Crystal Structures of PF-06438179/GP1111, an Infliximab Biosimilar
Abstract not provided
Lerch, Thomas F.↗
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Results for “PENELOPE”
Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.
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Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs
Not Available
Cell Biology↗
Prenatal exposure to mixtures of persistent endocrine disrupting chemicals and postnatal body size in British girls
Endocrine disrupting chemical (EDC) exposure is ubiquitous. EDC exposure during critical windows of development may interfere with the body's endocrine system, affecting growth. Previous human studies have examined one EDC at a time in relation to infant growth. By studying mixtures, the human experience can be better approximated. We investigated the association of prenatal exposure to persistent EDCs (per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs)) as mixtures with postnatal body size among female offspring. We used a sub-sample of the Avon Longitudinal Study of Parents and Children (N = 425), based in the United Kingdom. We quantified 52 EDCs in maternal serum collected during pregnancy. We used Bayesian kernel machine regression with a random intercept to examine the association of prenatal concentrations of EDC mixtures with longitudinal postnatal body size measures for each EDC class separately (PFAS, PCBs, and OCPs) and for all three classes combined. Weight and height measures at 0, 2, 9, and 19 months were obtained by health professionals as part of routine child health surveillance. The mixture representing all three classes combined (31 chemicals) (n = 301) was inversely associated with postnatal body size. Holding all EDCs in the 31-chemical mixture at the 75th percentile compared to the 50th percentile was associated with 0.15 lower weight-for-age z-score (95% credible interval –0.26, –0.03). Weak inverse associations were also seen for height-for-age and body mass index-for-age scores. Furthermore, these results suggest that prenatal exposure to mixtures of persistent EDCs may affect postnatal body size.
59 BASIC BIOLOGICAL SCIENCES↗
Formation, cooling history and age of impact events on the IIE iron parent body: Evidence from the Miles meteorite
Most iron meteorites formed in planetary cores during differentiation, but the IIE iron meteorites have chemical and physical features that are inconsistent with this origin. By combining mineral chemistry, mineral modes and three-dimensional petrography, we reconstruct the bulk chemistry of the felsic silicate-bearing Miles IIE iron meteorite and demonstrate that the silicate inclusion compositions are similar to partial melts produced experimentally from an H chondrite composition. We use the reconstructed bulk composition, mineralogy and thermodynamic modelling to show that melting above ~ 1200°C under reducing conditions formed metal (Fe-Ni alloy) and felsic silicate partial melts. Upon cooling, the melts crystallized Mg-rich pyroxenes, Na- and K-rich feldspars, and tridymite. Importantly, this mechanism enriches cosmochemically volatile elements (i.e., those with a 50% condensation temperature of ~430–830°C, like Na and K) to the level found in the felsic silicate inclusions. The presence of crystallographically disordered srilankite (only stable above 1160°C) and an absence of Widmanstätten texture require both high peak temperatures and rapid cooling, which cannot be explained by core formation. Instead, they point to small melt volumes, a transient heat pulse, and small thermal mass, and imply efficient physical segregation of silicate and metallic melts through buoyancy separation followed by rapid cooling that arrested the separation of metal and silicate liquid phases. In situ 207 Pb/ 206 Pb age of 4542.3 ± 4.0 Ma in Zr-oxide and phosphate minerals dates the melting event that formed the silicate inclusions. This age aligns with the earliest ages found in other IIE iron meteorite silicates and requires a heating event ~25 million years after the solar system formed. We found 39 Ar/ 40 Ar ages of 3495 ± 52 Ma (low-T) and 4303 ± 7 Ma (high-T) in a K-feldspar grain, with the 3495 Ma age aligning with later thermal events recorded in other IIE iron meteorites. Dating reveals the complex petrogenetic and thermal history of Miles and the IIE iron meteorites. This is the first IIE iron meteorite found to record evidence of heating at 4.5 and 3.5 Ga likely from impact events. We propose that high-velocity impact(s) into an iron-rich, porous chondritic parent body at ~4.54 Ga produced immiscible metal and silicate melts that cooled rapidly and trapped low density silicate inclusions within high density metal. Other IIE irons that formed at lower peak temperatures (900–1000°C) contain chondritic silicate inclusions and relict chondrules, supporting this conceptual model. In conclusion, this petrogenesis is consistent with thermodynamic modelling, experimental data and the wide range of peak temperatures and cooling rates observed in the IIE iron meteorites.
