Implications of Race Adjustment in Lung-Function Equations.

BACKGROUND: Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified. METHODS: We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K. Biobank, the Multi-Ethnic Study of Atherosclerosis, and the Organ Procurement and Transplantation Network. Using these data, we compared the race-based 2012 Global Lung Function Initiative (GLI-2012) equations with race-neutral equations introduced in 2022 (GLI-Global). Evaluated outcomes included national projections of clinical, occupational, and financial reclassifications; individual lung-allocation scores for transplantation priority; and concordance statistics (C statistics) for clinical prediction tasks. RESULTS: Among the 249 million persons in the United States between 6 and 79 years of age who are able to produce high-quality spirometric results, the use of GLI-Global equations may reclassify ventilatory impairment for 12.5 million persons, medical impairment ratings for 8.16 million, occupational eligibility for 2.28 million, grading of chronic obstructive pulmonary disease for 2.05 million, and military disability compensation for 413,000. These potential changes differed according to race; for example, classifications of nonobstructive ventilatory impairment may change dramatically, increasing 141% (95% confidence interval [CI], 113 to 169) among Black persons and decreasing 69% (95% CI, 63 to 74) among White persons. Annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among White veterans. GLI-2012 and GLI-Global equations had similar discriminative accuracy with regard to respiratory symptoms, health care utilization, new-onset disease, death from any cause, death related to respiratory disease, and death among persons on a transplant waiting list, with differences in C statistics ranging from -0.008 to 0.011. CONCLUSIONS: The use of race-based and race-neutral equations generated similarly accurate predictions of respiratory outcomes but assigned different disease classifications, occupational eligibility, and disability compensation for millions of persons, with effects diverging according to race. (Funded by the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences.).

Discovery of a Transferrin Receptor 1-Binding Aptamer and Its Application in Cancer Cell Depletion for Adoptive T-Cell Therapy Manufacturing.

The clinical manufacturing of chimeric antigen receptor (CAR) T cells includes cell selection, activation, gene transduction, and expansion. While the method of T-cell selection varies across companies, current methods do not actively eliminate the cancer cells in the patient's apheresis product from the healthy immune cells. Alarmingly, it has been found that transduction of a single leukemic B cell with the CAR gene can confer resistance to CAR T-cell therapy and lead to treatment failure. In this study, we report the identification of a novel high-affinity DNA aptamer, termed tJBA8.1, that binds transferrin receptor 1 (TfR1), a receptor broadly upregulated by cancer cells. Using competition assays, high resolution cryo-EM, and de novo model building of the aptamer into the resulting electron density, we reveal that tJBA8.1 shares a binding site on TfR1 with holo-transferrin, the natural ligand of TfR1. We use tJBA8.1 to effectively deplete B lymphoma cells spiked into peripheral blood mononuclear cells with minimal impact on the healthy immune cell composition. Lastly, we present opportunities for affinity improvement of tJBA8.1. As TfR1 expression is broadly upregulated in many cancers, including difficult-to-treat T-cell leukemias and lymphomas, our work provides a facile, universal, and inexpensive approach for comprehensively removing cancerous cells from patient apheresis products for safe manufacturing of adoptive T-cell therapies.

High Frequency of Microvascular Dysfunction in US Outpatient Clinics: A Sign of High Residual Risk? Data from 7,105 Patients.

Previous studies have linked peripheral microvascular dysfunction measured by arterial tonometry to high residual risk in on-statin patients. Digital thermal monitoring (DTM) of microvascular function is a new and simplified technique based on fingertip temperature measurements that has been correlated with the burden of atherosclerosis and its risk factors. Here, we report analyses of DTM data from two large US registries: Registry-I (6,084 cases) and Registry-II (1,021 cases) across 49 US outpatient clinics. DTM tests were performed using a VENDYS device during a 5-minute arm-cuff reactive hyperemia. Fingertip temperature falls during cuff inflation and rebounds after deflation. Adjusted maximum temperature rebound was reported as vascular reactivity index (VRI). VRI distributions were similar in both registries, with mean ± SD of 1.58 ± 0.53 in Registry-I and 1.52 ± 0.43 in Registry-II. In the combined dataset, only 18% had optimal VRI (≥2.0) and 82% were either poor (<1.0) or intermediate (1.0-2.0). Women had slightly higher VRI than men (1.62 ± 0.56 vs. 1.54 ± 0.47, p < 0.001). VRI was inversely but mildly correlated with age (r = -0.19, p < 0.001). Suboptimal VRI was found in 72% of patients <50 years, 82% of 50-70 years, and 86% of ≥70 years. Blood pressure was not correlated with VRI. In this largest registry of peripheral microvascular function measurements, suboptimal scores were highly frequent among on-treatment patients, possibly suggesting a significant residual risk. Prospective studies are warranted to validate microvascular dysfunction as an indicator of residual risk.

