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Plant roots navigate in the soil environment following the gravity vector. Cell divisions in the meristem and rapid cell growth in the elongation zone propel the root tips through the soil. Actively elongating cells acidify their apoplast to enable cell wall extension by the activity of plasma membrane AHA H+-ATPases. The phytohormone auxin, central regulator of gravitropic response and root development, inhibits root cell growth, likely by rising the pH of the apoplast. However, the role of auxin in the regulation of the apoplastic pH gradient along the root tip is unclear. Here, we show, by using an improved method for visualization and quantification of root surface pH, that the Arabidopsis thaliana root surface pH shows distinct acidic and alkaline zones, which are not primarily determined by the activity of AHA H+-ATPases. Instead, the distinct domain of alkaline pH in the root transition zone is controlled by a rapid auxin response module, consisting of the AUX1 auxin influx carrier, the AFB1 auxin co-receptor, and the CNCG14 calcium channel. We demonstrate that the rapid auxin response pathway is required for an efficient navigation of the root tip. [ABSTRACT FROM AUTHOR]

Methylation patterns established and maintained at CpG sites may be altered by single nucleotide polymorphisms (SNPs) within these sites and may affect the regulation of nearby genes. Our aims were to: 1) identify and generate a database of SNPs potentially subject to epigenetic control by DNA methylation via their involvement in creating, removing or displacing CpG sites (meSNPs), and; 2) investigate the association of these meSNPs with CpG islands (CGIs), and with methylation profiles of DNA extracted from tissues from cattle with divergent feed efficiencies detected using MIRA-Seq. Using the variant annotation for 56,969,697 SNPs identified in Run5 of the 1000 Bull Genomes Project and the UMD3.1.1 bovine reference genome sequence assembly, we identified and classified 12,836,763 meSNPs according to the nature of variation created at CpGs. The majority of the meSNPs were located in intergenic regions (68%) or introns (26.3%). We found an enrichment (p<0.01) of meSNPs located in CGIs relative to the genome as a whole, and also in differentially methylated sequences in tissues from animals divergent for feed efficiency. Seven meSNPs, located in differentially methylated regions, were fixed for methylation site creating (MSC) or destroying (MSD) alleles in the differentially methylated genomic sequences of animals differing in feed efficiency. These meSNPs may be mechanistically responsible for creating or deleting methylation targets responsible for the differential expression of genes underlying differences in feed efficiency. Our methyl SNP database (dbmeSNP) is useful for identifying potentially functional "epigenetic polymorphisms" underlying variation in bovine phenotypes. [ABSTRACT FROM AUTHOR]

Protein methylation is a very diverse, widespread, and important post-translational modification affecting all aspects of cellular biology in eukaryotes. Methylation on the side-chain of lysine residues in histones has received considerable attention due to its major role in determining chromatin structure and the epigenetic regulation of gene expression. Over the last 20 years, lysine methylation of non-histone proteins has been recognized as a very common modification that contributes to the fine-tuned regulation of protein function. In plants, our knowledge in this field is much more fragmentary than in yeast and animal cells. In this review, we describe the plant enzymes involved in the methylation of non-histone substrates, and we consider historical and recent advances in the identification of non-histone lysine-methylated proteins in photosynthetic organisms. Finally, we discuss our current knowledge about the role of protein lysine methylation in regulating molecular and cellular functions in plants, and consider challenges for future research. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) is an MRI-based technique that delineates white matter tracts in the brain by tracking the diffusion of water in neural tissue. This methodology, known as "tractography", has been extensively applied in clinical neuroscience to explore nervous system architecture and diseases. More recently, tractography has been used to assist with neurosurgical targeting in functional neurosurgery. This review provides an overview of DTI principles, and discusses current applications of tractography for improving and helping develop novel deep brain stimulation (DBS) targets. [ABSTRACT FROM AUTHOR]

The northern elephant seal, Mirounga angustirostris, was heavily hunted and declared extinct in the 19th century. However, a colony remained on remote Guadalupe Island, Mexico and the species has since repopulated most of its historical distribution. Here, we present a comprehensive evaluation of genetic variation in the species. First, we assess the effect of the demographic bottleneck on microsatellite variability and compare it with that found in other pinnipeds, demonstrating levels of variation similar to that in species that continue to be threatened with extinction. Next, we use sequence data from these markers to demonstrate that some of the limited polymorphism predates the bottleneck. However, most contemporary variation appears to have arisen recently and persisted due to exponential growth. We also describe how we use the range in allele size of microsatellites to estimate ancestral effective population size before the bottleneck, demonstrating a large reduction in effective size. We then employ a classical method for bacteria to estimate the microsatellite mutation rate in the species, deriving an estimate that is extremely similar to that estimated for a similar set of loci in humans, indicating consistency of microsatellite mutation rates in mammals. Finally, we find slight significant structure between some geographically separated colonies, although its biological significance is unclear. This work demonstrates that genetic analysis can be useful for evaluating the population biology of the northern elephant seal, in spite of the bottleneck that removed most genetic variation from the species. [ABSTRACT FROM AUTHOR]

We report 1212 radial-velocity (RV) measurements obtained in the years 2009-2013 using an iodine cell for the spectroscopic binary ν Octantis (K1 III/IV). This system (abin ~ 2.6 au, P ~ 1050 d) is conjectured to have a Jovian planet with a semimajor axis half that of the binary host. The extreme geometry only permits long-term stability if the planet is in a retrograde orbit. Whilst the reality of the planet (P ~ 415 d) remains uncertain, other scenarios (stellar variability or apsidal motion caused by a yet unobserved third star) continue to appear substantially less credible based on cross-correlation function bisectors, line-depth ratios and many other independent details. If this evidence is validated but the planet is disproved, the claims of other planets using RVs will be seriously challenged. We also describe a significant revision to the previously published RVs and the full set of 1437 RVs now encompasses nearly 13 yr. The sensitive orbital dynamics allow us to constrain the 3D architecture with a broad prior probability distribution on the mutual inclination, which with posterior samples obtained from an N-body Markov chain Monte Carlo is found to be 152:5±0.70.6. None of these samples are dynamically stable beyond 106 yr. However, a grid search around the best-fitting solution finds a region that has many models stable for 107 yr, and includes one model within 1σ that is stable for at least 108 yr. The planet's exceptional nature demands robust independent verification and makes the theoretical understanding of its formation a worthy challenge. [ABSTRACT FROM AUTHOR]

