The Impact of the ‘Mis-Peptidome’ on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet’s disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8⁺ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the “mis-immunopeptidome” that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8⁺ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.     

Design of Trehalose-Based Amide/Sulfonamide C-type Lectin Receptor Signaling Compounds

Mincle agonists have been shown to induce inflammatory cytokine production, such as tumor necrosis factor-alpha (TNF) and promote the development of a Th1/Th17 immune response that might be crucial to development of effective vaccination against pathogens such as Mycobacterium tuberculosis. As an expansion of our previous work, a library of 6,6′-amide and sulfonamide α,α-d -trehalose compounds with various substituents on the aromatic ring was synthesized efficiently in good to excellent yields. These compounds were evaluated for their ability to activate the human C-type lectin receptor Mincle by the induction of cytokines from human peripheral blood mononuclear cells. A preliminary structure–activity relationship (SAR) of these novel trehalose diamides and sulfonamides revealed that aryl amide-linked trehalose compounds demonstrated improved activity and relatively high potency cytokine production compared to the Mincle ligand trehalose dibehenate adjuvant (TDB) and the natural ligand trehalose dimycolate (TDM) inducing dose-dependent and human-Mincle-specific stimulation in a HEK reporter cell line.     

Phase equilibria studies in the CaO–SiO2–Al2O3–MgO system with CaO/SiO2 ratio of 0.9

Phase equilibria and liquidus temperatures in the CaO–SiO₂–Al₂O₃–MgO system at a CaO/SiO₂ weight ratio of 0.9 in the liquid phase have been experimentally determined employing high-temperature equilibration and quenching technique followed by electron probe X-ray microanalysis. Isotherms at 1573, 1623, 1673, and 1773 K were determined and the primary phase fields of wollastonite, melilite, olivine, periclase, spinel, and corundum have been located. Compositions of the olivine and melilite solid solutions were analyzed and discussed. Comparisons between the newly constructed diagram, existing data, and FactSage predicted phase diagrams were performed and differences were discussed. The present study will be useful for guidance of industrial practices and further development of thermodynamic modeling.     

Non‐geostationary satellite orbit communications satellite constellations history

This special issue of the journal on ‘constellations’ comes at a critical time in their development as a second wave of such non‐geostationary satellite orbit (NGSO) systems is being planned and deployed. These mega‐constellations as they have become known are, with a few exceptions, very much larger than those in the first wave and are focused on broadband and 5G applications rather than speech and narrow band data as those deployed in the first wave during the 1990s. However, as we explain in this editorial, there are many similarities in the design and business plans to the first wave and, perhaps, many similar lessons to be learned.     

Physico-chemical controls on phosphorus cycling in two lowland streams. Part 2--the sediment phase

This article investigates the temporal and spatial controls on sediment-phosphorus (P) dynamics in two contrasting sub-catchments of the River Kennet, England. Suspended sediment (collected under representative flow conditions) and size-fractionated bedload (collected weekly for one year) from the Rivers Lambourn and Enborne was analysed for a range of physico-chemical determinands. Total P concentrations were highest in the most mobile fractions of sediment: suspended sediment, fine silt and clay and organic matter (mean concentrations of 1758, 1548 and 1440 microg P g(-1) dry sediment, respectively). Correlation analysis showed significant relationships between total P and total iron (n= 110), total manganese (n= 110), organic matter (n= 110) and specific surface area (n= 28) in the Lambourn (r2 0.71, 0.68, 0.62 and 0.52, respectively) and between total P and total iron (n= 110), total manganese (n= 110) and organic matter (n= 110) in the Enborne (r2 0.74, 0.85 and 0.68, respectively). These data highlight the importance of metal oxyhydroxide adsorption of P on fine particulates and organic matter. However, high total P concentrations in the granule gravel and coarse sand size fraction during the summer period (mean concentration 228 microg P g(-1) dry sediment) also highlight the role of calcite co-precipitation on P dynamics in the Lambourn. P to cation ratios in Lambourn sediment indicated that fine silt and clay and granule gravel and coarse sand size fractions were potential sources of P release to the water column during specific periods of the summer and autumn. In the Enborne, however, only the granule gravel and coarse sand size fraction had high ratios and a slow, constant release of P was observed. In addition, scanning electron microscopy work confirmed the association of P with calcite in the Lambourn and P with iron on clay particles in the Enborne. The study highlighted the importance of the chemical and physical properties of the sediment in influencing the mechanisms controlling P storage and release within river channels.     

