Title: Keep Beauty Regimen Safe During Pregnancy, Doctor Advises
Category: Health News
Created: 4/30/2013 2:35:00 PM
Last Editorial Review: 5/1/2013 12:00:00 AM

Title: By 9 Months, Baby's Visual Learning Kicks In: Study
Category: Health News
Created: 4/30/2014 9:35:00 AM
Last Editorial Review: 4/30/2014 12:00:00 AM

Title: Home Visits May Help Heart Bypass Patients Fare Better
Category: Health News
Created: 5/1/2014 9:35:00 AM
Last Editorial Review: 5/1/2014 12:00:00 AM

Title: Trampolines Linked to More Than 1 Million ER Visits Over a Decade
Category: Health News
Created: 5/2/2014 12:35:00 PM
Last Editorial Review: 5/2/2014 12:00:00 AM

Title: Health Visits May Offer Chance to Prevent Suicide
Category: Health News
Created: 4/24/2015 12:00:00 AM
Last Editorial Review: 4/27/2015 12:00:00 AM

Title: Pediatrics Group Advises Doctors on How to Spot Child Abuse
Category: Health News
Created: 4/27/2015 12:00:00 AM
Last Editorial Review: 4/28/2015 12:00:00 AM

Title: Female Pelvis Widens, Then Shrinks Over a Lifetime, Study Finds
Category: Health News
Created: 4/25/2016 12:00:00 AM
Last Editorial Review: 4/26/2016 12:00:00 AM

Title: After Age 50, Yearly Eye Checks May Catch Common Cause of Vision Loss
Category: Health News
Created: 4/28/2018 12:00:00 AM
Last Editorial Review: 4/30/2018 12:00:00 AM

Title: Make Your Amusement Park Visits Safe
Category: Health News
Created: 5/4/2018 12:00:00 AM
Last Editorial Review: 5/4/2018 12:00:00 AM

Title: 'Buzzing' in Ear Alerted Boy to Very Unwelcome Visitor
Category: Health News
Created: 5/1/2019 12:00:00 AM
Last Editorial Review: 5/2/2019 12:00:00 AM

Title: Health Tip: What to Expect From a Gynecologist Visit
Category: Health News
Created: 5/3/2019 12:00:00 AM
Last Editorial Review: 5/3/2019 12:00:00 AM

Title: With Macular Degeneration, 1 Missed Visit to Eye Doc Can Mean Vision Loss
Category: Health News
Created: 2/7/2020 12:00:00 AM
Last Editorial Review: 2/10/2020 12:00:00 AM

Title: Rising Number of Older Americans at Risk of Vision Loss
Category: Health News
Created: 3/12/2020 12:00:00 AM
Last Editorial Review: 3/13/2020 12:00:00 AM

The most recent meeting of the PMC Advisory Committee was held at the National Library of Medicine on June 15, 2009. The committee meets at least once a year and its members are appointed by the NIH Director from the biomedical information communities and the general public. Dr. Gary Ward, of the Department of Microbiology & Molecular Genetics at the University of Vermont, has been appointed to serve as Chair of the Committee through January 2011.

Four new members have been appointed to serve on the PMC National Advisory Committee: Mike Rossner of Rockefeller University Press, Jan Fassler of the University of Iowa, Ivy Anderson of the California Digital Library, and Delores Meglio from the Knovel Corporation. Each member will serve a 4-year term. The next meeting of the committee is scheduled for June 4, 2010. For more information on the committee, see PMC National Advisory Committee.

Four new members have been appointed to serve on the PMC National Advisory Committee: Philip Bourne, of the University of California, San Diego; Sophia Colamarino, an independent consultant in San Francisco; Paul Courant, of the University of Michigan; and Patricia Thibodeau, of Duke University. Each member will serve a 4-year term. The next meeting of the committee is scheduled for Friday, June 17, 2011. For more information on the committee, see PMC National Advisory Committee.

The PMC Advisory Committee will hold its annual meeting at the National Library of Medicine on Friday, June 17, 2011 from 9:30 am to 3 pm. Four new committee members will be joining the group, see New Members Appointed to PMC Advisory Committee. Presentations will include discussions relating to the NIH Public Access policy and a viewing of the PMC 10th Anniversary video. For more information, see PMC National Advisory Committee.