To overcome the ethical and technical limitations of in vivo human disease models, the broader scientific community frequently employs model organism-derived cell lines to investigate disease mechanisms, pathways, and therapeutic strategies. Despite the widespread use of certain in vitro models, many still lack contemporary genomic analysis supporting their use as a proxy for the affected human cells and tissues. Consequently, it is imperative to determine how accurately and effectively any proposed biological surrogate may reflect the biological processes it is assumed to model. One such cellular surrogate of human disease is the established mouse neural precursor cell line, SN4741, which has been used to elucidate mechanisms of neurotoxicity in Parkinson disease for over 25 years. Here, we are using a combination of classic and contemporary genomic techniques – karyotyping, RT-qPCR, single cell RNA-seq, bulk RNA-seq, and ATAC-seq – to characterize the transcriptional landscape, chromatin landscape, and genomic architecture of this cell line, and evaluate its suitability as a proxy for midbrain dopaminergic neurons in the study of Parkinson disease. We find that SN4741 cells possess an unstable triploidy and consistently exhibits low expression of dopaminergic neuron markers across assays, even when the cell line is shifted to the non-permissive temperature that drives differentiation. The transcriptional signatures of SN4741 cells suggest that they are maintained in an undifferentiated state at the permissive temperature and differentiate into immature neurons at the non-permissive temperature; however, they may not be dopaminergic neuron precursors, as previously suggested. Additionally, the chromatin landscapes of SN4741 cells, in both the differentiated and undifferentiated states, are not concordant with the open chromatin profiles of ex vivo, mouse E15.5 forebrain- or midbrain-derived dopaminergic neurons. Overall, our data suggest that SN4741 cells may reflect early aspects of neuronal differentiation but are likely not a suitable proxy for dopaminergic neurons as previously thought. The implications of this study extend broadly, illuminating the need for robust biological and genomic rationale underpinning the use of in vitro models of molecular processes. [ABSTRACT FROM AUTHOR]

Crystallographic studies of insulin bound to receptor domains have defined the primary hormone-receptor interface. Weinvestigated the role of TyrB26, a conserved aromatic residue at this interface. To probe the evolutionary basis for such conservation, we constructed 18 variants at B26. Surprisingly, nonaromatic polar or charged side chains (such as Glu, Ser, or ornithine (Orn)) conferred high activity, whereas the weakestbinding analogs contained Val, Ile, and Leu substitutions. Modeling of variant complexes suggested that the B26 side chains pack within a shallow depression at the solvent-exposed periphery of the interface. This interface would disfavor large aliphatic side chains. The analogs with highest activity exhibited reduced thermodynamic stability and heightened susceptibility to fibrillation. Perturbed self-assembly was also demonstrated in studies of the charged variants (Orn and Glu); indeed, the GluB26 analog exhibited aberrant aggregation in either the presence or absence of zinc ions. Thus, although TyrB26 is part of insulin's receptor-binding surface, our results suggest that its conservation has been enjoined by the aromatic ring's contributions to native stabilityand self-assembly. We envisage that such classical structural relationships reflect the implicit threat of toxic misfolding (rather than hormonal function at the receptor level) as a general evolutionary determinant of extant protein sequences. [ABSTRACT FROM AUTHOR]

We discuss an on-line tool that facilitates access to the large collection of climate impacts on crop yields produced by the Agricultural Model Intercomparison and Improvement Project. This collection comprises the output of seven crop models which were run on a global grid using climate data from five different general circulation models under the current set of representative pathways. The output of this modeling endeavor consists of more than 36,000 publicly available global grids at a spatial resolution of one half degree. We offer flexible ways to aggregate these data while reducing the technical barriers implied by learning new download platforms and specialized formats. The tool is accessed trough any standard web browser without any special bandwidth requirement. [ABSTRACT FROM AUTHOR]

The effect of administration of nanoliposome encapsulated malunggay (Moringa oleifera) phenolic extract in dogs given cholesterol on body fat and hepatic and renal ultrasonograms was investigated in this study. Six adult male dogs were given cholesterol without (T1) or with non-encapsulated (T2) and nanoliposome encapsulated (T3) malunggay (M. oleifera) phenolic extract. Data on the back fat thickness, body condition score and hepatic and renal ultrasonograms were collected at weeks 0, 1 and 5. Dogs in T3 showed inconsistent changes in the back fat thickness and body condition score. Moreover, T3 dogs exhibited decrease in both hepatic and renal echo mean values. The initial findings suggest that monitoring of the liver and kidney in cases of dyslipidemia or hyperlipidemia should be considered since ultrasonogram results indicate probable development of liver and kidney problems. Further studies are recommended to verify these results. [ABSTRACT FROM AUTHOR]

The hematologic profile and biochemical values in adult dogs given nanoliposome-encapsulated malunggay (Moringa oleifera) phenolic extract were determined in this study. Six adult dogs were divided into three groups: Group A: cholesterol only; Group B: cholesterol with malunggay phenolic extract; and Group C: cholesterol with nanoliposome-encapsulated malunggay phenolic extract, with two dogs per group. Each dog was subjected to a complete blood count at weeks 0, 1 and 5 and serum biochemistry tests at weeks 0 and 5. The results showed that thrombocytopenia and a decrease in the elevated blood urea nitrogen level were observed after administration of the nanoliposome-encapsulated malunggay phenolic extract. It also showed below normal cholesterol and low density lipoprotein levels and within normal triglyceride and high density lipoprotein levels after the experiment. These preliminary findings suggest that nanoliposome-encapsulated malunggay phenolic extract may have an effect on the platelets, kidneys, and lipid profile. However, further studies should be done to verify this association. [ABSTRACT FROM AUTHOR]

Negamycin is a natural product with broad-spectrum antibacterial activity and efficacy in animal models of infection. Although its precise mechanism of action has yet to be delineated, negamycin inhibits cellular protein synthesis and causes cell death. Here, we show that single point mutations within 16S rRNA that confer resistance to negamycin are in close proximity of the tetracycline binding site within helix 34 of the small subunit head domain. As expected from its direct interaction with this region of the ribosome, negamycin was shown to displace tetracycline. However, in contrast to tetracycline-class antibiotics, which serve to prevent cognate tRNA from entering the translating ribosome, single-molecule fluorescence resonance energy transfer investigations revealed that negamycin specifically stabilizes near-cognate ternary complexes within the A site during the normally transient initial selection process to promote miscoding. The crystal structure of the 70S ribosome in complex with negamycin, determined at 3.1 A resolution, sheds light on this finding by showing that negamycin occupies a site that partially overlaps that of tetracycline-class antibiotics. Collectively, these data suggest that the small subunit head domain contributes to the decoding mechanism and that small-molecule binding to this domain may either prevent or promote tRNA entry by altering the initial selection mechanism after codon recognition and before GTPase activation. [ABSTRACT FROM AUTHOR]

