Title: AHA News: Director John Singleton's Fatal Stroke Spotlights Black Americans' Hypertension Risk
Category: Health News
Created: 5/2/2019 12:00:00 AM
Last Editorial Review: 5/2/2019 12:00:00 AM

Title: Company Selling Direct-to-Consumer Coronavirus Antibody Test
Category: Health News
Created: 4/30/2020 12:00:00 AM
Last Editorial Review: 5/1/2020 12:00:00 AM

Title: Dirty Air Might Raise Your Odds for Dementia
Category: Health News
Created: 3/31/2020 12:00:00 AM
Last Editorial Review: 4/1/2020 12:00:00 AM

ABSTRACT

Population-level analyses are rapidly becoming inadequate to answer many of biomedical science and microbial ecology’s most pressing questions. The role of microbial populations within ecosystems and the evolutionary selective pressure on individuals depend fundamentally on the metabolic activity of single cells. Yet, many existing single-cell technologies provide only indirect evidence of metabolic specialization because they rely on correlations between transcription and phenotype established at the level of the population to infer activity. In this study, we take a top-down approach using isotope labels and secondary ion mass spectrometry to track the uptake of carbon and nitrogen atoms from different sources into biomass and directly observe dynamic changes in anabolic specialization at the level of single cells. We investigate the classic microbiological phenomenon of diauxic growth at the single-cell level in the model methylotroph Methylobacterium extorquens. In nature, this organism inhabits the phyllosphere, where it experiences diurnal changes in the available carbon substrates, necessitating an overhaul of central carbon metabolism. We show that the population exhibits a unimodal response to the changing availability of viable substrates, a conclusion that supports the canonical model but has thus far been supported by only indirect evidence. We anticipate that the ability to monitor the dynamics of anabolism in individual cells directly will have important applications across the fields of ecology, medicine, and biogeochemistry, especially where regulation downstream of transcription has the potential to manifest as heterogeneity that would be undetectable with other existing single-cell approaches.

IMPORTANCE Understanding how genetic information is realized as the behavior of individual cells is a long-term goal of biology but represents a significant technological challenge. In clonal microbial populations, variation in gene regulation is often interpreted as metabolic heterogeneity. This follows the central dogma of biology, in which information flows from DNA to RNA to protein and ultimately manifests as activity. At present, DNA and RNA can be characterized in single cells, but the abundance and activity of proteins cannot. Inferences about metabolic activity usually therefore rely on the assumption that transcription reflects activity. By tracking the atoms from which they build their biomass, we make direct observations of growth rate and substrate specialization in individual cells throughout a period of growth in a changing environment. This approach allows the flow of information from DNA to be constrained from the distal end of the regulatory cascade and will become an essential tool in the rapidly advancing field of single-cell metabolism.

ABSTRACT

Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile. However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils.

IMPORTANCE Clostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile. Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.

ABSTRACT

Bacillus subtilis contains two known cyclic di-GMP (c-di-GMP)-dependent receptors, YdaK and DgrA, as well as three diguanylate cyclases (DGCs): soluble DgcP and membrane-integral DgcK and DgcW. DgrA regulates motility, while YdaK is responsible for the formation of a putative exopolysaccharide, dependent on the activity of DgcK. Using single-molecule tracking, we show that a majority of DgcK molecules are statically positioned in the cell membrane but significantly less so in the absence of YdaK but more so upon overproduction of YdaK. The soluble domains of DgcK and of YdaK show a direct interaction in vitro, which depends on an intact I-site within the degenerated GGDEF domain of YdaK. These experiments suggest a direct handover of a second messenger at a single subcellular site. Interestingly, all three DGC proteins contribute toward downregulation of motility via the PilZ protein DgrA. Deletion of dgrA also affects the mobility of DgcK within the membrane and also that of DgcP, which arrests less often at the membrane in the absence of DgrA. Both, DgcK and DgcP interact with DgrA in vitro, showing that divergent as well as convergent direct connections exist between cyclases and their effector proteins. Automated determination of molecule numbers in live cells revealed that DgcK and DgcP are present at very low copy numbers of 6 or 25 per cell, respectively, such that for DgcK, a part of the cell population does not contain any DgcK molecule, rendering signaling via c-di-GMP extremely efficient.