58 GEOSCIENCES↗
An interlaboratory comparison of mid-infrared spectra acquisition: Instruments and procedures matter
Diffuse reflectance spectroscopy has been extensively employed to deliver timely and cost-effective predictions of a number of soil properties. However, although several soil spectral laboratories have been established worldwide, the distinct characteristics of instruments and operations still hamper further integration and interoperability across mid-infrared (MIR) soil spectral libraries. In this study, we conducted a large-scale ring trial experiment to understand the lab-to-lab variability of multiple MIR instruments. By developing a systematic evaluation of different mathematical treatments with modeling algorithms, including regular preprocessing and spectral standardization, we quantified and evaluated instruments' dissimilarity and how this impacts internal and shared model performance. We found that all instruments delivered good predictions when calibrated internally using the same instruments' characteristics and standard operating procedures by solely relying on regular spectral preprocessing that accounts for light scattering and multiplicative/additive effects, e.g., using standard normal variate (SNV). When performing model transfer from a large public library (the USDA NSSCKSSL MIR library) to secondary instruments, good performance was also achieved by regular preprocessing (e. g., SNV) if both instruments shared the same manufacturer. However, significant differences between the KSSL MIR library and contrasting ring trial instruments responses were evident and confirmed by a semi-unsupervised spectral clustering. For heavily contrasting setups, spectral standardization was necessary before transferring prediction models. Non-linear model types like Cubist and memory-based learning delivered more precise estimates because they seemed to be less sensitive to spectral variations than global partial least square regression. In summary, the results from this study can assist new laboratories in building spectroscopy capacity utilizing existing MIR spectral libraries and support the recent global efforts to make soil spectroscopy universally accessible with centralized or shared operating procedures.
58 GEOSCIENCES↗
What are mycorrhizal traits?
Traits are inherent properties of organisms, but how are they defined for organismal networks such as mycorrhizal symbioses? Mycorrhizal symbioses are complex and diverse belowground symbioses between plants and fungi that have proved challenging to fit into a unified and coherent trait framework. Here we propose an inclusive mycorrhizal trait framework that classifies traits as morphological, physiological, and phenological features that have functional implications for the symbiosis. We further classify mycorrhizal traits by location – plant, fungus, or the symbiosis – which highlights new questions in trait-based mycorrhizal ecology designed to charge and challenge the scientific community. This new framework is an opportunity for researchers to interrogate their data to identify novel insights and gaps in our understanding of mycorrhizal symbioses.
59 BASIC BIOLOGICAL SCIENCES↗
Astrovirology: how viruses enhance our understanding of life in the Universe
Abstract Viruses are the most numerically abundant biological entities on Earth. As ubiquitous replicators of molecular information and agents of community change, viruses have potent effects on the life on Earth, and may play a critical role in human spaceflight, for life-detection missions to other planetary bodies and planetary protection. However, major knowledge gaps constrain our understanding of the Earth's virosphere: (1) the role viruses play in biogeochemical cycles, (2) the origin(s) of viruses and (3) the involvement of viruses in the evolution, distribution and persistence of life. As viruses are the only replicators that span all known types of nucleic acids, an expanded experimental and theoretical toolbox built for Earth's viruses will be pivotal for detecting and understanding life on Earth and beyond. Only by filling in these knowledge and technical gaps we will obtain an inclusive assessment of how to distinguish and detect life on other planetary surfaces. Meanwhile, space exploration requires life-support systems for the needs of humans, plants and their microbial inhabitants. Viral effects on microbes and plants are essential for Earth's biosphere and human health, but virus–host interactions in spaceflight are poorly understood. Viral relationships with their hosts respond to environmental changes in complex ways which are difficult to predict by extrapolating from Earth-based proxies. These relationships should be studied in space to fully understand how spaceflight will modulate viral impacts on human health and life-support systems, including microbiomes. In this review, we address key questions that must be examined to incorporate viruses into Earth system models, life-support systems and life detection. Tackling these questions will benefit our efforts to develop planetary protection protocols and further our understanding of viruses in astrobiology.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Computationally restoring the potency of a clinical antibody against Omicron
The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs and revealed how quickly viral escape can curtail effective options. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.