Well-Defined Mannosylated Polymer for Peptide Vaccine Delivery with Enhanced Antitumor Immunity.

Peptide-based cancer vaccines offer production and safety advantages but have had limited clinical success due to their intrinsic instability, rapid clearance, and low cellular uptake. Nanoparticle-based delivery vehicles can improve the in vivo stability and cellular uptake of peptide antigens. Here, a well-defined, self-assembling mannosylated polymer is developed for anticancer peptide antigen delivery. The amphiphilic polymer is prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization, and the peptide antigens are conjugated to the pH-sensitive hydrophobic block through the reversible disulfide linkage for selective release after cell entry. The polymer-peptide conjugates self-assemble into sub-100 nm micelles at physiological pH and dissociate at endosomal pH. The mannosylated micellar corona increases the accumulation of vaccine cargoes in the draining inguinal lymph nodes and facilitates nanoparticle uptake by professional antigen presenting cells. In vivo studies demonstrate that the mannosylated micelle formulation improves dendritic cell activation and enhances antigen-specific T cell responses, resulting in higher antitumor immunity in tumor-bearing mice compared to free peptide antigen. The mannosylated polymer is therefore a simple and promising platform for the delivery of peptide cancer vaccines.

Embolic Hypodermic Needle Causing Traumatic Cardiac Tamponade: A Case Report.

We present a unique case of a broken fragment of a hypodermic needle breaking and embolizing to the heart. This needle subsequently penetrated the right ventricle and the patient developed hemopericardium which resulted in cardiac tamponade physiology. DATA SOURCES: None. STUDY SELECTION: None. DATA EXTRACTION: None. DATA SYNTHESIS: Recognizing the potential for unusual and serious complications of IV illicit drug use is an important part of providing effective and timely medical care in this vulnerable population. CONCLUSIONS: An embolic needle phenomenon can have significant sequela, including direct cardiac trauma leading to tamponade and subsequent cardiac collapse. Partnering with the patient to take a detailed history was critical in uncovering the underlying etiology of this patient's cardiogenic shock.

Machine Learning Outperforms ACC / AHA CVD Risk Calculator in MESA.

Background Studies have demonstrated that the current US guidelines based on American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equations Risk Calculator may underestimate risk of atherosclerotic cardiovascular disease ( CVD ) in certain high-risk individuals, therefore missing opportunities for intensive therapy and preventing CVD events. Similarly, the guidelines may overestimate risk in low risk populations resulting in unnecessary statin therapy. We used Machine Learning ( ML ) to tackle this problem. Methods and Results We developed a ML Risk Calculator based on Support Vector Machines ( SVM s) using a 13-year follow up data set from MESA (the Multi-Ethnic Study of Atherosclerosis) of 6459 participants who were atherosclerotic CVD-free at baseline. We provided identical input to both risk calculators and compared their performance. We then used the FLEMENGHO study (the Flemish Study of Environment, Genes and Health Outcomes) to validate the model in an external cohort. ACC / AHA Risk Calculator, based on 7.5% 10-year risk threshold, recommended statin to 46.0%. Despite this high proportion, 23.8% of the 480 "Hard CVD " events occurred in those not recommended statin, resulting in sensitivity 0.76, specificity 0.56, and AUC 0.71. In contrast, ML Risk Calculator recommended only 11.4% to take statin, and only 14.4% of "Hard CVD " events occurred in those not recommended statin, resulting in sensitivity 0.86, specificity 0.95, and AUC 0.92. Similar results were found for prediction of "All CVD " events. Conclusions The ML Risk Calculator outperformed the ACC/AHA Risk Calculator by recommending less drug therapy, yet missing fewer events. Additional studies are underway to validate the ML model in other cohorts and to explore its ability in short-term CVD risk prediction.