The following new members have been appointed to serve on the PMC National Advisory Committee: Martha Bedard, Dean of Libraries at the University of New Mexico; and Lorraine Haricombe, Dean of Libraries at the University of Kansas and a member of SPARC's board. The next meeting of the committee is scheduled for June 19, 2012. For more information, see PMC National Advisory Committee.

As of February 1, 2013, the following new members have been appointed to serve on the PMC National Advisory Committee: Ms. Sharon Terry of the Genetic Alliance; Dr. C. Victor Jongneel of the University of Illinois at Urbana-Champaign; Dr. Bevin Engelward of the Massachusetts Institute of Technology; Dr. Randall Morse of the Wadsworth Center; and Dr. Adelita Cantu of the University of Texas. For more information, see PMC National Advisory Committee.

This year's PMC Advisory Committee meeting will be held on Tuesday, June 10. The meeting will take place in the NLM Board room starting at 9:30 am. Stay tuned for further details.

Title: Could ED Drugs Threaten Men's Vision?
Category: Health News
Created: 2/7/2020 12:00:00 AM
Last Editorial Review: 2/7/2020 12:00:00 AM

ABSTRACT

Transporters belonging to the chromosomally encoded resistance-nodulation-division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria. However, the cotransfer of large gene clusters encoding RND-type pumps from the chromosome to a plasmid appears infrequent, and no plasmid-mediated RND efflux pump gene cluster has yet been found to confer resistance to tigecycline. Here, we identified a novel RND efflux pump gene cluster, designated tmexCD1-toprJ1, on plasmids from five pandrug-resistant Klebsiella pneumoniae isolates of animal origin. TMexCD1-TOprJ1 increased (by 4- to 32-fold) the MICs of tetracyclines (including tigecycline and eravacycline), quinolones, cephalosporins, and aminoglycosides for K. pneumoniae, Escherichia coli, and Salmonella. TMexCD1-TOprJ1 is closely related (64.5% to 77.8% amino acid identity) to the MexCD-OprJ efflux pump encoded on the chromosome of Pseudomonas aeruginosa. In an IncFIA plasmid, pHNAH8I, the tmexCD1-toprJ1 gene cluster lies adjacent to two genes encoding site-specific integrases, which may have been responsible for its acquisition. Expression of TMexCD1-TOprJ1 in E. coli resulted in increased tigecycline efflux and in K. pneumoniae negated the efficacy of tigecycline in an in vivo infection model. Expression of TMexCD1-TOprJ1 reduced the growth of E. coli and Salmonella but not K. pneumoniae. tmexCD1-toprJ1-positive Enterobacteriaceae isolates were rare in humans (0.08%) but more common in chicken fecal (14.3%) and retail meat (3.4%) samples. Plasmid-borne tmexCD1-toprJ1-like gene clusters were identified in sequences in GenBank from Enterobacteriaceae and Pseudomonas strains from multiple continents. The possibility of further global dissemination of the tmexCD1-toprJ1 gene cluster and its analogues in Enterobacteriaceae via plasmids may be an important consideration for public health planning.

IMPORTANCE In an era of increasing concerns about antimicrobial resistance, tigecycline is likely to have a critically important role in the treatment of carbapenem-resistant Enterobacteriaceae, the most problematic pathogens in human clinical settings—especially carbapenem-resistant K. pneumoniae. Here, we identified a new plasmid-borne RND-type tigecycline resistance determinant, TMexCD1-TOprJ1, which is widespread among K. pneumoniae isolates from food animals. tmexCD1-toprJ1 appears to have originated from the chromosome of a Pseudomonas species and may have been transferred onto plasmids by adjacent site-specific integrases. Although tmexCD1-toprJ1 still appears to be rare in human clinical isolates, considering the transferability of the tmexCD1-toprJ1 gene cluster and the broad substrate spectrum of TMexCD1-TOprJ1, further dissemination of this mobile tigecycline resistance determinant is possible. Therefore, from a "One Health" perspective, measures are urgently needed to monitor and control its further spread. The current low prevalence in human clinical isolates provides a precious time window to design and implement measures to tackle this.