IMPORTANCE Second messengers are free to diffuse through the cells and to activate all responsive elements. Cyclic di-GMP (c-di-GMP) signaling plays an important role in the determination of the life style transition between motility and sessility/biofilm formation but involves numerous distinct synthetases (diguanylate cyclases [DGCs]) or receptor pathways that appear to act in an independent manner. Using Bacillus subtilis as a model organism, we show that for two c-di-GMP pathways, DGCs and receptor molecules operate via direct interactions, where a synthesized dinucleotide appears to be directly used for the protein-protein interaction. We show that very few DGC molecules exist within cells; in the case of exopolysaccharide (EPS) formation via membrane protein DgcK, the DGC molecules act at a single site, setting up a single signaling pool within the cell membrane. Using single-molecule tracking, we show that the soluble DGC DgcP arrests at the cell membrane, interacting with its receptor, DgrA, which slows down motility. DgrA also directly binds to DgcK, showing that divergent as well as convergent modules exist in B. subtilis. Thus, local-pool signal transduction operates extremely efficiently and specifically.

After more than 20 years of minimal funding, the U.S. is opening its purse strings to research on gun violence prevention.

To the Editor—Bourbon virus (Thogotovirus, Orthomyxoviridae) was discovered in 2014 when a patient with history of multiple tick bites in Kansas died from an unknown infection [1]. Human infections from Bourbon virus have now been recognized in several states (i.e., Kansas, Oklahoma, Missouri). The virus was detected in collections of the lone star tick (Amblyomma americanum) in Missouri [2]. A serosurvey of domestic and wild mammals in Missouri noted the presence of Bourbon virus-neutralizing antibodies in serum samples collected from a variety of species, but most frequently in white-tailed deer (Odocoileus virginianus) and raccoon (Procyon lotor) [3]. We report here that neutralizing antibodies against Bourbon virus were detected in white-tailed deer in North Carolina, suggesting that the virus is present in the state. We screened 32 white-tailed deer for the presence of Bourbon virus-specific neutralizing antibodies. Of 20 plasma samples that reacted with the virus, 18 were confirmed with neutralizing antibody titers ranging from 10 to ≥ 320 for a seroprevalence rate of 56% (95% confidence interval 39%–72%). The seropositive samples were from deer killed during the 2014 hunting season from Stanly and New Hanover counties.

The incidence of Bourbon virus infection in humans in North Carolina is unknown. However, given the abundance of the lone star tick in the state, and the notable proportion of deer with evidence of infection, human infections have likely gone unnoticed or possibly misdiagnosed. Human infection with Bourbon virus results in a nonspecific viral syndrome that includes fever, nausea, diarrhea, myalgia (muscle pain), arthralgia...

In 2019, the National Academy of Medicine (NAM) turned to the all-important state level to draw insights on the status of health and health care within the context of the NAM Vital Directions for Health and Health Care initiative. The NAM held a two-day symposium in the Research Triangle to bring together various stakeholders to better understand actions that states and localities are taking to achieve—and the barriers they face in pursuing—more affordable, value-driven quality care and health outcomes. The NAM purposefully chose to pivot to the state level with North Carolina given that it has been at the forefront of health care transformation and illustrates the promise but also the challenges facing US health and health care nationally. A 19-member planning committee, cochaired by NAM President Victor Dzau and Secretary Mandy Cohen of the North Carolina Department of Health and Human Services, selected topics that resonate with the state's activities within the context of the Vital Directions framework, ranging from empowering people and connecting care through the integration of social, physical, and behavioral health to payer alignment though the advancement of new payment models (Figure 1). The priorities discussed during the symposium continue to be central to health reform in North Carolina and are further explored in the commentaries in this issue.