Clay mineral diversity and abundance in sedimentary rocks of Gale crater, Mars.

Clay minerals provide indicators of the evolution of aqueous conditions and possible habitats for life on ancient Mars. Analyses by the Mars Science Laboratory rover Curiosity show that ~3.5-billion year (Ga) fluvio-lacustrine mudstones in Gale crater contain up to ~28 weight % (wt %) clay minerals. We demonstrate that the species of clay minerals deduced from x-ray diffraction and evolved gas analysis show a strong paleoenvironmental dependency. While perennial lake mudstones are characterized by Fe-saponite, we find that stratigraphic intervals associated with episodic lake drying contain Al-rich, Fe3+-bearing dioctahedral smectite, with minor (3 wt %) quantities of ferripyrophyllite, interpreted as wind-blown detritus, found in candidate aeolian deposits. Our results suggest that dioctahedral smectite formed via near-surface chemical weathering driven by fluctuations in lake level and atmospheric infiltration, a process leading to the redistribution of nutrients and potentially influencing the cycling of gases that help regulate climate.

Serum Nuclease Susceptibility of mRNA Cargo in Condensed Polyplexes.

Messenger RNA (mRNA) is a biomolecule with a wide range of promising clinical applications. However, the unstable nature of mRNA and its susceptibility to degradation by ribonucleases (RNases) necessitate the use of specialized formulations for delivery. Polycations are an emerging class of synthetic carriers capable of packaging nucleic acids, and may serve as suitable RNase-resistant formulations for mRNA administration. Here, we explore the application of VIPER and sunflower polycations, two polycations previously synthesized by our group, for the delivery of mRNA in comparison to branched poly(ethylenimine); all three polycations have been shown to efficiently deliver plasmid DNA (pDNA) to cultured cells. Despite successful mRNA condensation and packaging, transfection studies reveal that these three polycations can only efficiently deliver mRNA under serum-free conditions, while pDNA delivery is achieved even in the presence of serum. RNase resistance studies confirm that nuclease degradation of mRNA cargo remains a significant barrier to mRNA delivery using these polycations. These results emphasize the need for additional strategies for nuclease protection of mRNA cargo beyond electrostatic complexation with polycation.

New Indices of Endothelial Function Measured by Digital Thermal Monitoring of Vascular Reactivity: Data from 6084 Patients Registry.

Background. Endothelial function is viewed as a barometer of cardiovascular health and plays a central role in vascular reactivity. Several studies showed digital thermal monitoring (DTM) as a simple noninvasive method to measure vascular reactivity that is correlated with atherosclerosis risk factors and coronary artery disease. Objectives. To further evaluate the relations between patient characteristics and DTM indices in a large patient registry. Methods. DTM measures were correlated with age, sex, heart rate, and systolic and diastolic blood pressure in 6084 patients from 18 clinics. Results. DTM vascular reactivity index (VRI) was normally distributed and inversely correlated with age (r = -0.21, p < 0.0001). Thirteen percent of VRI tests were categorized as poor vascular reactivity (VRI < 1.0), 70 percent as intermediate (1.0 ≤ VRI < 2.0), and 17 percent as good (VRI ≥ 2.0). Poor VRI (<1.0) was noted in 6% of <50 y, 10% of 50-70 y, and 18% of ≥70 y. In multiple linear regression analyses, age, sex, and diastolic blood pressure were significant but weak predictors of VRI. Conclusions. As the largest database of finger-based vascular reactivity measurement, this report adds to prior findings that VRI is a meaningful physiological marker and reflects a high level of residual risk found in patients currently under care.

Silicic volcanism on Mars evidenced by tridymite in high-SiO2 sedimentary rock at Gale crater.