ABSTRACT

This research analyzed six Aspergillus fumigatus genes encoding putative efflux proteins for their roles as transporters. The A. fumigatus genes abcA, abcC, abcF, abcG, abcH, and abcI were cloned into plasmids and overexpressed in a Saccharomyces cerevisiae strain in which the highly active endogenous ABC transporter gene PDR5 was deleted. The activity of each transporter was measured by efflux of rhodamine 6G and accumulation of alanine β-naphthylamide. The transporters AbcA, AbcC, and AbcF had the strongest efflux activities of these compounds. All of the strains with plasmid-expressed transporters had more efflux activity than did the PDR5-deleted background strain. We performed broth microdilution drug susceptibility testing and agar spot assays using an array of compounds and antifungal drugs to determine the transporter specificity and drug susceptibility of the strains. The transporters AbcC and AbcF showed the broadest range of substrate specificity, while AbcG and AbcH had the narrowest range of substrates. Strains expressing the AbcA, AbcC, AbcF, or AbcI transporter were more resistant to fluconazole than was the PDR5-deleted background strain. Strains expressing AbcC and AbcF were additionally more resistant to clotrimazole, itraconazole, ketoconazole, and posaconazole than was the background strain. Finally, we analyzed the expression levels of the genes by reverse transcription-quantitative PCR (RT-qPCR) in triazole-susceptible and -resistant A. fumigatus clinical isolates. All of these transporters are expressed at a measurable level, and transporter expression varied significantly between strains, demonstrating the high degree of phenotypic variation, plasticity, and divergence of which this species is capable.

IMPORTANCE One mechanism behind drug resistance is altered export out of the cell. This work is a multifaceted analysis of membrane efflux transporters in the human fungal pathogen A. fumigatus. Bioinformatics evidence infers that there is a relatively large number of genes in A. fumigatus that encode ABC efflux transporters. However, very few of these transporters have been directly characterized and analyzed for their potential role in drug resistance.

Our objective was to determine if these undercharacterized proteins function as efflux transporters and then to better define whether their efflux substrates include antifungal drugs used to treat fungal infections. We chose six A. fumigatus potential plasma membrane ABC transporter genes for analysis and found that all six genes produced functional transporter proteins. We used two fungal systems to look for correlations between transporter function and drug resistance. These transporters have the potential to produce drug-resistant phenotypes in A. fumigatus. Continued characterization of these and other transporters may assist in the development of efflux inhibitor drugs.

ABSTRACT

Packaging of genomic RNA (gRNA) by retroviruses is essential for infectivity, yet the subcellular site of the initial interaction between the Gag polyprotein and gRNA remains poorly defined. Because retroviral particles are released from the plasma membrane, it was previously thought that Gag proteins initially bound to gRNA in the cytoplasm or at the plasma membrane. However, the Gag protein of the avian retrovirus Rous sarcoma virus (RSV) undergoes active nuclear trafficking, which is required for efficient gRNA encapsidation (L. Z. Scheifele, R. A. Garbitt, J. D. Rhoads, and L. J. Parent, Proc Natl Acad Sci U S A 99:3944–3949, 2002, https://doi.org/10.1073/pnas.062652199; R. Garbitt-Hirst, S. P. Kenney, and L. J. Parent, J Virol 83:6790–6797, 2009, https://doi.org/10.1128/JVI.00101-09). These results raise the intriguing possibility that the primary contact between Gag and gRNA might occur in the nucleus. To examine this possibility, we created a RSV proviral construct that includes 24 tandem repeats of MS2 RNA stem-loops, making it possible to track RSV viral RNA (vRNA) in live cells in which a fluorophore-conjugated MS2 coat protein is coexpressed. Using confocal microscopy, we observed that both wild-type Gag and a nuclear export mutant (Gag.L219A) colocalized with vRNA in the nucleus. In live-cell time-lapse images, the wild-type Gag protein trafficked together with vRNA as a single ribonucleoprotein (RNP) complex in the nucleoplasm near the nuclear periphery, appearing to traverse the nuclear envelope into the cytoplasm. Furthermore, biophysical imaging methods suggest that Gag and the unspliced vRNA physically interact in the nucleus. Taken together, these data suggest that RSV Gag binds unspliced vRNA to export it from the nucleus, possibly for packaging into virions as the viral genome.