Terpene volatiles are found in many important fruit crops, but their relationship to flavor is poorly understood. Here, we demonstrate using sensory descriptive and discriminant analysis that 1,8-cineole contributes a key floral/eucalyptus note to the aroma of ripe 'Hort16A’ kiwifruit (Actinidia chinensis). Two quantitative trait loci (QTLs) for 1,8-cineole production were identified on linkage groups 27 and 29a in a segregating A. chinensis population, with the QTL on LG29a colocating with a complex cluster of putative terpene synthase (TPS)-encoding genes. Transient expression in Nicotiana benthamiana and analysis of recombinant proteins expressed in Escherichia coli showed four genes in the cluster (AcTPS1a–AcTPS1d) encoded functional TPS enzymes, which produced predominantly sabinene, 1,8-cineole, geraniol, and springene, respectively. The terpene profile produced by AcTPS1b closely resembled the terpenes detected in red-fleshed A. chinensis. AcTPS1b expression correlated with 1,8-cineole content in developing/ripening fruit and also showed a positive correlation with 1,8-cineole content in the mapping population, indicating the basis for segregation is an expression QTL. Transient overexpression of AcTPS1b in Actinidia eriantha fruit confirmed this gene produced 1,8-cineole in Actinidia. Structure-function analysis showed AcTPS1a and AcTPS1b are natural variants at key TPS catalytic site residues previously shown to change enzyme specificity in vitro. Together, our results indicate that AcTPS1b is a key gene for production of the signature flavor terpene 1,8-cineole in ripe kiwifruit. Using a sensory-directed strategy for compound identification provides a rational approach for applying marker-aided selection to improving flavor in kiwifruit as well as other fruits.

BEAF (Boundary Element-Associated Factor) was originally identified as a Drosophila melanogaster chromatin domain insulator-binding protein, suggesting a role in gene regulation through chromatin organization and dynamics. Genome-wide mapping found that BEAF usually binds near transcription start sites, often of housekeeping genes, suggesting a role in promoter function. This would be a nontraditional role for an insulator-binding protein. To gain insight into molecular mechanisms of BEAF function, we identified interacting proteins using yeast two-hybrid assays. Here, we focus on the transcription factor Serendipity (Sry-). Interactions were confirmed in pull-down experiments using bacterially expressed proteins, by bimolecular fluorescence complementation, and in a genetic assay in transgenic flies. Sry- interacted with promoter-proximal BEAF both when bound to DNA adjacent to BEAF or > 2-kb upstream to activate a reporter gene in transient transfection experiments. The interaction between BEAF and Sry- was detected using both a minimal developmental promoter (y) and a housekeeping promoter (RpS12), while BEAF alone strongly activated the housekeeping promoter. These two functions for BEAF implicate it in playing a direct role in gene regulation at hundreds of BEAF-associated promoters.

Isoprene has the highest emission into Earth’s atmosphere of any nonmethane hydrocarbon. Atmospheric processing of alkenes, including isoprene, via ozonolysis leads to the formation of zwitterionic reactive intermediates, known as Criegee intermediates (CIs). Direct studies have revealed that reactions involving simple CIs can significantly impact the tropospheric oxidizing capacity, enhance...

Vitamin A has diverse biological functions and is essential for human survival at every point from embryogenesis to adulthood. Vitamin A and its derivatives have been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental, but how its...

Background:

Direct-to-consumer prescription drug advertising is prevalent and affects patient care. Previous research that examined its effect on the patient-provider relationship predates many changes in the advertising and medical landscape that have occurred in the last decade, such as the rise in online promotion and the push for value-based medicine.

Many noncoding RNAs are known to play a role in the cell directly linked to their structure. Structure prediction based on the sole sequence is, however, a challenging task. On the other hand, thanks to the low cost of sequencing technologies, a very large number of homologous sequences are becoming available for many RNA families. In the protein community, the idea of exploiting the covariance of mutations within a family to predict the protein structure using the direct-coupling-analysis (DCA) method has emerged in the last decade. The application of DCA to RNA systems has been limited so far. We here perform an assessment of the DCA method on 17 riboswitch families, comparing it with the commonly used mutual information analysis and with state-of-the-art R-scape covariance method. We also compare different flavors of DCA, including mean-field, pseudolikelihood, and a proposed stochastic procedure (Boltzmann learning) for solving exactly the DCA inverse problem. Boltzmann learning outperforms the other methods in predicting contacts observed in high-resolution crystal structures.