Tridymite, a low-pressure, high-temperature (>870 °C) SiO2 polymorph, was detected in a drill sample of laminated mudstone (Buckskin) at Marias Pass in Gale crater, Mars, by the Chemistry and Mineralogy X-ray diffraction instrument onboard the Mars Science Laboratory rover Curiosity The tridymitic mudstone has ∼40 wt.% crystalline and ∼60 wt.% X-ray amorphous material and a bulk composition with ∼74 wt.% SiO2 (Alpha Particle X-Ray Spectrometer analysis). Plagioclase (∼17 wt.% of bulk sample), tridymite (∼14 wt.%), sanidine (∼3 wt.%), cation-deficient magnetite (∼3 wt.%), cristobalite (∼2 wt.%), and anhydrite (∼1 wt.%) are the mudstone crystalline minerals. Amorphous material is silica-rich (∼39 wt.% opal-A and/or high-SiO2 glass and opal-CT), volatile-bearing (16 wt.% mixed cation sulfates, phosphates, and chlorides-perchlorates-chlorates), and has minor TiO2 and Fe2O3T oxides (∼5 wt.%). Rietveld refinement yielded a monoclinic structural model for a well-crystalline tridymite, consistent with high formation temperatures. Terrestrial tridymite is commonly associated with silicic volcanism, and detritus from such volcanism in a "Lake Gale" catchment environment can account for Buckskin's tridymite, cristobalite, feldspar, and any residual high-SiO2 glass. These cogenetic detrital phases are possibly sourced from the Gale crater wall/rim/central peak. Opaline silica could form during diagenesis from high-SiO2 glass, as amorphous precipitated silica, or as a residue of acidic leaching in the sediment source region or at Marias Pass. The amorphous mixed-cation salts and oxides and possibly the crystalline magnetite (otherwise detrital) are primary precipitates and/or their diagenesis products derived from multiple infiltrations of aqueous solutions having variable compositions, temperatures, and acidities. Anhydrite is post lithification fracture/vein fill.

Mineralogy, provenance, and diagenesis of a potassic basaltic sandstone on Mars: CheMin X-ray diffraction of the Windjana sample (Kimberley area, Gale Crater).

The Windjana drill sample, a sandstone of the Dillinger member (Kimberley formation, Gale Crater, Mars), was analyzed by CheMin X-ray diffraction (XRD) in the MSL Curiosity rover. From Rietveld refinements of its XRD pattern, Windjana contains the following: sanidine (21% weight, ~Or95); augite (20%); magnetite (12%); pigeonite; olivine; plagioclase; amorphous and smectitic material (~25%); and percent levels of others including ilmenite, fluorapatite, and bassanite. From mass balance on the Alpha Proton X-ray Spectrometer (APXS) chemical analysis, the amorphous material is Fe rich with nearly no other cations-like ferrihydrite. The Windjana sample shows little alteration and was likely cemented by its magnetite and ferrihydrite. From ChemCam Laser-Induced Breakdown Spectrometer (LIBS) chemical analyses, Windjana is representative of the Dillinger and Mount Remarkable members of the Kimberley formation. LIBS data suggest that the Kimberley sediments include at least three chemical components. The most K-rich targets have 5.6% K2O, ~1.8 times that of Windjana, implying a sediment component with >40% sanidine, e.g., a trachyte. A second component is rich in mafic minerals, with little feldspar (like a shergottite). A third component is richer in plagioclase and in Na2O, and is likely to be basaltic. The K-rich sediment component is consistent with APXS and ChemCam observations of K-rich rocks elsewhere in Gale Crater. The source of this sediment component was likely volcanic. The presence of sediment from many igneous sources, in concert with Curiosity's identifications of other igneous materials (e.g., mugearite), implies that the northern rim of Gale Crater exposes a diverse igneous complex, at least as diverse as that found in similar-age terranes on Earth.

A Chemopreventive Nanodiamond Platform for Oral Cancer Treatment.

Standard oral cancer therapy generally includes a combination of surgery with chemotherapy and/or radiotherapy. This treatment paradigm has not changed in some time. In this paper, we propose a chemopreventive nanodiamond platform for the delivery of celecoxib (Celebrex) to oral cancer lesions. This innovative platform allows for sustained drug release under physiological conditions, potentially enhancing chemopreventive efficacy of celecoxib without the physical and toxicological damage associated with conventional means of drug delivery.

Nanodiamond-Gutta Percha Composite Biomaterials for Root Canal Therapy.