IMPORTANCE Retroviruses cause severe diseases in animals and humans, including cancer and acquired immunodeficiency syndromes. To propagate infection, retroviruses assemble new virus particles that contain viral proteins and unspliced vRNA to use as gRNA. Despite the critical requirement for gRNA packaging, the molecular mechanisms governing the identification and selection of gRNA by the Gag protein remain poorly understood. In this report, we demonstrate that the Rous sarcoma virus (RSV) Gag protein colocalizes with unspliced vRNA in the nucleus in the interchromatin space. Using live-cell confocal imaging, RSV Gag and unspliced vRNA were observed to move together from inside the nucleus across the nuclear envelope, suggesting that the Gag-gRNA complex initially forms in the nucleus and undergoes nuclear export into the cytoplasm as a viral ribonucleoprotein (vRNP) complex.

ABSTRACT

Cell division requires proper spatial coordination with the chromosome, which undergoes dynamic changes during chromosome replication and segregation. FtsZ is a bacterial cytoskeletal protein that assembles into the Z-ring, providing a platform to build the cell division apparatus. In the model bacterium Caulobacter crescentus, the cellular localization of the Z-ring is controlled during the cell cycle in a chromosome replication-coupled manner. Although dynamic localization of the Z-ring at midcell is driven primarily by the replication origin-associated FtsZ inhibitor MipZ, the mechanism ensuring accurate positioning of the Z-ring remains unclear. In this study, we showed that the Z-ring colocalizes with the replication terminus region, located opposite the origin, throughout most of the C. crescentus cell cycle. Spatial organization of the two is mediated by ZapT, a previously uncharacterized protein that interacts with the terminus region and associates with ZapA and ZauP, both of which are part of the incipient division apparatus. While the Z-ring and the terminus region coincided with the presence of ZapT, colocalization of the two was perturbed in cells lacking zapT, which is accompanied by delayed midcellular positioning of the Z-ring. Moreover, cells overexpressing ZapT showed compromised positioning of the Z-ring and MipZ. These findings underscore the important role of ZapT in controlling cell division processes. We propose that ZapT acts as a molecular bridge that physically links the terminus region to the Z-ring, thereby ensuring accurate site selection for the Z-ring. Because ZapT is conserved in proteobacteria, these findings may define a general mechanism coordinating cell division with chromosome organization.

IMPORTANCE Growing bacteria require careful tuning of cell division processes with dynamic organization of replicating chromosomes. In enteric bacteria, ZapA associates with the cytoskeletal Z-ring and establishes a physical linkage to the chromosomal replication terminus through its interaction with ZapB-MatP-DNA complexes. However, because ZapB and MatP are found only in enteric bacteria, it remains unclear how the Z-ring and the terminus are coordinated in the vast majority of bacteria. Here, we provide evidence that a novel conserved protein, termed ZapT, mediates colocalization of the Z-ring with the terminus in Caulobacter crescentus, a model organism that is phylogenetically distant from enteric bacteria. Given that ZapT facilitates cell division processes in C. crescentus, this study highlights the universal importance of the physical linkage between the Z-ring and the terminus in maintaining cell integrity.

This season’s flu vaccine was 45% effective overall and 55% effective among children and teens, the Centers for Disease Control and Prevention reported in February.

Objective

To assess the risk of subsequent stroke among older patients discharged from an emergency department (ED) without a diagnosis of TIA or stroke.

During meiotic prophase, concurrent transcription, recombination, and chromosome synapsis place substantial topological strain on chromosomal DNA, but the role of topoisomerases in this context remains poorly defined. Here, we analyzed the roles of topoisomerases I and II (Top1 and Top2) during meiotic prophase in Saccharomyces cerevisiae. We show that both topoisomerases accumulate primarily in promoter-containing intergenic regions of actively transcribing genes, including many meiotic double-strand break (DSB) hotspots. Despite the comparable binding patterns, top1 and top2 mutations have different effects on meiotic recombination. TOP1 disruption delays DSB induction and shortens the window of DSB accumulation by an unknown mechanism. By contrast, temperature-sensitive top2-1 mutants exhibit a marked delay in meiotic chromosome remodeling and elevated DSB signals on synapsed chromosomes. The problems in chromosome remodeling were linked to altered Top2 binding patterns rather than a loss of Top2 catalytic activity, and stemmed from a defect in recruiting the chromosome remodeler Pch2/TRIP13 to synapsed chromosomes. No chromosomal defects were observed in the absence of TOP1. Our results imply independent roles for Top1 and Top2 in modulating meiotic chromosome structure and recombination.