Insulin provides a model for the therapeutic application of protein engineering. A paradigm in molecular pharmacology was defined by design of rapid-acting insulin analogs for the prandial control of glycemia. Such analogs, a cornerstone of current diabetes regimens, exhibit accelerated subcutaneous absorption due to more rapid disassembly of oligomeric species relative to wild-type insulin. This strategy is limited by a molecular trade-off between accelerated disassembly and enhanced susceptibility to degradation. Here, we demonstrate that this trade-off may be circumvented by nonstandard mutagenesis. Our studies employed LysB28, ProB29-insulin ("lispro") as a model prandial analog that is less thermodynamically stable and more susceptible to fibrillation than is wild-type insulin. We have discovered that substitution of an invariant tyrosine adjoining the engineered sites in lispro (TyrB26) by 3-iodo-Tyr (i) augments its thermodynamic stability (ΔΔGu 0.5 ±0.2 kcal/ mol), (ii) delays onset of fibrillation (lag time on gentle agitation at 37 °C was prolonged by 4-fold), (iii) enhances affinity for the insulin receptor (1.5 ± 0.1-fold), and (iv) preserves biological activity in a rat model of diabetes mellitus. 1HNMRstudies suggest that the bulky iodo-substituent packs within a nonpolar interchain crevice. Remarkably, the 3-iodo-TyrB26 modification stabilizes an oligomeric form of insulin pertinent to pharmaceutical formulation (the R6 zinc hexamer) but preserves rapid disassembly of the oligomeric form pertinent to subcutaneous absorption (T6 hexamer). By exploiting this allosteric switch, 3-iodo-TyrB26-lispro thus illustrates how a nonstandard amino acid substitution can mitigate the unfavorable biophysical properties of an engineered protein while retaining its advantages. [ABSTRACT FROM AUTHOR]

Proteins targeted to the plasma membrane (PM) of cells are degraded at different rates. Sorting motifs contained within the cytoplasmic domains of transmembrane proteins, post-translational modifications (e.g. ubiquitination), and assembly into multiprotein or protein-lipid complexes all may affect the efficiency of endocytosis and recycling and influence the delivery to degradative compartments. Using the SNAP-tag labeling system, we examined the turnover of a model PM protein, the α chain of the interleukin-2 receptor (Tac). The surface lifetimes of SNAP-Tac fusions were influenced by their mode of entry into cells (clathrin-dependent versus clathrin-independent), their orientation in the PM (transmembrane versus glycosylphosphatidylinositol- anchored), and ubiquitination in their cytosolic domains. In addition, shedding of SNAP-Tac into the medium was greatly influenced by its O-linked glycosylation status. For a number of PM proteins, delivery to lysosomes and ectodomain shedding represent distinct parallel mechanisms to determine protein half-life. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has resulted in a predominantly global quarantine response that has been associated with social isolation, loneliness, and anxiety. The foregoing experiences have been amply documented to have profound impacts on health, morbidity, and mortality. This narrative review uses the extant neurobiological and theoretical literature to explore the association between social isolation, loneliness, and anxiety in the context of quarantine during the COVID-19 pandemic. Emerging evidence suggests that distinct health issues (e.g., a sedentary lifestyle, a diminished overall sense of well-being) are associated with social isolation and loneliness. The health implications of social isolation and loneliness during quarantine have a heterogenous and comorbid nature and, as a result, form a link to anxiety. The limbic system plays a role in fear and anxiety response; the bed nucleus of the stria terminalis, amygdala, HPA axis, hippocampus, prefrontal cortex, insula, and locus coeruleus have an impact in a prolonged anxious state. In the conclusion, possible solutions are considered and remarks are made on future areas of exploration. [ABSTRACT FROM AUTHOR]

Potassium ion (K+) plays a critical role as an essential electrolyte in all biological systems. Genetically encoded fluorescent K+ biosensors are promising tools to further improve our understanding of K+-dependent processes under normal and pathological conditions. Here, we report the crystal structure of a previously reported genetically encoded fluorescent K+ biosensor, GINKO1, in the K+-bound state. Using structure-guided optimization and directed evolution, we have engineered an improved K+ biosensor, designated GINKO2, with higher sensitivity and specificity. We have demonstrated the utility of GINKO2 for in vivo detection and imaging of K+ dynamics in multiple model organisms, including bacteria, plants, and mice. Potassium ions play a critical role as an essential electrolyte in all biological systems. This study describes high performance genetically encoded potassium ion sensors to enable in vivo measurement of potassium ion concentrations across multiple model organisms. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegias (HSPs) are a group of inherited, progressive neurodegenerative conditions characterised by prominent lower-limb spasticity and weakness, caused by a length-dependent degeneration of the longest corticospinal upper motor neurons. While more than 80 spastic paraplegia genes (SPGs) have been identified, many cases arise from mutations in genes encoding proteins which generate and maintain tubular endoplasmic reticulum (ER) membrane organisation. The ER-shaping proteins are essential for the health and survival of long motor neurons, however the mechanisms by which mutations in these genes cause the axonopathy observed in HSP have not been elucidated. To further develop our understanding of the ER-shaping proteins, this study outlines the generation of novel in vivo and in vitro models, using CRISPR/Cas9-mediated gene editing to knockout the ER-shaping protein ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1), mutations in which give rise to the HSP subtype SPG61. Loss of Arl6IP1 in Drosophila results in progressive locomotor deficits, emulating a key aspect of HSP in patients. ARL6IP1 interacts with ER-shaping proteins and is required for regulating the organisation of ER tubules, particularly within long motor neuron axons. Unexpectedly, we identified physical and functional interactions between ARL6IP1 and the phospholipid transporter oxysterol-binding protein-related protein 8 in both human and Drosophila model systems, pointing to a conserved role for ARL6IP1 in lipid homeostasis. Furthermore, loss of Arl6IP1 from Drosophila neurons results in a cell non-autonomous accumulation of lipid droplets in axonal glia. Importantly, treatment with lipid regulating liver X receptor-agonists blocked lipid droplet accumulation, restored axonal ER organisation, and improved locomotor function in Arl6IP1 knockout Drosophila. Our findings indicate that disrupted lipid homeostasis contributes to neurodegeneration in HSP, identifying a potential novel therapeutic avenue for the treatment of this disorder. [ABSTRACT FROM AUTHOR]

Corneal ectasia is a complication of refractive surgery, and keratoconus is a contraindication to this type of procedure. Surface ablation may be an option for selected cases of mild keratoconus, with patient education being fundamental to this treatment as well as a complete evaluation of the cornea and optical properties of the patient. Here we report the clinical outcome of a patient 15 years after advanced surface ablation in a case of mild (fruste) keratoconus. [ABSTRACT FROM AUTHOR]

Conventional sintering techniques of yttria‐tetragonal zirconia polycrystals (Y‐TZP) ceramics have presented limitations regarding the sintering time and temperature, increasing the cost of the final dental and biomedical products. Herein, microwave sintering comes to be an interesting alternative by providing fast heating, high densification, and grain‐size control. The aim of this study was to compare the effect of microwave sintering of Y‐TZP dental ceramics prepared from a pre‐sintered commercial block and produced from powders synthesized in a laboratorial scale by the precipitation route. The synthetized and commercial discs were submitted to microwave sintering at 1450°C and 1350°C for 15, 30, and 60 minutes. Densification, fracture toughness, grain size, and crystalline phase quantification of the sintered groups were evaluated. Both synthetized and commercial groups sintered at 1450°C for 15 and 30 minutes showed the higher densification results (98% TD). XRD quantitative phase analysis indicates that samples present 89% tetragonal and 11% cubic phases, except for the group prepared from coprecipitated powders sintered at 1450°C for 30 minutes, that presented 79% and 21% of tetragonal and cubic phases. The microwave sintering at 1450°C allows hardness and fracture toughness values comparable to conventional sintering. [ABSTRACT FROM AUTHOR]

The article discusses a report on ribosome structures and how drugs affect ribosome activity. Topics include the ribosome apparatus, the role of the glutarimide compounds cycloheximide and lactimidomycin that counter tumour proliferation and techniques like X-ray crystallography and cryoelectron microscopy (cryoEM). An image depicting the binding sites of protein-translation inhibitors in the yeast ribosome is also presented.