60 APPLIED LIFE SCIENCES↗
Nanocomposite liposomes for pH-controlled porphyrin release into human prostate cancer cells
Nanocomposite liposomes are relatively stable in weak basic solutions but effectively release porphyrins at acidic pH, as indicated by the difference in fluorescence.
60 APPLIED LIFE SCIENCES↗
Development of a Versatile, Full-featured Search Functionality for Indico
Indico, CERN’s popular open-source tool for event management, is in widespread use among facilities that make up the HEP community. It is extensible through a robust plugin architecture that provides features such as search and video conferencing integration. In 2018, Indico version 2 was released with many notable improvements, but without a full-featured search functionality that could be implemented easily outside of CERN. At both Fermi and Brookhaven National Laboratories, the user community viewed the lack of this popular feature as a significant impediment to deployment of the new software. In the meantime, CERN embarked upon a major redesign of their core search service, one that would also necessitate a rewrite of the Indico search interface. Seeing this pressing need, the two US labs decided to collaborate, with assistance from the CERN development team, on a project to develop the requisite search functionality for the larger user community. The resulting design exploits the simplified schema defined in the new CERN Search micro-service, based on Invenio and Elasticsearch, while still providing a flexible path to implementation for alternative backend search services. It is intended to provide a software package that can be installed easily and used out of the box, by anyone at any site. This paper will discuss the design choices and architectural challenges, and provide an overview of the deployment and use of these new plugins.
Constanta, Penelope↗
The Gene Ontology resource: enriching a GOld mine
The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles annotated. As the project matures, we continue our efforts to review older annotations in light of newer findings, and, to maintain consistency with other ontologies. As a result, 20,000 annotations derived from experimental data were reviewed, corresponding to 2.5% of experimental GO annotations. The website (http://geneontology.org) was redesigned for quick access to documentation, downloads and tools. To maintain an accurate resource and support traceability and reproducibility, we have made available a historical archive covering the past 15 years of GO data with a consistent format and file structure for both the ontology and annotations.
59 BASIC BIOLOGICAL SCIENCES↗
Status and Challenges in the MQXFB Nb 3 Sn Quadrupoles for the HL-LHC
The inner triplet (or low-β) quadrupole magnets are among the components to be upgraded in LHC interaction regions for the HL-LHC project. The new quadrupole magnets, called MQXF, are based on Nb 3 Sn superconducting magnet technology, with a conductor peak field of 11.3 T. CERN is in charge of the fabrication of the MQXFB variant, the longest Nb 3 Sn accelerator magnets designed and manufactured up to now, with a magnetic length of 7.2 m. Two magnets, MQXFBP3 and MQXFB02, reached the HL-LHC project requirements. However, they still exhibited a limitation at 4.5 K with a phenomenology similar to the one observed on the first two prototypes. After improvements on the cold mass (longitudinal welding) and magnet assembly (elimination of overstress on the conductor during loading) procedures, a series of modifications were implemented in MQXFB03 at the level of the coil fabrication to address and/or reduce weaknesses in the coils. The magnet was tested and was the first to achieve performance requirements at both 1.9 K and 4.5 K, with no signs of conductor limitation at 4.5 K. MQXFB is now in the series production phase, with around 2/3 of the coils completed and half of the magnets assembled. We provide in this paper an overview of the MQXFB program, with a summary of the main recent achievements and an overall status of the fabrication.
43 PARTICLE ACCELERATORS↗
Diversity and Composition of Methanotroph Communities in Caves
Recent observations have shown the atmospheric greenhouse gas methane (CH 4 ) is consumed by microorganisms (methanotrophs) in caves at rates comparable to CH 4 oxidation in surface soils. Caves are abundant in karst landscapes that comprise 14% of Earth’s land surface area, and therefore may represent a potentially important, but overlooked, CH 4 sink.
59 BASIC BIOLOGICAL SCIENCES↗
Policy-relevant differences between secondhand and thirdhand smoke: strengthening protections from involuntary exposure to tobacco smoke pollutants
Starting in the 1970s, individuals, businesses and the public have increasingly benefited from policies prohibiting smoking indoors, saving thousands of lives and billions of dollars in healthcare expenditures. Smokefree policies to protect against secondhand smoke exposure, however, do not fully protect the public from the persistent and toxic chemical residues from tobacco smoke (also known as thirdhand smoke) that linger in indoor environments for years after smoking stops. Nor do these policies address the economic costs that individuals, businesses and the public bear in their attempts to remediate this toxic residue. We discuss policy-relevant differences between secondhand smoke and thirdhand smoke exposure: persistent pollutant reservoirs, pollutant transport, routes of exposure, the time gap between initial cause and effect, and remediation and disposal. We examine four policy considerations to better protect the public from involuntary exposure to tobacco smoke pollutants from all sources. We call for (a) redefining smokefree as free of tobacco smoke pollutants from secondhandandthirdhand smoke; (b) eliminating exemptions to comprehensive smoking bans; (c) identifying indoor environments with significant thirdhand smoke reservoirs; and (d) remediating thirdhand smoke. We use the case of California as an example of how secondhand smoke-protective laws may be strengthened to encompass thirdhand smoke protections. The health risks and economic costs of thirdhand smoke require that smokefree policies, environmental protections, real estate and rental disclosure policies, tenant protections, and consumer protection laws be strengthened to ensure that the public is fully protected from and informed about the risks of thirdhand smoke exposure.
Public, Environmental & Occupational Health↗
Subtropical Jet in Reanalysis Data from STJ_PV
Subtropical jet position from a new method for locating the subtropical jet, called the tropopause gradient method. It is based on the peak gradient in potential temperature along the dynamic tropopause. This data has the identified subtropical jet latitude, level, and intensity across four different reanalysis products (CFSR-2, ERA-Interim, JRA-55, and MERRA-2), at both daily and monthly output frequency.
58 GEOSCIENCES↗
Status of MQXFB Quadrupole Magnets for HL-LHC
The MQXFB magnets are superconducting quadrupoles with nominal peak field on the conductor of 11.3 T. With their magnetic length of 7.2 m, they stand as the longest Nb3Sn accelerator magnets designed and manufactured up to now. Together with the companion MQXFA 4.2 m long units, built by the US Accelerator Research Program, they are at the heart of HL-LHC, as they shall replace the inner triplet quadrupoles at either side of the ATLAS and CMS interaction regions of the LHC. This technology has benefited from many years of development, and this specific design was validated with successful short models (MQXFS, 1.2 m long). More recently, several MQXFA magnets were shown to satisfy HL-LHC requirements. In this paper, we report on the cold test results of four MQXFB magnets, focusing on performance, training, behavior after thermal and powering cycles, and field quality. We then provide an update of the overall status, including ongoing verifications of design changes at the level of the coil fabrication.
43 PARTICLE ACCELERATORS↗
Islands Within Islands: Bacterial Phylogenetic Structure and Consortia in Hawaiian Lava Caves and Fumaroles
Lava caves, tubes, and fumaroles in Hawai‘i present a range of volcanic, oligotrophic environments from different lava flows and host unexpectedly high levels of bacterial diversity. These features provide an opportunity to study the ecological drivers that structure bacterial community diversity and assemblies in volcanic ecosystems and compare the older, more stable environments of lava tubes, to the more variable and extreme conditions of younger, geothermally active caves and fumaroles. Using 16S rRNA amplicon-based sequencing methods, we investigated the phylogenetic distinctness and diversity and identified microbial interactions and consortia through co-occurrence networks in 70 samples from lava tubes, geothermal lava caves, and fumaroles on the island of Hawai‘i. Our data illustrate that lava caves and geothermal sites harbor unique microbial communities, with very little overlap between caves or sites. We also found that older lava tubes (500–800 yrs old) hosted greater phylogenetic diversity (Faith's PD) than sites that were either geothermally active or younger (<400 yrs old). Geothermally active sites had a greater number of interactions and complexity than lava tubes. Average phylogenetic distinctness, a measure of the phylogenetic relatedness of a community, was higher than would be expected if communities were structured at random. This suggests that bacterial communities of Hawaiian volcanic environments are phylogenetically over-dispersed and that competitive exclusion is the main driver in structuring these communities. This was supported by network analyses that found that taxa (Class level) co-occurred with more distantly related organisms than close relatives, particularly in geothermal sites. Network “hubs” (taxa of potentially higher ecological importance) were not the most abundant taxa in either geothermal sites or lava tubes and were identified as unknown families or genera of the phyla, Chloroflexi and Acidobacteria. These results highlight the need for further study on the ecological role of microbes in caves through targeted culturing methods, metagenomics, and long-read sequence technologies.
59 BASIC BIOLOGICAL SCIENCES↗