Endogenous viral elements (EVEs) are found in many eukaryotic genomes. Despite considerable knowledge about genomic elements such as transposons (TEs) and retroviruses, we still lack information about nonretroviral EVEs. Aedes aegypti mosquitoes have a highly repetitive genome that is covered with EVEs. Here, we identified 129 nonretroviral EVEs in the AaegL5 version of the A. aegypti genome. These EVEs were significantly associated with TEs and preferentially located in repeat-rich clusters within intergenic regions. Genome-wide transcriptome analysis showed that most EVEs generated transcripts although only around 1.4% were sense RNAs. The majority of EVE transcription was antisense and correlated with the generation of EVE-derived small RNAs. A single genomic cluster of EVEs located in a 143 kb repetitive region in chromosome 2 contributed with 42% of antisense transcription and 45% of small RNAs derived from viral elements. This region was enriched for TE-EVE hybrids organized in the same coding strand. These generated a single long antisense transcript that correlated with the generation of phased primary PIWI-interacting RNAs (piRNAs). The putative promoter of this region had a conserved binding site for the transcription factor Cubitus interruptus, a key regulator of the flamenco locus in Drosophila melanogaster. Here, we have identified a single unidirectional piRNA cluster in the A. aegypti genome that is the major source of EVE transcription fueling the generation of antisense small RNAs in mosquitoes. We propose that this region is a flamenco-like locus in A. aegypti due to its relatedness to the major unidirectional piRNA cluster in Drosophila melanogaster.

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates.

Premature infants have a higher incidence of indirect hyperbilirubinemia than term infants. Management of neonatal indirect hyperbilirubinemia in late preterm and term neonates has been well addressed by recognized, consensus-based guidelines. However, the extension of these guidelines to the preterm population has been an area of uncertainty because of limited evidence. This leads to variation in clinical practice and lack of recognition of the spectrum of bilirubin-induced neurologic dysfunction (BIND) in this population. Preterm infants are metabolically immature and at higher risk for BIND at lower bilirubin levels than their term counterparts. Early use of phototherapy to eliminate BIND and minimize the need for exchange transfusion is the goal of treatment in premature neonates. Although considered relatively safe, phototherapy does have side effects, and some NICUs tend to overuse phototherapy. In this review, we describe the epidemiology and pathophysiology of BIND in preterm neonates, and discuss our approach to standardized management of indirect hyperbilirubinemia in the vulnerable preterm population. The proposed treatment charts suggest early use of phototherapy in preterm neonates with the aim of reducing exposure to high irradiance levels, minimizing the need for exchange transfusions, and preventing BIND. The charts are pragmatic and have additional curves for stopping phototherapy and escalating its intensity. Having a standardized approach would support future research and quality improvement initiatives that examine dose and duration of phototherapy exposure with relation to outcomes.

Routine identification of fungal pathogens from positive blood cultures by culture-based methods can be time-consuming, delaying treatment with appropriate antifungal agents. The GenMark Dx ePlex investigational use only blood culture identification fungal pathogen panel (BCID-FP) rapidly detects 15 fungal targets simultaneously in blood culture samples positive for fungi by Gram staining. We aimed to determine the performance of the BCID-FP in a multicenter clinical study. Blood culture samples collected at 10 United States sites and tested with BCID-FP at 4 sites were compared to the standard-of-care microbiological and biochemical techniques, fluorescence in situ hybridization using peptide nucleic acid probes (PNA-FISH) and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Discrepant results were analyzed by bi-directional PCR/sequencing of residual blood culture samples. A total of 866 clinical samples, 120 retrospectively and 21 prospectively collected, along with 725 contrived samples were evaluated. Sensitivity and specificity of detection of Candida species (C. albicans, C. auris, C. dubliniensis, C. famata, C. glabrata, C. guilliermondii, C. kefyr, C. krusei, C. lusitaniae, C. parapsilosis, and C. tropicalis) ranged from 97.1 to 100% and 99.8 to 100%, respectively. For the other organism targets, sensitivity and specificity were as follows: 100% each for Cryptococcus neoformans and C. gattii, 98.6% and 100% for Fusarium spp., and 96.2% and 99.9% for Rhodotorula spp., respectively. In 4 of the 141 clinical samples, the BCID-FP panel correctly identified an additional Candida species, undetected by standard-of-care methods. The BCID-FP panel offers a faster turnaround time for identification of fungal pathogens in positive blood cultures that may allow for earlier antifungal interventions and includes C. auris, a highly multidrug-resistant fungus.