Key Points

JABFM seeks to widely disseminate its peer-reviewed publications, increasing article visibility for the purpose of advancing scientific knowledge. We describe the journal’s approach to dissemination and recommend a number of strategies for authors to implement, including press releases and social media. Providing the article’s digital object identifier (DOI) is most useful, compared with links that can break, or attaching the article PDF, which will depress reader metrics. All JABFM articles are freely accessible online worldwide.

Wael Salem, Benjamin Cellini, Mark A. Frye, and Jean-Michel Mongeau

Most animals shift gaze by a ‘fixate and saccade’ strategy, where the fixation phase stabilizes background motion. A logical prerequisite for robust detection and tracking of moving foreground objects, therefore, is to suppress the perception of background motion. In a virtual reality magnetic tether system enabling free yaw movement, Drosophila implemented a fixate and saccade strategy in the presence of a static panorama. When the spatial wavelength of a vertical grating was below the Nyquist wavelength of the compound eyes, flies drifted continuously­ and gaze could not be maintained at a single location. Because the drift occurs from a motionless stimulus—thus any perceived motion stimuli are generated by the fly itself—it is illusory, driven by perceptual aliasing. Notably, the drift speed was significantly faster than under a uniform panorama suggesting perceptual enhancement due to aliasing. Under the same visual conditions in a rigid tether paradigm, wing steering responses to the unresolvable static panorama were not distinguishable from a resolvable static pattern, suggesting visual aliasing is induced by ego motion. We hypothesized that obstructing the control of gaze fixation also disrupts detection and tracking of objects. Using the illusory motion stimulus, we show that magnetically tethered Drosophila track objects robustly in flight even when gaze is not fixated as flies continuously drift. Taken together, our study provides further support for parallel visual motion processing and reveals the critical influence of body motion on visuomotor processing. Motion illusions can reveal important shared principles of information processing across taxa.

Myriam Franzke, Christian Kraus, David Dreyer, Keram Pfeiffer, M. Jerome Beetz, Anna L. Stöckl, James J. Foster, Eric J. Warrant, and Basil el Jundi

Monarch butterflies (Danaus plexippus) are prominent for their annual long-distance migration from North America to their overwintering area in Central Mexico. To find their way on this long journey, they use a sun compass as their main orientation reference but will also adjust their migratory direction with respect to mountain ranges. This indicates that the migratory butterflies also attend to the panorama to guide their travels. While the compass has been studied in detail in migrating butterflies, little is known about the orientation abilities of non-migrating butterflies. Here we studied if non-migrating butterflies - that stay in a more restricted area to feed and breed - also use a similar compass system to guide their flights. Performing behavioral experiments on tethered flying butterflies in an indoor LED flight simulator, we found that the monarchs fly along straight tracks with respect to a simulated sun. When a panoramic skyline was presented as the only orientation cue, the butterflies maintained their flight direction only during short sequences suggesting that they potentially use it for flight stabilization. We further found that when we presented the two cues together, the butterflies incorporate both cues in their compass. Taken together, we here show that non-migrating monarch butterflies can combine multiple visual cues for robust orientation, an ability that may also aid them during their migration.

Annette E. Allen, Joshua W. Mouland, Jessica Rodgers, Beatriz Bano-Otalora, Ronald H. Douglas, Glen Jeffery, Anthony A. Vugler, Timothy M. Brown, and Robert J. Lucas

