CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are ...common in the
gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare 'variants of uncertain significance', which are increasingly detected as more exome and genome sequencing of diverse populations is conducted.
Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, ...and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.
Heavy cold ions at Mars are gravitationally bound to the planet unless some process provides energy to them. Observations show that cold (<20 eV) and dense (∼>1 cm−3) O+/O2+ ions with bulk velocities ...equal to energies ∼1 keV can reach deep into the nightside Martian magnetosheath. These ions are co‐located with a change of the sign of the sunward component of the magnetic field. This magnetic field topology implies the persistence of a localized planetary ions escape channel associated with draped magnetic field lines that are convecting tailward. The observed ion populations propagate approximately in the same direction as surrounding magnetosheath flow and are likely to be almost unheated ionospheric ions from low altitudes. The paper discusses planetary ion energization via Hall electric field originated from ions and electron separation associated with magnetic field curvature.
Plain Language Summary
In‐situ observations above the nightside of Mars show the presence of localized dense planetary ion fluxes at altitudes exceeding 2,000 km and escaping from the planet at high energies, comparable to that of the solar wind. These fluxes are accompanied by the reversal of sunward component of magnetic field. Unlike most atmospheric escape channels, the reported phenomenon is characterized by an increase in heavy to light ions density ratio with the distance from the planet at the observed altitudes up to nearly 5,000 km, as well as an increase in overall plasma number density inside this escape channel relative to the ambient sheath environment. This behavior is consistent with acceleration process initiated by a bent magnetic flux tube.
Key Points
Ions of different species gain similar energies in the Martian magnetosheath by Hall electric fields associated with magnetic curvature
A high concentration of ionospheric ions correlates with a near void of shocked solar wind protons and a magnetic field reversal
Number density at the reversal increases with distance from Mars in comparison to the surrounding sheath at least till two Martian radii
The importance of prior error correlations in data assimilation has long been known; however, observation‐error correlations have typically been neglected. Recent progress has been made in estimating ...and accounting for observation‐error correlations, allowing for the optimal use of denser observations. Given this progress, it is now timely to ask how prior and observation‐error correlations interact and how this affects the value of the observations in the analysis. Addressing this question is essential to understanding the optimal design of future observation networks for high‐resolution numerical weather prediction. This article presents new results, which unify and advance upon previous studies on this topic.
The interaction of the prior and observation‐error correlations is illustrated with a series of two‐variable experiments in which the mapping between the state and observed variables (the observation operator) is allowed to vary. In an optimal system, the reduction in the analysis‐error variance and spread of information is shown to be greatest when the observation and prior errors have complementary statistics: for example, in the case of direct observations, when the correlations between the observation and prior errors have opposite signs. This can be explained in terms of the relative uncertainty of the observations and prior on different spatial scales. The results from these simple two‐variable experiments are used to inform the optimal observation density for observations of a circular domain (with 32 grid points). It is found that dense observations are most beneficial when they provide a more accurate estimate of the state at smaller scales than the prior estimate. In the case of second‐order auto‐regressive correlation functions, this is achieved when the length‐scales of the observation‐error correlations are greater than those of the prior estimate and the observations are direct measurements of the state variables.
This article addresses the question of how prior and observation‐error correlations interact and how this affects the value of the observations in the analysis. It is found that the reduction in the analysis‐error variance and spread of information is greatest when the observation and prior errors have complementary statistics. These results are then used to inform the optimal density of observations with correlated errors to provide insight into how future observation networks should be designed in order to meet the needs of high‐resolution numerical weather prediction.
Megakaryocytes (MKs), the precursor cells for platelets, migrate from the endosteal niche of the bone marrow (BM) toward the vasculature, extending proplatelets into sinusoids, where circulating ...blood progressively fragments them into platelets. Nonmuscle myosin IIA (NMIIA) heavy chain gene (MYH9) mutations cause macrothrombocytopenia characterized by fewer platelets with larger sizes leading to clotting disorders termed myosin-9–related disorders (MYH9-RDs). MYH9-RD patient MKs have proplatelets with thicker and fewer branches that produce fewer and larger proplatelets, which is phenocopied in mouse Myh9-RD models. Defective proplatelet formation is considered to be the principal mechanism underlying the macrothrombocytopenia phenotype. However, MYH9-RD patient MKs may have other defects, as NMII interactions with actin filaments regulate physiological processes such as chemotaxis, cell migration, and adhesion. How MYH9-RD mutations affect MK migration and adhesion in BM or NMIIA activity and assembly prior to proplatelet production remain unanswered. NMIIA is the only NMII isoform expressed in mature MKs, permitting exploration of these questions without complicating effects of other NMII isoforms. Using mouse models of MYH9-RD (NMIIAR702C+/−GFP+/−, NMIIAD1424N+/−, and NMIIAE1841K+/−) and in vitro assays, we investigated MK distribution in BM, chemotaxis toward stromal-derived factor 1, NMIIA activity, and bipolar filament assembly. Results indicate that different MYH9-RD mutations suppressed MK migration in the BM without compromising bipolar filament formation but led to divergent adhesion phenotypes and NMIIA contractile activities depending on the mutation. We conclude that MYH9-RD mutations impair MK chemotaxis by multiple mechanisms to disrupt migration toward the vasculature, impairing proplatelet release and causing macrothrombocytopenia.