Thermal degradation of insulin complicates its delivery and use. Previous efforts to engineer ultra-stable analogs were confounded by prolonged cellular signaling in vivo, of unclear safety and complicating mealtime therapy. We therefore sought an ultra-stable analog whose potency and duration of action on intravenous bolus injection in diabetic rats are indistinguishable from wild-type (WT) insulin. Here, we describe the structure, function, and stability of such an analog, a 57-residue single-chain insulin (SCI) with multiple acidic substitutions. Cell-based studies revealed native-like signaling properties with negligible mitogenic activity. Its crystal structure, determined as a novel zinc-free hexamer at 2.8 Å, revealed a native insulin fold with incomplete or absent electron density in the C domain; complementary NMR studies are described in the accompanying article. The stability of the analog (ΔGU 5.0(±0.1) kcal/mol at 25 °C) was greater than that of WT insulin (3.3(±0.1) kcal/mol). On gentle agitation, the SCI retained full activity for >140 days at 45 °C and >48 h at 75 °C. These findings indicate that marked resistance to thermal inactivation in vitro is compatible with native duration of activity in vivo Further, whereas WT insulin forms large and heterogeneous aggregates above the standard 0.6 mm pharmaceutical strength, perturbing the pharmacokinetic properties of concentrated formulations, dynamic light scattering, and size-exclusion chromatography revealed only limited SCI self-assembly and aggregation in the concentration range 1-7 mm Such a combination of favorable biophysical and biological properties suggests that SCIs could provide a global therapeutic platform without a cold chain. [ABSTRACT FROM AUTHOR]

Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies. [ABSTRACT FROM AUTHOR]

Noninvasive assessment of pulmonary hemodynamics is often performed by echocardiographic estimation of the pulmonary artery systolic pressure (ePASP), despite limitations in the advanced lung disease population. Other noninvasive hemodynamic variables, such as echocardiographic pulmonary vascular resistance (ePVR), have not been studied in this population. We performed a retrospective analysis of 147 advanced lung disease patients who received both echocardiography and right heart catheterization for lung transplant evaluation. The ePVR was estimated by four previously described equations. Noninvasive and invasive hemodynamic parameters were compared in terms of correlation, agreement, and accuracy. The ePVR models strongly correlated with invasively determined PVR and had good accuracy with biases of <1 Wood units (WU), although with moderate precision and wide 95% limits of agreement varying from 5.9 to 7.8 Wood units. The ePVR models were accurate to within 1.9 WU in over 75% of patients. In comparison to the ePASP, ePVR models performed similarly in terms of correlation, accuracy, and precision when estimating invasive hemodynamics. In screening for pulmonary hypertension, ePVR models had equivalent testing characteristics to the ePASP. Mid‐systolic notching of the right ventricular outflow tract Doppler signal identified a subgroup of 11 patients (7%) with significantly elevated PVR and mean pulmonary artery pressures without relying on the acquisition of a tricuspid regurgitation signal. Analysis of ePVR and determination of the notching pattern of the right ventricular outflow tract Doppler flow velocity envelope provide reliable insights into hemodynamics in advanced lung disease patients, although limitations in precision exist. [ABSTRACT FROM AUTHOR]

Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (TyrB26) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-TyrB26]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (TyrB16, PheB24, PheB25, 3-I-TyrB26, and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-TyrB26]insulin analog (determined as an R6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-TyrB26 in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-TyrB26 engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins. [ABSTRACT FROM AUTHOR]

In the last 300 thousand years, the genus Chlorocebus expanded from equatorial Africa into the southernmost latitudes of the continent, where colder climate was a probable driver of natural selection. We investigated population-level genetic variation in the mitochondrial uncoupling protein 1 (UCP1) gene region—implicated in non-shivering thermogenesis (NST)—in 73 wild savannah monkeys from three taxa representing this southern expansion (Chlorocebus pygerythrus hilgerti, Chlorocebus cynosuros and Chlorocebus pygerythrus pygerythrus) ranging from Kenya to South Africa. We found 17 single nucleotide polymorphisms with extended haplotype homozygosity consistent with positive selective sweeps, 10 of which show no significant linkage disequilibrium with each other. Phylogenetic generalized least-squares modelling with ecological covariates suggest that most derived allele frequencies are significantly associated with solar irradiance and winter precipitation, rather than overall low temperatures. This selection and association with irradiance is demonstrated by a relatively isolated population in the southern coastal belt of South Africa. We suggest that sunbathing behaviours common to savannah monkeys, in combination with the strength of solar irradiance, may mediate adaptations to thermal stress via NST among savannah monkeys. The variants we discovered all lie in non-coding regions, some with previously documented regulatory functions, calling for further validation and research. [ABSTRACT FROM AUTHOR]

Crystallographic studies of insulin bound to fragments of the insulin receptor have recently defined the topography of the primary hormone-receptor interface. Here, we have investigated the role of PheB24, an invariant aromatic anchor at this interface and site of a human mutation causing diabetes mellitus. An extensive set of B24 substitutions has been constructed and tested for effects on receptor binding. Although aromaticity has long been considered a key requirement at this position, MetB24 was found to confer essentially native affinity and bioactivity. Molecular modeling suggests that this linear side chain can serve as an alternative hydrophobic anchor at the hormone-receptor interface. These findings motivated further substitution of PheB24 by cyclohexanylalanine (Cha), which contains a nonplanar aliphatic ring. Contrary to expectations, [ChaB24]insulin likewise exhibited high activity. Furthermore, its resistance to fibrillation and the rapid rate of hexamer disassembly, properties of potential therapeutic advantage, were enhanced. The crystal structure of the ChaB24 analog, determined as an R6 zinc-stabilized hexamer at a resolution of 1.5A, closely resembles that of wild-type insulin. The nonplanar aliphatic ring exhibits two chair conformations with partial occupancies, each recapitulating the role of PheB24 at the dimer interface. Together, these studies have defined structural requirements of an anchor residue within the B24-binding pocket of the insulin receptor; similar molecular principles are likely to pertain to insulin-related growth factors. Our results highlight in particular the utility of nonaromatic side chains as probes of the B24 pocket and suggest that the nonstandard Cha side chain may have therapeutic utility. [ABSTRACT FROM AUTHOR]