Pyrazinamide (PZA) is considered the pivot drug in all tuberculosis treatment regimens due to its particular action on the persistent forms of Mycobacterium tuberculosis. However, no drug susceptibility test (DST) is considered sufficiently reliable for routine application. Although molecular tests are endorsed, their application is limited to known PZA resistance associated mutations. Microbiological DSTs for PZA have been restricted by technical limitations, especially the necessity for an acidic pH. Here, for the first time, MODS culture at neutral pH was evaluated using high PZA concentrations (400 and 800 μg/ml) to determine PZA susceptibility directly from sputum samples. Sputum samples were cultured with PZA for up to 21 days at 37°C. Plate reading was performed at two time points: R1 (mean, 10 days) and R2 (mean, 13 days) for each PZA concentration. A consensus reference test, composed of MGIT-PZA, pncA sequencing, and the classic Wayne test, was used. A total of 182 samples were evaluated. The sensitivity and specificity for 400 μg/ml ranged from 76.9 to 89.7 and from 93.0 to 97.9%, respectively, and for 800 μg/ml ranged from 71.8 to 82.1 and from 95.8 to 98.6%, respectively. Compared to MGIT-PZA, our test showed a similar turnaround time (medians of 10 and 12 days for PZA-sensitive and -resistant isolates, respectively). In conclusion, MODS-PZA is presented as a fast, simple, and low-cost DST that could complement the MODS assay to evaluate resistance to the principal first-line antituberculosis drugs. Further optimization of test conditions would be useful in order to increase its performance.

Dalton Buysse, Anna-Katharina Pfitzner, Matt West, Aurelien Roux, and Greg Odorizzi

The ESCRT-III protein complex executes reverse-topology membrane scission. The scission mechanism is unclear but is linked to remodeling of ESCRT-III complexes at the membrane surface. At endosomes, ESCRT-III mediates the budding of intralumenal vesicles (ILVs). In Saccharomyces cerevisiae, ESCRT-III activity at endosomes is regulated through an unknown mechanism by Doa4, an ubiquitin hydrolase that deubiquitylates transmembrane proteins sorted into ILVs. We report that the non-catalytic N-terminus of Doa4 binds Snf7, the predominant ESCRT-III subunit. Through this interaction, Doa4 overexpression alters Snf7 assembly status and inhibits ILV membrane scission. In vitro, the Doa4 N-terminus inhibits association of Snf7 with Vps2, which functions with Vps24 to arrest Snf7 polymerization and remodel Snf7 polymer structure. In vivo, Doa4 overexpression inhibits Snf7 interaction with Vps2 and also with the ATPase Vps4, which is recruited by Vps2 and Vps24 to remodel ESCRT-III complexes by catalyzing subunit turnover. Our data suggest a mechanism by which the deubiquitylation machinery regulates ILV biogenesis by interfering with ESCRT-III remodeling.

Yi Liu, Jaeyoun Kim, Reuben Philip, Vaishali Sridhar, Megha Chandrashekhar, Jason Moffat, Mark van Breugel, and Laurence Pelletier

PLK4 has emerged as a prime target for cancer therapeutics, and its overexpression is frequently observed in various types of human cancer. Recent studies have further revealed an unexpected oncogenic activity of PLK4 in regulating cancer cell migration and invasion. However, the molecular basis behind the role of PLK4 in these processes still remains only partly understood. Our previous work has demonstrated that an intact CEP85–STIL binding interface is necessary for robust PLK4 activation and centriole duplication. Here, we show that CEP85 and STIL are also required for directional cancer cell migration. Mutational and functional analyses reveal that the interactions between CEP85, STIL and PLK4 are essential for effective directional cell motility. Mechanistically, we show that PLK4 can drive the recruitment of CEP85 and STIL to the leading edge of cells to promote protrusive activity, and that downregulation of CEP85 and STIL leads to a reduction in ARP2 (also known as ACTR2) phosphorylation and reorganization of the actin cytoskeleton, which in turn impairs cell migration. Collectively, our studies provide molecular insight into the important role of the CEP85–STIL complex in modulating PLK4-driven cancer cell migration.

This article has an associated First Person interview with the first author of the paper.