Adverse effects of pore-pressure drainage on stress measurements performed in deep tunnels: an example from the Lower Kihansi hydroelectric power project, Tanzania

We describe a campaign to measure stress within a gneissic ridge near the edge of the Tanzanian craton. The measurements were conducted to determine whether the level of minimum principal stress along the trajectory of a hydropower pressure tunnel attained the level of 10 MPa, as required to leave the tunnel unlined. Extrapolation of early hydrofracture and overcoring measurements conducted mostly in boreholes drilled behind face suggested that the requisite level was not quite met. However, the minimum principal stress estimates from the instantaneous shut-in pressures (ISIPs) of the hydrofracture tests generally showed large scatter and were sometimes less than the estimated pre-disturbance pore pressure. It was suspected that the stress tests were affected by stress alteration around the tunnel due to pore pressure drainage. To test this, hydrofracture and hydro-jacking tests were conducted in two long, horizontal holes drilled ahead of the excavation face into relatively undrained rock, and a third vertical hole drilled behind the face. All were near the critical location where the pressure tunnel enters the powerhouse. The minimum principal stress estimates in the ahead-of-face holes were found to be much higher than those from the behind-face hole, consistent with the hypothesis. Estimates of the drawdown in pore pressure about the tunnel and test holes suggested a coupling factor between drawdown and minimum principal stress magnitude of approximately unity. This is slightly higher than predicted from an hydromechanical model that explains the coupling between the pore-pressure and stress fields in terms of fracture compliance and poro-elasticity of intact blocks. Nonetheless, both results demonstrate the importance of accounting for drawdown when conducting stress measurements in boreholes drilled from tunnels. We also note some instances where hydrofracture and hydro-jacking tests yielded different estimates for the minimum principal stress magnitude.     

The collapse of welded aluminium plate girders—an experimental study

Twenty-two tests conducted to study the collapse behaviour of welded aluminium girders are described. The girders are of varying proportions, have transverse or longitudinal web stiffeners and are subjected to different combinations of shear and bending loads. It is observed that, although shear sway mechanisms similar to those for steel girders do develop, the webs of aluminium girders may fracture in the heat affected zones adjacent to the perimeter welds. These fractures develop at some stage during the formation of the collapse mechanism and are the consequence, rather than the cause, of failure. It is shown that the tension field theory, originally developed for steel girders, may overestimate the shear-carrying capacity of aluminium girders and it is concluded that the theory requires some modification before it can be applied with confidence to aluminium girders.     

Plant crown traits and carbon sequestration capability by Platanus hybrida Brot. in Rome

Measurements of carbon dioxide (CO₂) concentration carried out in the city of Rome in the period January–December 2005 showed a mean yearly CO₂ concentration of 414 ± 45 ppm; polluted sites (P sites) had 21% higher CO₂ concentration than control sites (C sites). The significant (p < 0.01) correlation analysis between CO₂ concentration and traffic density measured during the study period at P sites showed that traffic density explained 51% of the CO₂ variation. The CO₂ trend during the traffic limitation days (provision imposed by ordinance of the City Council) did not show significant differences as regards regular traffic days, suggesting the ineffectiveness of this provision. Leaf area index (LAI) of Platanus hybrida Brot. was on an average 11% lower at P sites than at C ones associated with a lower total photosynthetic leaf surface area (SPT, 34% lower at P sites than at C ones). P. hybrida had a total carbon sequestration of 117 ± 13 kg year⁻¹ (mean value of P and C sites) playing an important role in sequestering CO₂. Thus, the choice of plant species for urban areas may be set out taking into account their own air amelioration capability. Plant traits of each species may be used for urban tree planting programs to ameliorate urban air pollution.     

Methods to calculate the response time of heat and smoke detectors installed below large unobstructed ceilings

Recently developed methods to calculate the time required for ceiling mounted heat and smoke detectors to respond to growing fires are reviewed. A computer program that calculates activation times for both fixed temperature and rate of rise heat detectors in response to fires that increase in heat release rate proportionally with the square of time from ignition is given. This program produces nearly equivalent results to the tables published in Appendix C, Guide for Automatic Fire Detector Spacing (NFPA 72E, 1984). A separate method and corresponding program are provided to calculate response time for fires having arbitrary heat release rate histories. This method is based on quasi-steady ceiling layer gas flow assumptions. Assuming a constant proportionality between smoke and heat released from burning materials, a method is described to calculate smoke detector response time, modeling the smoke detector as a low temperature heat detector in either of the two response time models.Nomenclature A g/(c _p T ) - c _p specific heat capacity of ambient air - C _s smoke mass concentration - D effective binary diffusion coefficient - g acceleration of gravity - H vertical distance from fuel to ceiling - I light intensity - I_o initial light intensity - L light beam length - _s smoke gas mass production rate per unit volume - OD optical density per unit length (see Equation 8) - fire energy release rate - energy release rate per unit volume - r radial distance from fire axis to the detector - RTI response time index, the product of the detector thermal time constant and the square root of the gas speed used in the test to measure the time constant.⁹ - t time - t ₂ ^* dimensionless time t/[A^{–1/5 –1/5} H^4/5) - (t ₂ ^* ) _f dimensionless time for time delay for gas front travel - T ambient temperature - T gas temperature at detector location - T _s temperature of detector sensing elements - T T — T - T ₂ ^* dimensionless temperature differences T/[A^2/5(T _f /g) ^2/5 H^–3/5] - U gas speed at the detector location - U ₂ ^* dimensionless gas speed U/[A H]^1/5 - Y _s local ratio of smoke mass to total mass in flow - proportionality constant for t²-fire growth = Q/t² - ambient air density Reference: David D. Evans and David W. Stroup, Methods to Calculate the Response Time of Heat and Smoke Detectors Installed Below Large Unobstructed Ceilings,Fire Technology, Vol. 22, No. 1, February 1985, p. 54. Note: This paper is a contribution of the National Bureau of Standards and is not subject to copyright.