Elimination of the central solenoid would simplify the engineering design of a fusion nuclear science facility and tokamak based devices. The method of transient coaxial helicity injection (CHI) has successfully demonstrated formation of a high-quality closed flux plasma in NSTX and will be used as the front end of the start-up method for a full demonstration of noninductive current start-up, followed by noninductive current ramp-up using neutral beams in the NSTX-U device that is now under construction at the Princeton Plasma Physics Laboratory. CHI is implemented by driving current along open field lines that connect the lower inner and outer divertor plates of a spherical torus. The engineering system requirements and the design of the CHI system on NSTX-U are described. [ABSTRACT FROM PUBLISHER]

Lack of diversity regarding genetic and environmental backgrounds weakens the generalization and clinical applicability of research findings on psychotic disorders. Notably, Latin Americans have been generally neglected in genetic studies, comprising less than 2% of genome-wide association study samples. But Latin American populations represent a unique opportunity for research, given the exceptionally high ethnic admixture of this group. Increasing genetic diversity is essential to improve the fine mapping of known regions associated with psychotic disorders, discover novel genetic associations, and replicate studies. Additionally, Latin America is characterized by massive social, political, and economic inequalities, all known risk factors for mental health issues, including psychotic disorders. This article aims to 1) discuss the challenges and advantages of studying Latin America's particular genetic makeup and environmental context; 2) review previous studies conducted in the region; and 3) describe three Latin American research initiatives in progress: the Neuropsychiatric Genetics of Psychosis in Mexican Populations (NeuroMEX), the Paisa, and the Latin American Network for the Study of Early Psychosis (ANDES) studies. [ABSTRACT FROM AUTHOR]

Insulin-signaling requires conformational change: whereas the free hormone and its receptor each adopt autoinhibited conformations, their binding leads to structural reorganization. To test the functional coupling between insulin's "hinge opening" and receptor activation, we inserted an artificial ligand-dependent switch into the insulin molecule. Ligand-binding disrupts an internal tether designed to stabilize the hormone's native closed and inactive conformation, thereby enabling productive receptor engagement. This scheme exploited a diol sensor (meta-fluoro-phenylboronic acid at GlyA1) and internal diol (3,4-dihydroxybenzoate at LysB28). The sensor recognizes monosaccharides (fructose > glucose). Studies of insulin-signaling in human hepatoma-derived cells (HepG2) demonstrated fructose-dependent receptor autophosphorylation leading to appropriate downstream signaling events, including a specific kinase cascade and metabolic gene regulation (gluconeogenesis and lipogenesis). Addition of glucose (an isomeric ligand with negligible sensor affinity) did not activate the hormone. Similarly, metabolite-regulated signaling was not observed in control studies of 1) an unmodified insulin analog or 2) an analog containing a diol sensor without internal tethering. Although secondary structure (as probed by circular dichroism) was unaffected by ligand-binding, heteronuclear NMR studies revealed subtle local and nonlocal monosaccharide-dependent changes in structure. Insertion of a synthetic switch into insulin has thus demonstrated coupling between hinge-opening and allosteric holoreceptor signaling. In addition to this foundational finding, our results provide proof of principle for design of a mechanism-based metabolite-responsive insulin. In particular, replacement of the present fructose sensor by an analogous glucose sensor may enable translational development of a "smart" insulin analog to mitigate hypoglycemic risk in diabetes therapy. [ABSTRACT FROM AUTHOR]

Lentinus crinitus is a wild fungus, which produces mushrooms consumed by some Amazonian Indians. Besides, it is recognized for its diverse biological activities and biotechnological applications. However, there are few reports with limited information on basidiocarp chemical composition and cytotoxicity. Our study determined and evaluated the chemical composition, cytotoxicity, and antioxidant activity of L. crinitus pileus and stipe separately. Chromatographic methods were used to evaluate basidiocarp chemical composition. Cytotoxicity was verified using a cell culture from porcine liver and against a panel of human tumor cells from different models. Antioxidant activity was assessed by different in vitro methods. The pileus had higher levels of protein, ash, tocopherols, and organic acids, mainly malic acid, than the stipe. The stipe revealed higher contents of carbohydrates, energy, soluble sugars, and phenolic acids, mostly p-hydroxybenzoic acid. L. crinitus basidiocarp has mainly trehalose as soluble sugar, and less than 1% fat being ~60% polyunsaturated fatty acids (mostly linoleic and oleic acids), and ~13% saturated fatty acids (mostly palmitic acid). L. crinitus revealed high antioxidant activity for most methods and no cytotoxic activity against tumor and non-tumor cells. L. crinitus basidiocarp can be considered a functional food with applicability in food, cosmetic, and pharmaceutical industries. [ABSTRACT FROM AUTHOR]

Although the phases of left atrial (LA) function at rest have been studied, the physiological response of the LA to exercise is undefined. This study defines the exercise behavior of the normal left atrium by quantitating its volumetric response to graded effort. Healthy subjects (n = 131) were enrolled from the Health eHeart cohort. Echocardiograms were obtained at baseline and during ramped supine bicycle exercise. Left ventricular volume index, stroke volume index (LVSVI), left atrial end-systolic volume index (LAESVI), left atrial end-diastolic volume index (LAEDVI), and left atrial emptying fraction (LAEF), reservoir fraction, and conduit fraction were analyzed. The LVSVI increased with low exercise but did not increase further with peak exercise; cardiac output increased through the agency of heart rate. The LAESVI and LAEDVI decreased and the LAEF increased with exercise. As a result, the LA reservoir volume index was static throughout exercise. The reservoir fraction decreased from 46% at rest to 40% with low exercise (P < 0.001) in association with increased LVSVI and remained similar at peak exercise. The conduit volume index increased from 20 mL/m² at rest to 24mL/m² at low exercise and stayed the same at peak exercise. Similarly, the conduit fraction increased from 54% at rest to 60% at low exercise (P < 0.001) and did not change further with peak exercise. Although atrial function increased with exercise, the major contribution to the augmentation of LV stroke volume is LA conduit fraction, a marker of active ventricular relaxation. Furthermore, the major determinant of raising cardiac output during high-level exercise is heart rate. NEW & NOTEWORTHY Diseases of the left atrium (LA) are major sources of disability (e.g., strokes and fatigue), but its exercise physiology has been unstudied. Such knowledge may allow early recognition of disease and suggest therapies. We show that in normal subjects, low-level exercise decreases LA volume and increases its ejection fraction. However, these changes offset each other volumetrically, and the contribution to LV filling from a full to an empty LA (reservoir function) is static. Higher levels of exercise do not change LA reservoir contribution. Blood flowing directly from the pulmonary vein to LV (conduit flow) impelled by augmented LV active relaxation (suction) is the major source of a modest increase in LV stroke volume. The major source of increased cardiac output with exercise is heart rate. During all stages of exercise, the LA works hard but only to keep up. We believe that our findings provide an additional set of benchmarks through which to quantitate LA pathology and gauge its progression. [ABSTRACT FROM AUTHOR]