C-X-C motif chemokine receptor 4 (CXCR4) is expressed on the surface of various cell types involved in atherosclerosis, with a particularly rich receptor expression on macrophages and T cells. First pilot studies with ⁶⁸Ga-pentixafor, a novel CXCR4-directed PET tracer, have shown promise to noninvasively image inflammation within atherosclerotic plaques. The aim of this retrospective study was to investigate the performance of ⁶⁸Ga-pentixafor PET/CT for imaging atherosclerosis in comparison to ¹⁸F-FDG PET/CT. Methods: Ninety-two patients (37 women and 55 men; mean age, 62 ± 10 y) underwent ⁶⁸Ga-pentixafor and ¹⁸F-FDG PET/CT for staging of oncologic diseases. In these subjects, lesions in the walls of large arteries were identified using morphologic and PET criteria for atherosclerosis (n = 652). Tracer uptake was measured and adjusted for vascular lumen (background) signal by calculation of target-to-background ratios (TBRs) by 2 investigators masked to the other PET scan. On a lesion-to-lesion and patient basis, the TBRs of both PET tracers were compared and additionally correlated to the degree of arterial calcification as quantified in CT. Results: On a lesion-to-lesion basis, ⁶⁸Ga-pentixafor and ¹⁸F-FDG uptake showed a weak correlation (r = 0.28; P < 0.01). ⁶⁸Ga-pentixafor PET identified more lesions (n = 290; TBR ≥ 1.6, P < 0.01) and demonstrated higher uptake than ¹⁸F-FDG PET (1.8 ± 0.5 vs. 1.4 ± 0.4; P < 0.01). The degree of plaque calcification correlated negatively with both ⁶⁸Ga-pentixafor and ¹⁸F-FDG uptake (r = –0.38 vs. –0.31, both P < 0.00001). Conclusion: CXCR4-directed imaging of the arterial wall with ⁶⁸Ga-pentixafor PET/CT identified more lesions than ¹⁸F-FDG PET/CT, with only a weak correlation between tracers. Further studies to elucidate the underlying biologic mechanisms and sources of CXCR4 positivity, and to investigate the clinical utility of chemokine receptor–directed imaging of atherosclerosis, are highly warranted.

Metabolism and development must be closely coupled to meet the changing physiological needs of each stage in the life cycle. The molecular mechanisms that link these pathways, however, remain poorly understood. Here we show that the Drosophila estrogen-related receptor (dERR) directs a transcriptional switch in mid-pupae that promotes glucose oxidation and lipogenesis in young adults. dERR mutant adults are viable but display reduced locomotor activity, susceptibility to starvation, elevated glucose, and an almost complete lack of stored triglycerides. Molecular profiling by RNA-seq, ChIP-seq, and metabolomics revealed that glycolytic and pentose phosphate pathway genes are induced by dERR, and their reduced expression in mutants is accompanied by elevated glycolytic intermediates, reduced TCA cycle intermediates, and reduced levels of long chain fatty acids. Unexpectedly, we found that the central pathways of energy metabolism, including glycolysis, the tricarboxylic acid cycle, and electron transport chain, are coordinately induced at the transcriptional level in mid-pupae and maintained into adulthood, and this response is partially dependent on dERR, leading to the metabolic defects observed in mutants. Our data support the model that dERR contributes to a transcriptional switch during pupal development that establishes the metabolic state of the adult fly.

Codemasters during the latest Inside Xbox event announced Dirt 5 for the Xbox Series X. The game will also launch for the PlayStation 5, PlayStation 4, Xbox One, and Google Stadia. It will release in October 2020.

View the announcement trailer below:

Read an overview of the game via Xbox below:

Fresh out of the box from the latest Inside Xbox, myself and the whole Codemasters team are delighted to reveal Dirt 5 to the world (but especially you), launching this year on both Xbox One and Xbox Series X.

For a while now, our dedicated development team in Cheshire, UK has been under the hood of this machine, turning a concept into reality. Well, gaming reality. You get what I mean. That concept? To make the boldest, bravest, most stylish off-road racing game ever made, where intense, competitive action is just the beginning of what blows you away in Dirt 5.

To the uninitiated who may not be clued up on the legacy of Dirt, let’s go for a drive, all the way back to 1998, when Colin McRae Rally brought the world of off-road racing into gaming and into the mainstream. With the series morphing into Dirt in 2007, it’s delivered high-impact extreme racing ever since – most recently through the brutal, ultra-realistic Dirt Rally 2.0. This time around with Dirt 5, we’re doing things a little… differently.

Take a peek at our announce trailer, first revealed exclusively during Inside Xbox, and you’ll see what we mean – from the stunning locations, to the epic racing, to the variety of vehicles and surfaces. We’re putting you behind the wheel of incredible off-road machines, in iconic real-world settings, to race through dynamic routes and extreme conditions. But don’t forget the concept. All that racing action is only part of the story.

We wanted to go bigger, in all possible ways. Take Career, which hands you a deep story-based mode with a star-studded cast, led by the legendary Troy Baker and Nolan North. These legendary voices of gaming, and some familiar names from the car culture world, lay out a story with decision-based changes and a proper narrative to get your teeth into.

