whether the kinetics of MIF are different between males and females. We conducted a single-center prospective, observational study with repeated measurements of MIF in serum and urine on days 0, 2, and 4 from admission to the intensive care unit (ICU) in 50 adult septic patients. We found that in patients who died within 90 days, there was an increase in serum MIF level from day 0 to 4, whereas in the survivors there was rather a decrease (p = 0.018). The kinetics were sex-dependent as the same difference in the pattern was present in males (p = 0.014), but not in females (p = 0.418). We also found that urine MIF was markedly lower in patients who died than in survivors of sepsis (p < 0.050). Urine MIF levels did not show temporal changes: there was no meaningful difference between day 0 and 4. These results suggest that kinetics of serum MIF during the initial days from ICU admission can predict death, especially in male patients. Additionally, lower urine MIF levels can also indicate death without showing meaningful temporal kinetics

Exercise and probiotics attenuate the development of Alzheimer's disease in transgenic mice. role of microbiome

It has been suggested that exercise training and probiotic supplementation could decelerate the progress of functional and biochemical deterioration in APP/PS1 transgenic mice (APP/PS1TG). APP/PS1TG mice were subjected to exercise training and probiotic treatments and functional, biochemical and microbiome markers were analyzed. Under these conditions the mice significantly outperformed controls on The Morris Maze Test, and the number of beta-amyloid plaques decreased in the hippocampus. B. thetaiotaomicron levels correlated highly with the results of the Morris Maze Test (p < 0.05), and this group of bacteria was significantly elevated in the microbiome of the APP/PS1TG mice compared to the wild type. L. johnsonii levels positively correlated with the beta amyloid content and area. Data revealed that exercise and probiotic treatment can decrease the progress of Alzheimer's Disease and the beneficial effects could be partly mediated by alteration of the microbiome

Magnetic Field Measurements of First Pre-series Full-Length 4.2 m Quadrupole MQXFA03 Using PCB Rotating Coils for the Hi-Lumi LHC Project

The U.S. Hi-Lumi LHC Accelerator Upgrade Project (AUP) and CERN have joined efforts to develop high field quadrupoles for the Hi-Lumi LHC upgrade. The US national laboratories in the AUP project will deliver 10 magnets and each cryostat has two 4.2 m high gradient quadrupoles in it. These magnets are made of Nb3Sn conductors, with large aperture (150 mm) and integrated gradient of 556.9 T. This paper reports on magnetic measurements performed during the vertical test at Brookhaven National Laboratory (BNL) in 2019-2020. A warm measurement Z-Scan (+/−15 A) with 42 Z-positions before cool-down was performed at BNL. The results were directly compared to field data measured at LBNL during magnet assembly. Measured harmonics and magnetic center offsets (ΔX and ΔY) have provided timely and informative diagnostics on the magnet structure's shape at both warm and cold temperatures. A new centering fixture was designed and added to better center the warm bore tube which contains the rotating coil probe. After the quench training to 16.47 kA was achieved, a complete set of cold measurements (Z-Scan at 16.47 kA and I-Scan from 960 A to 16.47 kA and back to 960 A) was made. Periodic axial variation of allowed and nonallowed harmonics was observed which is related to the coil radial and/or mid-plane variations along the magnet axis. Overall, the average harmonics in the straight section are within the required field boundaries.The U.S. Hi-Lumi LHC Accelerator Upgrade Project (AUP) and CERN have joined efforts to develop high field quad-rupoles for the Hi-Lumi LHC upgrade. The US national laborato-ries in the AUP project will deliver 10 magnets and each cryostat has two 4.2 m high gradient quadrupoles in it. These magnets are made of Nb3Sn conductors, with large aperture (150 mm) and in-tegrated gradient of 556.9 T. This paper reports on magnetic measurements performed during the vertical test at Brookhaven National Laboratory (BNL) in 2019-2020. A warm measurement Z-Scan (+/- 15 A) with 42 Z-positions before cool-down was per-formed at BNL. The results were directly compared to field data measured at LBNL during magnet assembly. Measured harmonics and magnetic center offsets (ΔX and ΔY) have provided timely and informative diagnostics on the magnet structure’s shape at both warm and cold temperatures. A new centering fixture was de-signed and added to better center the warm bore tube which con-tains the rotating coil probe. After the quench training to 16.47 kA was achieved, a complete set of cold measurements (Z-Scan at 16.47 kA and I-Scan from 960 A to 16.47 kA and back to 960 A) was made. Periodic axial variation of allowed and nonallowed harmonics was observed which is related to the coil radial and/or mid-plane variations along the magnet axis. Overall, the average harmonics in the straight section are within the required field boundaries

Progress in the Development of the Nb3_3Sn MQXFB Quadrupole for the HiLumi Upgrade of the LHC

The high-luminosity upgrade of the Large Hadron Collider (HL-LHC) requires new high field and large-aperture quadrupole magnets for the low-beta inner triplets (MQXF). With a nominal operating gradient of 132.2 T/m in a 150 mm aperture and a conductor peak field of 11.3 T, the new quadrupole magnets are based on Nb3Sn superconducting technology. After a series of short models constructed in close collaboration by LARP (LHC Accelerator Research Program) and CERN, the development program is entering in the series production phase with CERN on one side and the US Accelerator Upgrade Project (US-AUP) on the other side assembling and testing full-length magnets. This paper describes the status of the development activities at CERN, in particular on the cold powering test of the first MQFXB prototype and on the construction of the second full scale prototype. Critical operations such as reaction heat treatment, coil impregnation and magnet assembly are discussed. Finally, the plan towards the series production is described

Status of the MQXFB Nb3_3Sn quadrupoles for the HL-LHC

The cold powering test of the first two prototypes of the MQXFB quadrupoles (MQXFBP1, now disassembled, and MQXFBP2), the Nb3Sn inner triplet magnets to be installed in the HL-LHC, has validated many features of the design, such as field quality and quench protection, but has found performance limitations. In fact, both magnets showed a similar phenomenology, characterized by reproducible quenches in the straight part inner layer pole turn, with absence of training and limiting the performance at 93% (MQXFBP1) and 98% (MQXFBP2) of the nominal current at 1.9 K, required for HL-LHC operation at 7 TeV. Microstructural inspections of the quenching section of the limiting coil in MQXFBP1 have identified fractured Nb3Sn sub-elements in strands located at one specific position of the inner layer pole turn, allowing to determine the precise origin of the performance limitation. In this paper we outline the strategy that has been defined to address the possible sources of performance limitation, namely coil manufacturing, magnet assembly and integration in the cold mass