Although the phases of left atrial (LA) function at rest have been studied, the physiological response of the LA to exercise is undefined. This study defines the exercise behavior of the normal left atrium by quantitating its volumetric response to graded effort. Healthy subjects (n = 131) were enrolled from the Health eHeart cohort. Echocardiograms were obtained at baseline and during ramped supine bicycle exercise. Left ventricular volume index, stroke volume index (LVSVI), left atrial end-systolic volume index (LAESVI), left atrial end-diastolic volume index (LAEDVI), and left atrial emptying fraction (LAEF), reservoir fraction, and conduit fraction were analyzed. The LVSVI increased with low exercise but did not increase further with peak exercise; cardiac output increased through the agency of heart rate. The LAESVI and LAEDVI decreased and the LAEF increased with exercise. As a result, the LA reservoir volume index was static throughout exercise. The reservoir fraction decreased from 46% at rest to 40% with low exercise (P < 0.001) in association with increased LVSVI and remained similar at peak exercise. The conduit volume index increased from 20 mL/m² at rest to 24 mL/m² at low exercise and stayed the same at peak exercise. Similarly, the conduit fraction increased from 54% at rest to 60% at low exercise (P < 0.001) and did not change further with peak exercise. Although atrial function increased with exercise, the major contribution to the augmentation of LV stroke volume is LA conduit fraction, a marker of active ventricular relaxation. Furthermore, the major determinant of raising cardiac output during high-level exercise is heart rate. [ABSTRACT FROM AUTHOR]

Although the phases of left atrial (LA) function at rest have been studied, the physiological response of the LA to exercise is undefined. This study defines the exercise behavior of the normal left atrium by quantitating its volumetric response to graded effort. Healthy subjects (n = 131) were enrolled from the Health eHeart cohort. Echocardiograms were obtained at baseline and during ramped supine bicycle exercise. Left ventricular volume index, stroke volume index (LVSVI), left atrial end-systolic volume index (LAESVI), left atrial end-diastolic volume index (LAEDVI), and left atrial emptying fraction (LAEF), reservoir fraction, and conduit fraction were analyzed. The LVSVI increased with low exercise but did not increase further with peak exercise; cardiac output increased through the agency of heart rate. The LAESVI and LAEDVI decreased and the LAEF increased with exercise. As a result, the LA reservoir volume index was static throughout exercise. The reservoir fraction decreased from 46% at rest to 40% with low exercise (P < 0.001) in association with increased LVSVI and remained similar at peak exercise. The conduit volume index increased from 20 mL/m² at rest to 24 mL/m² at low exercise and stayed the same at peak exercise. Similarly, the conduit fraction increased from 54% at rest to 60% at low exercise (P < 0.001) and did not change further with peak exercise. Although atrial function increased with exercise, the major contribution to the augmentation of LV stroke volume is LA conduit fraction, a marker of active ventricular relaxation. Furthermore, the major determinant of raising cardiac output during high-level exercise is heart rate. [ABSTRACT FROM AUTHOR]

Although the phases of left atrial (LA) function at rest have been studied, the physiological response of the LA to exercise is undefined. This study defines the exercise behavior of the normal left atrium by quantitating its volumetric response to graded effort. Healthy subjects (n = 131) were enrolled from the Health eHeart cohort. Echocardiograms were obtained at baseline and during ramped supine bicycle exercise. Left ventricular volume index, stroke volume index (LVSVI), left atrial end-systolic volume index (LAESVI), left atrial end-diastolic volume index (LAEDVI), and left atrial emptying fraction (LAEF), reservoir fraction, and conduit fraction were analyzed. The LVSVI increased with low exercise but did not increase further with peak exercise; cardiac output increased through the agency of heart rate. The LAESVI and LAEDVI decreased and the LAEF increased with exercise. As a result, the LA reservoir volume index was static throughout exercise. The reservoir fraction decreased from 46% at rest to 40% with low exercise (P < 0.001) in association with increased LVSVI and remained similar at peak exercise. The conduit volume index increased from 20 mL/m² at rest to 24 mL/m² at low exercise and stayed the same at peak exercise. Similarly, the conduit fraction increased from 54% at rest to 60% at low exercise (P < 0.001) and did not change further with peak exercise. Although atrial function increased with exercise, the major contribution to the augmentation of LV stroke volume is LA conduit fraction, a marker of active ventricular relaxation. Furthermore, the major determinant of raising cardiac output during high-level exercise is heart rate. [ABSTRACT FROM AUTHOR]

Proteins have evolved to be foldable, and yet determinants of foldability may be inapparent once the native state is reached. Insight has emerged from studies of diseases of protein misfolding, exemplified by monogenic diabetes mellitus due to mutations in proinsulin leading to endoplasmic reticulum stress and β-cell death. Cellular foldability of human proinsulin requires an invariant Phe within a conserved crevice at the receptor-binding surface (position B24). Any substitution, even related aromatic residue TyrB24, impairs insulin biosynthesis and secretion. As a seeming paradox, a monomeric TyrB24 insulin analog exhibits a native-like structure in solution with only a modest decrement in stability. Packing of TyrB24 is similar to that of PheB24, adjoining core cystine B19-A20 to seal the core; the analog also exhibits native self-assembly. Although affinity for the insulin receptor is decreased ~20-fold, biological activities in cells and rats were within the range of natural variation. Together, our findings suggest that the invariance of PheB24 among vertebrate insulins and insulin-like growth factors reflects an essential role in enabling efficient protein folding, trafficking, and secretion, a function that is inapparent in native structures. In particular, we envision that the para-hydroxyl group of TyrB24 hinders pairing of cystine B19-A20 in an obligatory on-pathway folding intermediate. The absence of genetic variation at B24 and other conserved sites near this disulfide bridge--excluded due to β-cell dysfunction--suggests that insulin has evolved to the edge of foldability. Nonrobustness of a protein's fitness landscape underlies both a rare monogenic syndrome and "diabesity" as a pandemic disease of civilization. [ABSTRACT FROM AUTHOR]