There’s the franchise’s deepest livery editor and in-race Photo Mode, where you can show off your creative side. Then you’ve got the 12-player multiplayer action with playful objective-based modes, the four-player split-screen for offline frolics with your pals, and even more brand new features we’ll be revealing more on soon… I’m basically listing stuff at this point, but there’s so much going on here!

And not to forget: Everything we’re laying out here is raised up a notch through the, quite frankly, intimidating power of Xbox Series X. The team here has made use of the tools to create an unprecedented level of graphical fidelity and optimized performance. What does that mean for you in Dirt 5? Constant action, greater potential in gameplay, and seeing every spec of mud kick up and splat onto your windscreen. Ah, bliss.

Before I leave you, I wanted to give you a pro tip; a little pocket of knowledge to store away until Dirt 5 bursts onto the scene this Autumn. When you jump into this game, forget the norm. Forget expectations. Forget the ‘regular’ way of playing. Dirt 5 dares you – and rewards you – for being creative, stylish, and sometimes for being a straight-up lunatic.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443421/dirt-5-announced-coming-to-xbox-series-x-ps5-ps4-xbox-one/

CORONAVIRUS has forced people to re-evaluate their finances as income takes a hit and budgets are stretched. One of the first port of calls for change has been direct debits and new research reveals that some people may find themselves with more cash available once this all ends.

Codemasters next racing game, DIRT 5 has been announced.

Twitch is doubling down on esports in this new era of social distancing as a number of traditional sporting events have been cancelled. The company this week introduced a new esports directory on its site that will make it easier for viewers to find live matches, information on players, games with active competition leagues, a […]

Oscar-winning Iranian director Asghar Farhadi said Sunday he will not attend the Academy Awards on Feb. 26, “even if exceptions were to be made for my trip,” as protests over President Donald Trump's immigration ban spread to Hollywood's biggest global stage.

Damien Comolli, who took the England international to Anfield, saw the Reds enter into transfer talks with the Cottagers during the summer of 2012

Director Josh Trank opens up about the bitterness and resentment he felt towards comic book movies following the critical and commercial failure of his 2015 film Fantastic Four, and praises superhero filmmakers James Gunn and Zack Snyder.

Miley Cyrus doesn't get a reply from all the celebrities she messages.

Gas cookers making people sick and exposing tens of millions to air pollution levels that would be illegal if they were outside

Gas stoves are making people sick, contributing pollution that makes indoor air up to two to five times dirtier than outdoor air, according to a new report.

Related: Microplastics found in greater quantities than ever before on seabed

Oscar-winning "Jojo Rabbit" screenwriter Taika Waititi will direct and co-write a new "Star Wars" feature film for theaters, Walt Disney Co said on Monday.

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Oscar-winning illustrator and film director Gene Deitch has died at the age of 95.

Award-winning film-maker Gurinder Chadha has hailed the "NHS heroes" who stayed at her aunt's bedside as she lost the fight with coronavirus complications in hospital.

Twitter users have been complaining that their direct messaging function (DMs) is down.

The coronavirus pandemic is transforming the funeral industry and leading people to seek alternatives to traditions dating back hundreds of years, experts say.

Felix Project volunteer Carrie Hogan shares her story You can donate here virginmoneygiving.com/fund/FoodforLondonNOW

Experiment in mice indicates exercise provides high level of protection from cancer, even among those with diabetes and obesity

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There’s been a bunch of scuttlebutt around this game being delisted from the eShop, supposedly mining bitcoin and a disagreement between the publisher and the IP owner. No matter the truth, grab it at retail pricing and don’t pay scalpers on eBay.

The sequel to 2017 orc-cop buddy movie Bright, starring Will Smith, has lined up a director.

As a longtime Paris resident, at first I feared Dirt might be yet another expat tale of moving to France en famille, with all its tedious clichés. I should have known better.

Announcement followed a day of newly revealed Star Wars projects

The singer said the milestone would be a "very special moment".

"We hereby want to communicate that the directors below signatories have transferred to President Bartomeu our decision to irrevocably resign from our status as FC Barcelona executives," the letter said.

Tottenham will have to be cautious in the transfer market with the financial impact of coronavirus compounding restrictions already in place thanks to the debt owed on their stadium, former director of football Damien Comolli has warned.