Root canal therapy (RCT) represents a standard of treatment that addresses infected pulp tissue in teeth and protects against future infection. RCT involves removing dental pulp comprising blood vessels and nerve tissue, decontaminating residually infected tissue through biomechanical instrumentation, and root canal obturation using a filler material to replace the space that was previously composed of dental pulp. Gutta percha (GP) is typically used as the filler material, as it is malleable, inert, and biocompatible. While filling the root canal space with GP is the standard of care for endodontic therapies, it has exhibited limitations including leakage, root canal reinfection, and poor mechanical properties. To address these challenges, clinicians have explored the use of alternative root filling materials other than GP. Among the classes of materials that are being explored as novel endodontic therapy platforms, nanodiamonds (NDs) may offer unique advantages due to their favorable properties, particularly for dental applications. These include versatile faceted surface chemistry, biocompatibility, and their role in improving mechanical properties, among others. This study developed a ND-embedded GP (NDGP) that was functionalized with amoxicillin, a broad-spectrum antibiotic commonly used for endodontic infection. Comprehensive materials characterization confirmed improved mechanical properties of NDGP over unmodified GP. In addition, digital radiography and microcomputed tomography imaging demonstrated that obturation of root canals with NDGP could be achieved using clinically relevant techniques. Furthermore, bacterial growth inhibition assays confirmed drug functionality of NDGP functionalized with amoxicillin. This study demonstrates a promising path toward NDGP implementation in future endodontic therapy for improved treatment outcomes.

Nanodiamond-mediated drug delivery and imaging: challenges and opportunities.

INTRODUCTION: The field of nanoparticle-based therapeutic systems is rapidly expanding encompassing a wide variety of practices ranging from detection to diagnosis to treatment. Recently a great potential of nanodiamond (ND) particles as a multimodal imaging/therapy platform has been demonstrated. AREAS COVERED: This review describes a unique set of properties of ND particles attractive for drug delivery and imaging applications and highlights the most recent ND-based multimodal imaging/therapy approaches and related biocompatibility studies. The spectrum of major advancements includes marked improvements in tumor treatment efficacy and safety based on integration of ND with doxorubicin (DOX). Recent progress of ND-mediated drug delivery in orthopedic, dental and ophthalmic applications is also discussed. EXPERT OPINION: ND particles possess a unique set of properties attractive for drug delivery applications, including exceptional biocompatibility, large carrier capacity and versatile surface chemistry properties, which enhance drug binding and provide sustainable drug release. Other unique attributes of NDs embrace bright stable fluorescence based on crystallographic defects. A roadmap toward a clinical translation comprises identification of ND-therapeutic compounds that display marked improvements over clinical standards with respects to efficacy, safety and cost.

The first X-ray diffraction measurements on Mars.

The Mars Science Laboratory landed in Gale crater on Mars in August 2012, and the Curiosity rover then began field studies on its drive toward Mount Sharp, a central peak made of ancient sediments. CheMin is one of ten instruments on or inside the rover, all designed to provide detailed information on the rocks, soils and atmosphere in this region. CheMin is a miniaturized X-ray diffraction/X-ray fluorescence (XRD/XRF) instrument that uses transmission geometry with an energy-discriminating CCD detector. CheMin uses onboard standards for XRD and XRF calibration, and beryl:quartz mixtures constitute the primary XRD standards. Four samples have been analysed by CheMin, namely a soil sample, two samples drilled from mudstones and a sample drilled from a sandstone. Rietveld and full-pattern analysis of the XRD data reveal a complex mineralogy, with contributions from parent igneous rocks, amorphous components and several minerals relating to aqueous alteration. In particular, the mudstone samples all contain one or more phyllosilicates consistent with alteration in liquid water. In addition to quantitative mineralogy, Rietveld refinements also provide unit-cell parameters for the major phases, which can be used to infer the chemical compositions of individual minerals and, by difference, the composition of the amorphous component.

In vitro recombinants of antibiotic-resistant Chlamydia trachomatis strains have statistically more breakpoints than clinical recombinants for the same sequenced loci and exhibit selection at unexpected loci.