Large-scale studies spanning diverse project sites, populations, languages, and measurements are increasingly important to relate psychological to biological variables. National and international consortia already are collecting and executing mega-analyses on aggregated data from individuals, with different measures on each person. In this research, we show that Asparouhov and Muthén's alignment method can be adapted to align data from disparate item sets and response formats. We argue that with these adaptations, the alignment method is well suited for combining data across multiple sites even when they use different measurement instruments. The approach is illustrated using data from the Whole Genome Sequencing in Psychiatric Disorders consortium and a real-data-based simulation is used to verify accurate parameter recovery. Factor alignment appears to increase precision of measurement and validity of scores with respect to external criteria. The resulting parameter estimates may further inform development of more effective and efficient methods to assess the same constructs in prospectively designed studies. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has devastated health infrastructure around the world. Both ACE2 (an entry receptor) and TMPRSS2 (used by the virus for spike protein priming) are key proteins to SARS-CoV-2 cell entry, enabling progression to COVID-19 in humans. Comparative genomic research into critical ACE2 binding sites, associated with the spike receptor binding domain, has suggested that African and Asian primates may also be susceptible to disease from SARS-CoV-2 infection. Savanna monkeys (Chlorocebus spp.) are a widespread non-human primate with well-established potential as a bi-directional zoonotic/anthroponotic agent due to high levels of human interaction throughout their range in sub-Saharan Africa and the Caribbean. To characterize potential functional variation in savanna monkey ACE2 and TMPRSS2, we inspected recently published genomic data from 245 savanna monkeys, including 163 wild monkeys from Africa and the Caribbean and 82 captive monkeys from the Vervet Research Colony (VRC). We found several missense variants. One missense variant in ACE2 (X:14,077,550; Asp30Gly), common in Ch. sabaeus, causes a change in amino acid residue that has been inferred to reduce binding efficiency of SARS-CoV-2, suggesting potentially reduced susceptibility. The remaining populations appear as susceptible as humans, based on these criteria for receptor usage. All missense variants observed in wild Ch. sabaeus populations are also present in the VRC, along with two splice acceptor variants (at X:14,065,076) not observed in the wild sample that are potentially disruptive to ACE2 function. The presence of these variants in the VRC suggests a promising model for SARS-CoV-2 infection and vaccine and therapy development. In keeping with a One Health approach, characterizing actual susceptibility and potential for bi-directional zoonotic/anthroponotic transfer in savanna monkey populations may be an important consideration for controlling COVID-19 epidemics in communities with frequent human/non-human primate interactions that, in many cases, may have limited health infrastructure. [ABSTRACT FROM AUTHOR]

Next-generation sequencing technology (NGS) enables the discovery of nearly all genetic variants present in a genome. A subset of these variants, however, may have poor sequencing quality due to limitations in NGS or variant callers. In genetic studies that analyze a large number of sequenced individuals, it is critical to detect and remove those variants with poor quality as they may cause spurious findings. In this paper, we present ForestQC, a statistical tool for performing quality control on variants identified from NGS data by combining a traditional filtering approach and a machine learning approach. Our software uses the information on sequencing quality, such as sequencing depth, genotyping quality, and GC contents, to predict whether a particular variant is likely to be false-positive. To evaluate ForestQC, we applied it to two whole-genome sequencing datasets where one dataset consists of related individuals from families while the other consists of unrelated individuals. Results indicate that ForestQC outperforms widely used methods for performing quality control on variants such as VQSR of GATK by considerably improving the quality of variants to be included in the analysis. ForestQC is also very efficient, and hence can be applied to large sequencing datasets. We conclude that combining a machine learning algorithm trained with sequencing quality information and the filtering approach is a practical approach to perform quality control on genetic variants from sequencing data. Author summary: Genetic disorders can be caused by many types of genetic mutations, including common and rare single nucleotide variants, structural variants, insertions, and deletions. Nowadays, next-generation sequencing (NGS) technology allows us to identify various genetic variants that are associated with diseases. However, variants detected by NGS might have poor sequencing quality due to biases and errors in sequencing technologies and analysis tools. Therefore, it is critical to remove variants with low quality, which could cause spurious findings in follow-up analyses. Previously, people applied either hard filters or machine learning models for variant quality control (QC), which failed to filter out those variants accurately. Here, we developed a statistical tool, ForestQC, for variant QC by combining a filtering approach and a machine learning approach. We applied ForestQC to one family-based whole-genome sequencing (WGS) dataset and one general case-control WGS dataset, to evaluate it. Results show that ForestQC outperforms widely used methods for variant QC by considerably improving the quality of variants. Also, ForestQC is very efficient and scalable to large-scale sequencing datasets. Our study indicates that combining filtering approaches and machine learning approaches enables effective variant QC. [ABSTRACT FROM AUTHOR]

Background and purpose: AV‐1451 (18F‐AV‐1451, flortaucipir) positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation. Methods: Nine clinically characterized C9orf72 expansion carriers and 18 age‐ and gender‐ matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV‐1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV‐1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures. Results: C9orf72 expansion carriers had increased AV‐1451 binding in the entorhinal cortex compared to controls. Primary age‐related tauopathy was observed postmortem in one patient. AV‐1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers. Conclusion: C9orf72 expansion carriers exhibited increased AV‐1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age‐related tauopathy. However, AV‐1451 accumulation was not associated with psychometric performance in our cohort. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic kidney disease (CKD) are at increased risk for heart failure (HF). We aimed to investigate differences in proteins associated with HF hospitalizations among patients with and without CKD in the Heart and Soul Study. Methods and results: We measured 1068 unique plasma proteins from baseline samples of 974 participants in The Heart and Soul Study who were followed for HF hospitalization over a median of 7 years. We sequentially applied forest regression and Cox survival analyses to select prognostic proteins. Among participants with CKD, four proteins were associated with HF at Bonferroni-level significance (p<2.5x10-4): Angiopoietin-2 (HR[95%CI] 1.45[1.33, 1.59]), Spondin-1 (HR[95%CI] 1.13 [1.06, 1.20]), tartrate-resistant acid phosphatase type 5 (HR[95%CI] 0.65[0.53, 0.78]) and neurogenis locus notch homolog protein 1 (NOTCH1) (HR[95%CI] 0.67[0.55, 0.80]). These associations persisted at p<0.01 after adjustment for age, estimated glomerular filtration and history of HF. CKD was a significant interaction term in the associations of NOTCH1 and Spondin-1 with HF. Pathway analysis showed a trend for higher representation of the Cardiac Hypertrophy and Complement/Coagulation pathways among proteins prognostic of HF in the CKD sub-group. Conclusions: These results suggest that markers of heart failure differ between patients with and without CKD. Further research is needed to validate novel markers in cohorts of patients with CKD and adjudicated HF events. [ABSTRACT FROM AUTHOR]

Despite substantial research and policy interest in pixel level cropland allocation data, few sources are available that span a large geographic area. The data used for much of this research are derived from complex modeling techniques that may include model simulation and other data processing. We develop a transparent econometric framework that uses pixel level biophysical measurements and aggregate cropland statistics to develop pixel level cropland allocation predictions. Such pixel level land use data can be used to investigate the impact of human activities on the environment. Validation exercises show that our approach is effective at downscaling cropland allocation to multiple levels of resolution. [ABSTRACT FROM AUTHOR]

Abstract: Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aβ1–40, Aβ1–42, total tau, and p‐tau181 in 329 members of a multigenerational pedigree. Linkage and genome‐wide association were used to elucidate a genetic contribution to these traits. Results: Aβ1–40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p‐tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aβ1–40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome‐wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non‐human primate model of amyloid‐related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aβ1–40 and p‐tau181 as potentially valuable biomarkers of these processes. [ABSTRACT FROM AUTHOR]

