Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain.

Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer

Exploring the Limits of High Altitude GPS for Future Lunar Missions

An increasing number of spacecraft are relying on the Global Positioning System (GPS) for navigation at altitudes near or above the GPS constellation itself - the region known as the Space Service Volume (SSV). While the formal definition of the SSV ends at geostationary altitude, the practical limit of high-altitude space usage is not known, and recent missions have demonstrated that signal availability is sufficient for operational navigation at altitudes halfway to the moon. This paper presents simulation results based on a high-fidelity model of the GPS constellation, calibrated and validated through comparisons of simulated GPS signal availability and strength with flight data from recent high-altitude missions including the Geostationary Operational Environmental Satellite 16 (GOES-16) and the Magnetospheric Multiscale (MMS) mission. This improved model is applied to the transfer to a lunar near-rectilinear halo orbit (NRHO) of the class being considered for the international Deep Space Gateway concept. The number of GPS signals visible and their received signal strengths are presented as a function of receiver altitude in order to explore the practical upper limit of high-altitude space usage of GPS

Exploring the Limits of High Altitude GPS for Future Lunar Missions

An increasing number of spacecraft are relying on the Global Positioning System (GPS) for navigation at altitudes near or above the GPS constellation itself - the region known as the Space Service Volume (SSV). While the formal definition of the SSV ends at geostationary altitude, the practical limit of high-altitude space usage is not known, and recent missions have demonstrated that signal availability is sufficient for operational navigation at altitudes halfway to the moon. This paper presents simulation results based on a high-fidelity model of the GPS constellation, calibrated and validated through comparisons of simulated GPS signal availability and strength with flight data from recent high-altitude missions including the Geostationary Operational Environmental Satellite 16 (GOES-16) and the Magnetospheric Multiscale (MMS) mission. This improved model is applied to the transfer to a lunar near-rectilinear halo orbit (NRHO) of the class being con- sidered for the international Deep Space Gateway concept. The number of GPS signals visible and their received signal strengths are presented as a function of receiver altitude in order to explore the practical upper limit of high-altitude space usage of GPS

The Binding of Factor H to a Complex of Physiological Polyanions and C3b on Cells Is Impaired in Atypical Hemolytic Uremic Syndrome

Factor H (fH) is essential for complement homeostasis in fluid-phase and on surfaces. Its two C-terminal domains (CCP 19-20) anchor fH to self surfaces where it prevents C3b amplification in a process requiring its N-terminal four domains. In atypical hemolytic uremic syndrome (aHUS), mutations clustering towards the C-terminus of fH may disrupt interactions with surface-associated C3b or polyanions and thereby diminish the ability of fH to regulate complement. To test this we compared a recombinant protein encompassing CCP 19-20 with sixteen mutants. The mutations had only very limited and localized effects on protein structure. While we found four aHUS-linked fH mutations that decreased binding to C3b and/or to heparin (a model compound for cell-surface polyanionic carbohydrates), we identified five aHUS-associated mutants with increased affinity for either or both ligands. Strikingly, these variable affinities for the individual ligands did not correlate with the extent to which all the aHUS-associated mutants were found to be impaired in a more physiological assay that measured their ability to inhibit cell surface complement functions of full-length fH. Taken together, our data suggest that disruption of a complex fH-self surface recognition process, involving a balance of affinities for protein and physiological carbohydrate ligands, predisposes to aHUS

Photochemical dihydrogen production using an analogue of the active site of [NiFe] hydrogenase

The photoproduction of dihydrogen (H2) by a low molecular weight analogue of the active site of [NiFe] hydrogenase has been investigated by the reduction of the [NiFe2] cluster, 1, by a photosensitier PS (PS = [ReCl(CO)3(bpy)] or [Ru(bpy)3][PF6]2). Reductive quenching of the 3MLCT excited state of the photosensitiser by NEt3 or N(CH2CH2OH)3 (TEOA) generates PS•−, and subsequent intermolecular electron transfer to 1 produces the reduced anionic form of 1. Time-resolved infrared spectroscopy (TRIR) has been used to probe the intermediates throughout the reduction of 1 and subsequent photocatalytic H2 production from [HTEOA][BF4], which was monitored by gas chromatography. Two structural isomers of the reduced form of 1 (1a•− and 1b•−) were detected by Fourier transform infrared spectroscopy (FTIR) in both CH3CN and DMF (dimethylformamide), while only 1a•− was detected in CH2Cl2. Structures for these intermediates are proposed from the results of density functional theory calculations and FTIR spectroscopy. 1a•− is assigned to a similar structure to 1 with six terminal carbonyl ligands, while calculations suggest that in 1b•− two of the carbonyl groups bridge the Fe centres, consistent with the peak observed at 1714 cm−1 in the FTIR spectrum for 1b•− in CH3CN, assigned to a ν(CO) stretching vibration. The formation of 1a•− and 1b•− and the production of H2 was studied in CH3CN, DMF and CH2Cl2. Although the more catalytically active species (1a•− or 1b•−) could not be determined, photocatalysis was observed only in CH3CN and DMF