•MYH9-RD mutations R702C, D1424N, and E1841K impair MK chemotaxis from the endosteum to the vasculature, causing thrombocytopenia.•These mutations suppress chemotaxis via distinct mechanisms, including defective cell adhesion and actomyosin cytoskeleton misalignment.
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Metallo-β-lactamases (MBLs) degrade a broad spectrum of β-lactam antibiotics, and are a major disseminating source for multidrug resistant bacteria. Despite many biochemical studies in diverse MBLs, ...molecular understanding of the roles of residues in the enzyme's stability and function, and especially substrate specificity, is lacking. Here, we employ deep mutational scanning (DMS) to generate comprehensive single amino acid variant data on a major clinical MBL, VIM-2, by measuring the effect of thousands of VIM-2 mutants on the degradation of three representative classes of β-lactams (ampicillin, cefotaxime, and meropenem) and at two different temperatures (25°C and 37°C). We revealed residues responsible for expression and translocation, and mutations that increase resistance and/or alter substrate specificity. The distribution of specificity-altering mutations unveiled distinct molecular recognition of the three substrates. Moreover, these function-altering mutations are frequently observed among naturally occurring variants, suggesting that the enzymes have continuously evolved to become more potent resistance genes.
Photochemical escape of atomic oxygen is thought to be one of the dominant channels for Martian atmospheric loss today and played a potentially major role in climate evolution. Mars Atmosphere and ...Volatile Evolution Mission (MAVEN) is the first mission capable of measuring, in situ, the relevant quantities necessary to calculate photochemical escape fluxes. We utilize 18 months of data from three MAVEN instruments: Langmuir Probe and Waves, Neutral Gas and Ion Mass Spectrometer, and SupraThermal And Thermal Ion Composition. From these data, we calculate altitude profiles of the production rate of hot oxygen atoms from the dissociative recombination of O2+ and the probability that such atoms will escape the Mars atmosphere. From this, we determine escape fluxes for 815 periapsis passes. Derived average dayside hot O escape rates range from 1.2 to 5.5 × 1025 s−1, depending on season and EUV flux, consistent with several pre‐MAVEN predictions and in broad agreement with estimates made with other MAVEN measurements. Hot O escape fluxes do not vary significantly with dayside solar zenith angle or crustal magnetic field strength but depend on CO2 photoionization frequency with a power law whose exponent is 2.6 ± 0.6, an unexpectedly high value which may be partially due to seasonal and geographic sampling. From this dependence and historical EUV measurements over 70 years, we estimate a modern‐era average escape rate of 4.3 × 1025 s−1. Extrapolating this dependence to early solar system, EUV conditions gives total losses of 13, 49, 189, and 483 mbar of oxygen over 1–3 and 3.5 Gyr, respectively, with uncertainties significantly increasing with time in the past.
Key Points
Photochemical O escape fluxes from dissociative recombination of O2+ are calculated from MAVEN in situ data
Escape rates of 1.2 to 5.5 × 1025 s−1 are derived and depend on season, solar zenith angle, and EUV flux, consistent with previous models
We find a power law exponent of 2.6 for the EUV dependence of escape rate, implying 100 s of mbar of oxygen loss over 3.5 Gyr
The biconcave disk shape of the mammalian red blood cell (RBC) is unique to the RBC and is vital for its circulatory function. Due to the absence of a transcellular cytoskeleton, RBC shape is ...determined by the membrane skeleton, a network of actin filaments cross-linked by spectrin and attached to membrane proteins. While the physical properties of a uniformly distributed actin network interacting with the lipid bilayer membrane have been assumed to control RBC shape, recent experiments reveal that RBC biconcave shape also depends on the contractile activity of nonmuscle myosin IIA (NMIIA) motor proteins. Here, we use the classical Helfrich-Canham model for the RBC membrane to test the role of heterogeneous force distributions along the membrane and mimic the contractile activity of sparsely distributed NMIIA filaments. By incorporating this additional contribution to the Helfrich-Canham energy, we find that the RBC biconcave shape depends on the ratio of forces per unit volume in the dimple and rim regions of the RBC. Experimental measurements of NMIIA densities at the dimple and rim validate our prediction that (a) membrane forces must be non-uniform along the RBC membrane and (b) the force density must be larger in the dimple than the rim to produce the observed membrane curvatures. Furthermore, we predict that RBC membrane tension and the orientation of the applied forces play important roles in regulating this force-shape landscape. Our findings of heterogeneous force distributions on the plasma membrane for RBC shape maintenance may also have implications for shape maintenance in different cell types.