* Uranium (U) is a naturally occurring radionuclide that is toxic to plants. It is known to interfere with phosphate nutrition and to modify the expression of iron (Fe)-responsive genes. The transporters involved in the uptake of U from the environment are unknown. Here, we addressed whether IRT1, a high-affinity Fe2+ transporter, could contribute to U uptake in Arabidopsis thaliana. * An irt1 null mutant was grown hydroponically in different conditions of Fe bioavailability and phosphate supply, and challenged with uranyl. Several physiological parameters (fitness, photosynthesis) were measured to evaluate the response to U treatment. * We found that IRT1 is not a major route for U uptake in our experimental conditions. However, the analysis of irt1 indicated that uranyl interferes with Fe and phosphate homeostasis at different levels. In phosphate-sufficient conditions, the absence of the cation chelator EDTA in the medium has drastic consequences on the physiology of irt1, with important symptoms of Fe deficiency in chloroplasts. These effects are counterbalanced by U, probably because the radionuclide competes with Fe for complexation with phosphate and thus releases active Fe for metabolic and biogenic processes. * Our study reveals that challenging plants with U is useful to decipher the complex interplay between Fe and phosphate. [ABSTRACT FROM AUTHOR]

Domain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound "micro-receptors." In such structures, the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulin A and B chains. This "open" conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR. Here, we report the high-resolution solution structure and dynamics of such an active SCI. The hormone's closed-to-open transition is foreshadowed by segmental flexibility in the native state as probed by heteronuclear NMR spectroscopy and multiple conformer simulations of crystallographic protomers as described in the companion article. We propose a model of the SCI's IR-bound state based on molecular-dynamics simulations of a micro-receptor complex. In this model, a loop defined by the SCI's B and C domains encircles the C-terminal segment of the IR α-subunit. This binding mode predicts a conformational transition between an ultra-stable closed state (in the free hormone) and an active open state (on receptor binding). Optimization of this switch within an ultra-stable SCI promises to circumvent insulin's complex global cold chain. The analog's biphasic activity, which serendipitously resembles current premixed formulations of soluble insulin and microcrystalline suspension, may be of particular utility in the developing world. [ABSTRACT FROM AUTHOR]

A general problem is posed by analysis of transcriptional thresholds governing cell fate decisions in metazoan development. A model is provided by testis determination in therian mammals. Its key step, Sertoli cell differentiation in the embryonic gonadal ridge, is initiated by SRY, a Y-encoded architectural transcription factor. Mutations in human SRY cause gonadal dysgenesis leading to XY female development (Swyer syndrome). Here, we have characterized an inherited mutation compatible with either male or female somatic phenotypes as observed in an XY father and XY daughter, respectively. The mutation (a crevice-forming substitution at a conserved back surface of the SRY high mobility group box) markedly destabilizes the domain but preserves specific DNA affinity and induced DNA bend angle. On transient transfection of diverse human and rodent cell lines, the variant SRY exhibited accelerated proteasomal degradation (relative to wild type) associated with increased ubiquitination; in vitro susceptibility to ubiquitin-independent ("default") cleavage by the 20S core proteasome was unchanged. The variant's gene regulatory activity (as assessed in a cellular model of the rat embryonic XY gonadal ridge) was reduced by 2-fold relative to wild-type SRY at similar levels of mRNA expression. Chemical proteasome inhibition restored native-like SRY expression and transcriptional activity in association with restored occupancy of a sex-specific enhancer element in principal downstream gene Sox9, demonstrating that the variant SRY exhibits essentially native activity on a per molecule basis. Our findings define a novel mechanism of impaired organogenesis, accelerated ubiquitindirected proteasomal degradation of a master transcription factor leading to a developmental decision poised at the edge of ambiguity. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is an important pathogen of humans and animals. We genome sequenced 90 S. aureus isolates from The Gambia: 46 isolates from invasive disease in humans, 13 human carriage isolates, and 31 monkey carriage isolates. We inferred multiple anthroponotic transmissions of S. aureus from humans to green monkeys (Chlorocebus sabaeus) in The Gambia over different time scales. We report a novel monkey-associated clade of S. aureus that emerged from a human-to-monkey switch estimated to have occurred 2,700 years ago. Adaptation of this lineage to the monkey host is accompanied by the loss of phagecarrying genes that are known to play an important role in human colonization. We also report recent anthroponotic transmission of the well-characterized human lineages sequence type 6 (ST6) and ST15 to monkeys, probably because of steadily increasing encroachment of humans into the monkeys' habitat. Although we have found no evidence of transmission of S. aureus from monkeys to humans, as the two species come into ever-closer contact, there might be an increased risk of additional interspecies exchanges of potential pathogens. [ABSTRACT FROM AUTHOR]

Nonhuman primates (NHPs) are a historically important source of zoonotic viruses and are a gold-standard model for research on many human pathogens. However, with the exception of simian immunodeficiency virus (SIV) (family Retroviridae), the blood-borne viruses harbored by these animals in the wild remain incompletely characterized. Here, we report the discovery and characterization of two novel simian pegiviruses (family Flaviviridae) and two novel simian arteriviruses (family Arteriviridae) in wild African green monkeys from Zambia (malbroucks [Chlorocebus cynosuros]) and South Africa (vervet monkeys [Chlorocebus pygerythrus]). We examine several aspects of infection, including viral load, genetic diversity, evolution, and geographic distribution, as well as host factors such as age, sex, and plasma cytokines. In combination with previous efforts to characterize blood-borne RNA viruses in wild primates across sub-Saharan Africa, these discoveries demonstrate that in addition to SIV, simian pegiviruses and simian arteriviruses are widespread and prevalent among many African cercopithecoid (i.e., Old World) monkeys. [ABSTRACT FROM AUTHOR]

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined. [ABSTRACT FROM AUTHOR]

The observation that variants regulating gene expression (expression quantitative trait loci, eQTL) are at a high frequency among SNPs associated with complex traits has made the genome-wide characterization of gene expression an important tool in genetic mapping studies of such traits. As part of a study to identify genetic loci contributing to bipolar disorder and other quantitative traits in members of 26 pedigrees from Costa Rica and Colombia, we measured gene expression in lymphoblastoid cell lines derived from 786 pedigree members. The study design enabled us to comprehensively reconstruct the genetic regulatory network in these families, provide estimates of heritability, identify eQTL, evaluate missing heritability for the eQTL, and quantify the number of different alleles contributing to any given locus. In the eQTL analysis, we utilize a recently proposed hierarchical multiple testing strategy which controls error rates regarding the discovery of functional variants. Our results elucidate the heritability and regulation of gene expression in this unique Latin American study population and identify a set of regulatory SNPs which may be relevant in future investigations of complex disease in this population. Since our subjects belong to extended families, we are able to compare traditional kinship-based estimates with those from more recent methods that depend only on genotype information. [ABSTRACT FROM AUTHOR]