Calixpyrroles, calixpyridinopyrroles and calixpyridines

The present invention provides calixpyrrole, calixpyridinopyrrole, and calixpyridine macrocycles, having 4, 5, 6, 7, or 8 heterocyclic rings, as well as syntheses, derivatives, conjugates, multimers, and solid supports thereof. Such macrocycles have proved to be effective and selective ion- and neutral molecule-binding agents forming supramolecular ensembles, and ion- and neutral molecule-separation agents. The macrocycles are fully meso-non-hydrogen-substituted porphyrinogens, a few molecules of which were previously known but not recognized as possessing anion- or molecule-binding properties. The binding mode is noncovalent, primarily that of hydrogen-bonding, thereby providing a new mode for liquid chromatography, that of Hydrogen Bonding Liquid Chromatography. Further useful applications of the macrocycles provided herein include environmental remediation by removal of undesired ions or neutral molecules, and removal of phosphate for kidney dialysis.Board of Regents, University of Texas Syste

Pretreatment HLADQA1-HLADRB1 Testing for the Prevention of Azathioprine-Induced Pancreatitis in Inflammatory Bowel Disease: A Prospective Cohort Study

INTRODUCTION:Azathioprine-induced pancreatitis is an idiosyncratic and unpredictable response, occurring in up to 7% of azathioprine-exposed patients with inflammatory bowel disease (IBD). The haplotype HLADQA1-HLADRB1*07:01A\u3eC is strongly associated with azathioprine-induced pancreatitis in IBD. We aimed to evaluate whether pretreatment HLADQA1-HLADRB1*07:01A\u3eC screening will reduce the risk of azathioprine-induced pancreatitis.METHODS:Participants with IBD were screened for HLADQA1-HLADRB1*07:01A\u3eC, and participants with a variant genotype were excluded from azathioprine treatment. Wild-type participants were started on azathioprine and followed for 3 months. The incidence of pancreatitis was compared with unscreened historical controls.RESULTS:HLADQA1-HLADRB1*07:01A\u3eC screening resulted in an 11-fold reduction in the incidence of azathioprine-induced pancreatitis (n = 1/328 or 0.30% vs n = 13/373 or 3.4%). In propensity score-matched cohorts (age and sex), HLA DQA1-HLADRB1*07:01A\u3eC screening was significantly associated with a reduction in the incidence of AZA-induced pancreatitis independent of weight, glucocorticoid exposure, and smoking status (adjusted odds ratio = 0.075, 95% confidence interval = 0.01-0.58, P = 0.01). Up to 45% (n = 271/599) of participants were excluded from azathioprine therapy based on the haplotype in the HLADQA1-HLADRB1*07:01A\u3eC-screened cohort.DISCUSSION:HLADQA1-HLADRB1*07:01A\u3eC screening reduced the risk of azathioprine-induced pancreatitis; however, using this strategy to guide the use of azathioprine therapy in IBD may eliminate a large proportion of patients from being eligible for treatment with azathioprine. In regions where there is access to other IBD therapies, and given the short-term and long-term toxicities associated with azathioprine, HLADQA1-HLADRB1*07:01A\u3eC-screening may be a clinically relevant strategy for enhancing the safe use of azathioprine in IBD. In addition, cost-effectiveness analyses are needed to further solidify the utility of HLADQA1-HLADRB1*07:01A\u3eC screening in IBD populations

A cosmic dust detection suite for the deep space Gateway

The decade of the 2020s promises to be when humanity returns to space beyond Earth orbit, with several nations trying to place astronauts on the Moon, before going further into deep space. As part of such a programme, NASA and partner organisations, propose to build a Deep Space Gateway in lunar orbit by the mid-2020s. This would be visited regularly and offer a platform for science as well as for human activity. Payloads that can be mounted externally on the Gateway offer the chance to, amongst other scientific goals, monitor and observe the dust flux in the vicinity of the Moon. This paper looks at relevant technologies to measure dust which will impact the exposed surface at high speed. Flux estimates and a model payload of detectors are described. It is predicted that the flux is sufficient to permit studies of cometary vs. asteroidal dust and their composition, and to sample interstellar dust streams. This may also be the last opportunity to measure the natural dust flux near the Moon before the current, relatively pristine environment, is contaminated by debris, as humanity’s interest in the Moon generates increased activity in that vicinity in coming decades

Brecciation at the grain scale within the lithologies of the Winchcombe Mighei‐like carbonaceous chondrite

The Mighei‐like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine‐grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse‐grained primary components that are found directly alongside other coarse‐grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

Characterization of Granulations of Calcium and Apatite in Serum as Pleomorphic Mineralo-Protein Complexes and as Precursors of Putative Nanobacteria

Calcium and apatite granulations are demonstrated here to form in both human and fetal bovine serum in response to the simple addition of either calcium or phosphate, or a combination of both. These granulations are shown to represent precipitating complexes of protein and hydroxyapatite (HAP) that display marked pleomorphism, appearing as round, laminated particles, spindles, and films. These same complexes can be found in normal untreated serum, albeit at much lower amounts, and appear to result from the progressive binding of serum proteins with apatite until reaching saturation, upon which the mineralo-protein complexes precipitate. Chemically and morphologically, these complexes are virtually identical to the so-called nanobacteria (NB) implicated in numerous diseases and considered unusual for their small size, pleomorphism, and the presence of HAP. Like NB, serum granulations can seed particles upon transfer to serum-free medium, and their main protein constituents include albumin, complement components 3 and 4A, fetuin-A, and apolipoproteins A1 and B100, as well as other calcium and apatite binding proteins found in the serum. However, these serum mineralo-protein complexes are formed from the direct chemical binding of inorganic and organic phases, bypassing the need for any biological processes, including the long cultivation in cell culture conditions deemed necessary for the demonstration of NB. Thus, these serum granulations may result from physiologically inherent processes that become amplified with calcium phosphate loading or when subjected to culturing in medium. They may be viewed as simple mineralo-protein complexes formed from the deployment of calcification-inhibitory pathways used by the body to cope with excess calcium phosphate so as to prevent unwarranted calcification. Rather than representing novel pathophysiological mechanisms or exotic lifeforms, these results indicate that the entities described earlier as NB most likely originate from calcium and apatite binding factors in the serum, presumably calcification inhibitors, that upon saturation, form seeds for HAP deposition and growth. These calcium granulations are similar to those found in organisms throughout nature and may represent the products of more general calcium regulation pathways involved in the control of calcium storage, retrieval, tissue deposition, and disposal

Brecciation at the grain scale within the lithologies of the Winchcombe Mighei-like carbonaceous chondrite

The Mighei‐like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine‐grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse‐grained primary components that are found directly alongside other coarse‐grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

First synthesis of an expanded calixpyrrole

The synthesis of the first expanded calixpyrrole: a calix[5]arene-capped calix[5]pyrrole 2 has been achieved using p-tert-butylcalix[5]arene pentamethyl ketone 1 as a template