Occupational Exposures to Respirable Crystalline Silica During Hydraulic Fracturing

This report describes a previously uncharacterized occupational health hazard: work crew exposures to respirable crystalline silica during hydraulic fracturing. Hydraulic fracturing involves high pressure injection of large volumes of water and sand, and smaller quantities of well treatment chemicals, into a gas or oil well to fracture shale or other rock formations, allowing more efficient recovery of hydrocarbons from a petroleum-bearing reservoir. Crystalline silica (“frac sand”) is commonly used as a proppant to hold open cracks and fissures created by hydraulic pressure. Each stage of the process requires hundreds of thousands of pounds of quartz containing sand; millions of pounds may be needed for all zones of a well. Mechanical handling of frac sand creates respirable crystalline silica dust, a potential exposure hazard for workers. Researchers at the National Institute for Occupational Safety and Health collected 111 personal breathing zone samples at 11 sites in five states to evaluate worker exposures to respirable crystalline silica during hydraulic fracturing. At each of the 11 sites, full-shift samples exceeded occupational health criteria (e.g., the Occupational Safety and Health Administration calculated permissible exposure limit, the NIOSH recommended exposure limit, or the ACGIH threshold limit value), in some cases, by 10 or more times the occupational health criteria. Based on these evaluations, an occupational health hazard was determined to exist for workplace exposures to crystalline silica. Seven points of dust generation were identified, including sand handling machinery and dust generated from the work site itself. Recommendations to control exposures include product substitution (when feasible), engineering controls or modifications to sand handling machinery, administrative controls, and use of personal protective equipment. To our knowledge, this represents the first systematic study of work crew exposures to crystalline silica during hydraulic fracturing. Companies that conduct hydraulic fracturing using silica sand should evaluate their operations to determine the potential for worker exposure to respirable crystalline silica and implement controls as necessary to protect workers. [Supplementary materials are available for this article. Go to the publisher’s online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a file containing controls and recommendations to limit worker exposures to respirable crystalline silica at hydraulic fracturing work sites.

ISU Transportation Shop Redesign

TSM416: Technology CapstoneProblem Statement: The current shop ISU Transportation uses is too small for their vehicle fleet, does not have enough room for spare parts, doesn’t flow properly, and the employees are not all in the same building. ISU Transportation needs a shop to work on all their cars, flow properly, and function as a car maintenance shop should. ISU Transportation employees care about this because they need an easy-to-function shop

ISU Transportation Building Redesign

TSM416: Technology CapstoneProblem Statement: ISU Transportation Services is an organization within Iowa State University that works on and maintains all of the rental vehicles. They need a more efficient way of maintaining their fleet of vehicles. They do not have enough space for the number of vehicles they are taking care of anymore and, therefore, need a larger area to work on, store, and clean their vehicles. As of now, there is no budget for this new design, but we must consider different alternatives that can be used or not used in the final design to keep the overall cost reasonable

Identification of two principal amyloid-driving segments in variable domains of Ig light chains in systemic light-chain amyloidosis

Systemic light-chain amyloidosis (AL) is a human disease caused by overexpression of monoclonal immunoglobulin light chains that form pathogenic amyloid fibrils. These amyloid fibrils deposit in tissues and cause organ failure. Proteins form amyloid fibrils when they partly or fully unfold and expose segments capable of stacking into β-sheets that pair and thereby form a tight, dehydrated interface. These structures, termed steric zippers, constitute the spines of amyloid fibrils. Here, using a combination of computational (with ZipperDB and Boston University ALBase), mutational, biochemical, and protein structural analyses, we identified segments within the variable domains of Ig light chains that drive the assembly of amyloid fibrils in AL. We demonstrate that there are at least two such segments and that each one can drive amyloid fibril assembly independently of the other. Our analysis revealed that peptides derived from these segments form steric zippers featuring a typical dry interface with high-surface complementarity and occupy the same spatial location of the Greek-key immunoglobulin fold in both λ and κ variable domains. Of note, some predicted steric-zipper segments did not form amyloid fibrils or assembled into fibrils only when removed from the whole protein. We conclude that steric-zipper propensity must be experimentally validated and that the two segments identified here may represent therapeutic targets. In addition to elucidating the molecular pathogenesis of AL, these findings also provide an experimental approach for identifying segments that drive fibril formation in other amyloid diseases

Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain.

Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer