314 research outputs found
Developments and Further Applications of Ephemeral Data Derived Potentials
Machine-learned interatomic potentials are fast becoming an indispensable
tool in computational materials science. One approach is the ephemeral
data-derived potential (EDDP), which was designed to accelerate atomistic
structure prediction. The EDDP is simple and cost-efficient. It relies on
training data generated in small unit cells and is fit using a lightweight
neural network, leading to smooth interactions which exhibit the robust
transferability essential for structure prediction. Here, we present a variety
of applications of EDDPs, enabled by recent developments of the open-source
EDDP software. New features include interfaces to phonon and molecular dynamics
codes, as well as deployment of the ensemble deviation for estimating the
confidence in EDDP predictions. Through case studies ranging from elemental
carbon and lead to the binary scandium hydride and the ternary zinc cyanide, we
demonstrate that EDDPs can be trained to cover wide ranges of pressures and
stoichiometries, and used to evaluate phonons, phase diagrams, superionicity,
and thermal expansion. These developments complement continued success in
accelerated structure prediction.Comment: 22 pages, 15 figure
MACE-OFF23: Transferable Machine Learning Force Fields for Organic Molecules
Classical empirical force fields have dominated biomolecular simulation for
over 50 years. Although widely used in drug discovery, crystal structure
prediction, and biomolecular dynamics, they generally lack the accuracy and
transferability required for predictive modelling. In this paper, we introduce
MACE-OFF23, a transferable force field for organic molecules created using
state-of-the-art machine learning technology and first-principles reference
data computed with a high level of quantum mechanical theory. MACE-OFF23
demonstrates the remarkable capabilities of local, short-range models by
accurately predicting a wide variety of gas and condensed phase properties of
molecular systems. It produces accurate, easy-to-converge dihedral torsion
scans of unseen molecules, as well as reliable descriptions of molecular
crystals and liquids, including quantum nuclear effects. We further demonstrate
the capabilities of MACE-OFF23 by determining free energy surfaces in explicit
solvent, as well as the folding dynamics of peptides. Finally, we simulate a
fully solvated small protein, observing accurate secondary structure and
vibrational spectrum. These developments enable first-principles simulations of
molecular systems for the broader chemistry community at high accuracy and low
computational cost
Generation of cloned transgenic pigs rich in omega-3 fatty acids
Meat products are generally low in omega-3 (n-3) fatty acids, which are beneficial to human health. We describe the generation of cloned pigs that express a humanized Caenorhabditis elegans gene, fat-1, encoding an n-3 fatty acid desaturase. The hfat-1 transgenic pigs produce high levels of n-3 fatty acids from n-6 analogs, and their tissues have a significantly reduced ratio of n-6/n-3 fatty acids (P < 0.001). © 2006 Nature Publishing Group
Bordetella pertussis Whole Cell Immunization, Unlike Acellular Immunization, Mimics Naïve Infection by Driving Hematopoietic Stem and Progenitor Cell Expansion in Mice
Hematopoietic stem and progenitor cell (HSPC) compartments are altered to direct immune responses to infection. Their roles during immunization are not well-described. To elucidate mechanisms for waning immunity following immunization with acellular vaccines (ACVs) against Bordetella pertussis (Bp), we tested the hypothesis that immunization with Bp ACVs and whole cell vaccines (WCVs) differ in directing the HSPC characteristics and immune cell development patterns that ultimately contribute to the types and quantities of cells produced to fight infection. Our data demonstrate that compared to control and ACV-immunized CD-1 mice, immunization with an efficacious WCV drives expansion of hematopoietic multipotent progenitor cells (MPPs), increases circulating white blood cells (WBCs), and alters the size and composition of lymphoid organs. In addition to MPPs, common lymphoid progenitor (CLP) proportions increase in the bone marrow of WCV-immunized mice, while B220+ cell proportions decrease. Upon subsequent infection, increases in maturing B cell populations are striking in WCV-immunized mice. RNAseq analyses of HSPCs revealed that WCV and ACV-immunized mice vastly differ in developing VDJ gene segment diversity. Moreover, gene set enrichment analyses demonstrate WCV-immunized mice exhibit unique gene signatures that suggest roles for interferon (IFN) induced gene expression. Also observed in naïve infection, these IFN stimulated gene (ISG) signatures point toward roles in cell survival, cell cycle, autophagy, and antigen processing and presentation. Taken together, these findings underscore the impact of vaccine antigen and adjuvant content on skewing and/or priming HSPC populations for immune response
ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene.
OBJECTIVES: We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients.
BACKGROUND: CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction.
METHODS: In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1 using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription-polymerase chain reaction.
RESULTS: Three missense heterozygous ANKRD1 mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP.
CONCLUSIONS: ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling
Intranasal Acellular Pertussis Vaccine Provides Mucosal Immunity and Protects Mice from Bordetella Pertussis
Current acellular pertussis vaccines fall short of optimal protection against the human respiratory pathogen Bordetella pertussis resulting in increased incidence of a previously controlled vaccine- preventable disease. Natural infection is known to induce a protective mucosal immunity. Therefore, in this study, we aimed to use acellular pertussis vaccines to recapitulate these mucosal immune responses. We utilized a murine immunization and challenge model to characterize the efficacy of intranasal immunization (IN) with DTaP vaccine or DTaP vaccine supplemented with curdlan, a known Th1/Th17 promoting adjuvant. Protection from IN delivered DTaP was compared to protection mediated by intraperitoneal injection of DTaP and whole-cell pertussis vaccines. We tracked fluorescently labeled DTaP after immunization and detected that DTaP localized preferentially in the lungs while DTaP with curdlan was predominantly in the nasal turbinates. IN immunization with DTaP, with or without curdlan adjuvant, resulted in anti-B. pertussis and anti-pertussis toxin IgG titers at the same level as intraperitoneally administered DTaP. IN immunization was able to protect against B. pertussis challenge and we observed decreased pulmonary pro-inflammatory cytokines, neutrophil infiltrates in the lung, and bacterial burden in the upper and lower respiratory tract at day 3 post challenge. Furthermore, IN immunization with DTaP triggered mucosal immune responses such as production of B. pertussis-specific IgA, and increased IL-17A. Together, the induction of a mucosal immune response and humoral antibody-mediated protection associated with an IN administered DTaP and curdlan adjuvant warrant further exploration as a pertussis vaccine candidate formulation
Design, Qualification, and On Orbit Performance of the CALIPSO Aerosol Lidar Transmitter
The laser transmitter for the CALIPSO aerosol lidar mission has been operating on orbit as planned since June 2006. This document discusses the optical and laser system design and qualification process that led to this success. Space-qualifiable laser design guidelines included the use of mature laser technologies, the use of alignment sensitive resonator designs, the development and practice of stringent contamination control procedures, the operation of all optical components at appropriately derated levels, and the proper budgeting for the space-qualification of the electronics and software
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