Lateral gene transfer (LGT) is essential for generating between-strain genomic recombinants of Chlamydia trachomatis to facilitate the organism's evolution. Because there is no reliable laboratory-based gene transfer system for C. trachomatis, in vitro generation of recombinants from antibiotic-resistant strains is being used to study LGT. However, selection pressures imposed on in vitro recombinants likely affect statistical properties of recombination relative to naturally occurring clinical recombinants, including prevalence at particular loci. We examined multiple loci for 16 in vitro-derived recombinants of ofloxacin- and rifampin-resistant L(1) and D strains, respectively, grown with both antibiotics, and compared these with the same sequenced loci among 11 clinical recombinants. Breakpoints and recombination frequency were examined using phylogenetics, bioinformatics, and statistics. In vitro and clinical isolates clustered perfectly into two groups, without misclassification, using Ward's minimum variance based on breakpoint data. As expected, gyrA (confers ofloxacin resistance) and rpoB (confers rifampin resistance) had significantly more breakpoints among in vitro recombinants than among clinical recombinants (P < 0.0001 and P = 0.02, respectively, using the Wilcoxon rank sum test). Unexpectedly, trpA also had significantly more breakpoints for in vitro recombinants (P < 0.0001). There was also significant selection at other loci. The strongest bias was for ompA in strain D (P = 3.3 × 10(-8)). Our results indicate that the in vitro model differs statistically from natural recombination events. Additional genomic studies are needed to determine the factors responsible for the observed selection biases at unexpected loci and whether these are important for LGT to inform approaches for genetically manipulating C. trachomatis.

Identification of carbonate-rich outcrops on Mars by the Spirit rover.

Decades of speculation about a warmer, wetter Mars climate in the planet's first billion years postulate a denser CO2-rich atmosphere than at present. Such an atmosphere should have led to the formation of outcrops rich in carbonate minerals, for which evidence has been sparse. Using the Mars Exploration Rover Spirit, we have now identified outcrops rich in magnesium-iron carbonate (16 to 34 weight percent) in the Columbia Hills of Gusev crater. Its composition approximates the average composition of the carbonate globules in martian meteorite ALH 84001. The Gusev carbonate probably precipitated from carbonate-bearing solutions under hydrothermal conditions at near-neutral pH in association with volcanic activity during the Noachian era.

Digital thermal monitoring (DTM) of vascular reactivity closely correlates with Doppler flow velocity.

The noninvasive measurement of peripheral vascular reactivity, as an indicator of vascular function, provides a valuable tool for cardiovascular screening of at-risk populations. Practical and economical considerations demand that such a test be low-cost and simple to use. To this end, it is advantageous to substitute digital thermal monitoring (DTM) for the more costly and complex Doppler system commonly used for this measurement. A signal processing model was developed to establish the basis for the relationship between finger temperature reactivity and blood flow reactivity following a transient brachial artery occlusion and reperfusion protocol (reactive hyperemia). Flow velocity signals were acquired from the radial artery of human subjects via an 8 MHz Doppler probe while simultaneous DTM signals were acquired from a distal fingertip via DTM sensors. The model transforms the DTM temperature signals into normalized flow signals via a deconvolution method which employs an exponential impulse function. The DTM normalized flow signals were compared to simultaneous, low-frequency, normalized flow signals computed from Doppler sensors. The normalized flow signals, derived from DTM and Doppler sensors, were found to yield similar reactivity responses during reperfusion. The reactivity areas derived from DTM and Doppler sensors, indicative of hyperemic volumes, were found to be within +/- 15%. In conclusion, this signal processing model provides a means to measure vascular reactivity using DTM sensors, that is equivalent to that obtained by more complex Doppler systems.

The Urey instrument: an advanced in situ organic and oxidant detector for Mars exploration.

The Urey organic and oxidant detector consists of a suite of instruments designed to search for several classes of organic molecules in the martian regolith and ascertain whether these compounds were produced by biotic or abiotic processes using chirality measurements. These experiments will also determine the chemical stability of organic molecules within the host regolith based on the presence and chemical reactivity of surface and atmospheric oxidants. Urey has been selected for the Pasteur payload on the European Space Agency's (ESA's) upcoming 2013 ExoMars rover mission. The diverse and effective capabilities of Urey make it an integral part of the payload and will help to achieve a large portion of the mission's primary scientific objective: "to search for signs of past and present life on Mars." This instrument is named in honor of Harold Urey for his seminal contributions to the fields of cosmochemistry and the origin of life.