We utilize suprathermal ion and magnetic field measurements from the Mars Atmosphere and Volatile EvolutioN (MAVEN) mission, organized by the upstream magnetic field, to investigate the morphology ...and variability of flows, fields, and forces in the Mars‐solar wind interaction. We employ a combination of case studies and statistical investigations to characterize the interaction in both quasi‐parallel and quasi‐perpendicular regions and under high and low solar wind Mach number conditions. For the first time, we include a detailed investigation of suprathermal ion temperature and anisotropy. We find that the observed magnetic fields and suprathermal ion moments in the magnetosheath, bow shock, and upstream regions have observable asymmetries controlled by the interplanetary magnetic field, with particularly large asymmetries found in the ion parallel temperature and anisotropy. The greatest temperature anisotropies occur in quasi‐perpendicular regions of the magnetosheath and under low Mach number conditions. These results have implications for the growth and evolution of wave‐particle instabilities and their role in energy transport and dissipation. We utilize the measured parameters to estimate the average ion pressure gradient, J × B, and v × B macroscopic force terms. The pressure gradient force maintains nearly cylindrical symmetry, while the J × B force has larger asymmetries and varies in magnitude in comparison to the pressure gradient force. The v × B force felt by newly produced planetary ions exceeds the other forces in magnitude in the magnetosheath and upstream regions for all solar wind conditions.
Key Points
MAVEN measures the global distribution of suprathermal ions and magnetic fields around Mars, from which we can derive macroscopic forces
The flows, fields, and forces in the Mars‐solar wind interaction vary with both upstream magnetic field orientation and Mach number
Ion temperature and temperature anisotropy vary spatially and with solar wind parameters, with implications for plasma instabilities
Plain Language Summary
The solar wind that flows out from the Sun and pervades our solar system is largely deflected around Mars by its interaction with the upper atmosphere. However, this interaction also transfers energy to planetary ions, giving some of them sufficient velocity to escape from Mars. Therefore, the Mars‐solar wind interaction has implications for the long‐term evolution of the Martian atmosphere and its habitability. In this work, we study the structure and variability of the interaction and the macroscopic forces responsible for decelerating and deflecting the solar wind around Mars as well as those that accelerate planetary ions. We also investigate the asymmetries in this interaction and how they change in response to variations in the incoming solar wind flow and the magnetic field carried with the flow.
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•Design of a LIB pack with 3 LiFePO4 prismatic batteries arranged in series with 4 mini channels cooling plates.•Experiments of the pack under distinctive currents and different ...ambient temperatures.•Examination of LIB cells/pack with respect to the temperature and voltage profile.•Buildup of a modified polynomial model and approval with testing information.
Li-ion batteries (LIBs) are found to be deep spots in the Electric Vehicles (EVs) as well as Hybrid Electric Vehicles (HEVs) application. Combination of such high capacity LIBs in large serial-parallel configurations have been wrapped up with serious problems such as safety, durability, cost, and uniformity, which are imposing limitations on this broad application. A narrow area of these limitations, in which LIBs should operate safely and reliably, is the essential requirement of an effective control-thermal management scenario. In this paper, we examined the heat and mass transfer (temperature and mass flow rate of water) field as well as voltage profiles for a 20 Ah Graphite/LiFePO4 LIB pack at low currents of 20 A (1 C) and 40 A (2 C) with the selected ambient conditions using unique water-cooling methods with 35 °C, 25 °C, 15 °C, and 5 °C. This gives significant data information for the thermal behavior of LIB packs to design the temperature control (or thermal management) systems and develop an empirical voltage-thermal estimation model. In such manner, 3 prismatic LIBs with 20 Ah nominal capacity are arranged in a series with 4 micro-channel cooling plates placed within cells. There are six evenly placed thermocouples on the surface of each of these 3 battery cells used to extract time dependent temperatures. To make the data compatible for EV/HEV application, we developed a modified exponential-polynomial equivalent circuit model to simulate the temperature and voltage field. Outputs of the simulations are compared with the test data with specified C-rates and ambient conditions. The results demonstrate that increasing discharge currents and ambient conditions result in an increased surface temperature at 3 spots; close to the −ve electrode, close to the +ve electrode, and near the middle part of the LIB cell.
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