An animal's temporal niche – the time of day at which it is active – is known to drive a variety of adaptations in the visual system. This includes variations in the topography, spectral sensitivity and density of retinal photoreceptors, and changes in the eye's gross anatomy and spectral transmission characteristics. We have characterised visual spectral sensitivity in the murid rodent Rhabdomys pumilio (‘the four-striped grass mouse’), which is the same family as (nocturnal) mice and rats, but exhibits a strong diurnal niche. As is common in diurnal species, the Rhabdomys lens acts as a long-pass spectral filter, providing limited transmission of light <400nm. Conversely, we found strong sequence homologies with the Rhabdomys SWS and MWS opsins and those of related nocturnal species (mice and rats) whose SWS opsins are maximally sensitive in the near UV. We continued to assess in vivo spectral sensitivity of cone vision using electroretinography and multi-channel recordings from the visual thalamus. These revealed that responses across the human visible range could be adequately described by those of a single pigment (assumed to be MWS opsin) maximally sensitive ~500nm, but that sensitivity in the near UV required inclusion of a second pigment whose peak sensitivity lay well into the UV range (_max <400nm, likely ~360nm). We therefore conclude that, despite the UV-filtering effects of the lens, the Rhabdomys retains an SWS pigment with a UV-A _max. In effect, this somewhat paradoxical combination of long-pass lens and UV-A _max results in narrow-band sensitivity for SWS cone pathways in the UV-A range.

Long noncoding RNA molecules (lncRNAs) are estimated to account for the majority of eukaryotic genomic transcripts, and have been associated with multiple diseases in humans. However, our understanding of their structure–function relationships is scarce, with structural evidence coming mostly from indirect biochemical approaches or computational predictions. Here we describe direct visualization of the lncRNA HOTAIR (HOx Transcript AntIsense RNA) using atomic force microscopy (AFM) in nucleus-like conditions at 37°. Our observations reveal that HOTAIR has a discernible, although flexible, shape. Fast AFM scanning enabled the quantification of the motion of HOTAIR, and provided visual evidence of physical interactions with genomic DNA segments. Our report provides a biologically plausible description of the anatomy and intrinsic properties of HOTAIR, and presents a framework for studying the structural biology of lncRNAs.

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.

Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.

Discovery of the Breagh gas field in the Southern North Sea (SNS) has demonstrated the potential that the Lower Carboniferous (Visean, 346.7–330.9 Ma) Farne Group reservoirs have to contribute to the UK's future energy mix. New biostratigraphic correlations provide a basis to compare Asbian and Brigantian sedimentary cores from the Breagh Field and age-equivalent sediments exposed on the Northumberland Coast, which has proved critical in gaining an understanding of exploration and development opportunities. Thirteen facies associations characterize the mixed carbonate–siliciclastic system, grouped into: marine, delta front, delta shoreface, lower delta plain and upper delta plain gross depositional environments. The facies associations are interpreted as depositing in a mixed carbonate and siliciclastic fluvio-deltaic environment, and are arranged into coarsening- and cleaning-upward cycles (parasequences) bounded by flooding surfaces. Most cycles are characterized by mouth bars, distributary channels, interdistributary bays and common braided rivers, interpreted as river-dominated deltaic deposits. Some cycles include rare shoreface and tidally-influenced deposits, interpreted as river-dominated and wave- or tide-influenced deltaic deposits. The depositional processes that formed each cycle have important implications for the reservoir net/gross ratio (where this ratio indicates the proportion of sandstone beds in a cycle), thickness and lateral extent. The deltaic deposits were controlled by a combination of tectonic and eustatic (allocyclic) events and delta avulsion (autocyclic) processes, and are likely to reflect a changing tectonic regime, from extension within elongate fault-bounded basins (synrift) to passive regional thermal subsidence (post-rift). Deep incision by the Base Permian Unconformity across the Breagh Field has removed the Westphalian, Namurian and upper Visean, to leave the more prospective thicker clastic reservoirs within closure.

Thematic collection: This article is part of the Under-explored plays and frontier basins of the UK continental shelf collection available at: https://www.lyellcollection.org/cc/under-explored-plays-and-frontier-basins-of-the-uk-continental-shelf

As yet, very few vaccine candidates with activity in animals against Mycobacterium tuberculosis infection have been tested as therapeutic postexposure vaccines. We recently described two pools of mycobacterial proteins with this activity, and here we describe further studies in which four of these proteins (Rv1738, Rv2032, Rv3130, and Rv3841) were generated as a fusion polypeptide and then delivered in a novel yeast-based platform (Tarmogen) which itself has immunostimulatory properties, including activation of Toll-like receptors. This platform can deliver antigens into both the class I and class II antigen presentation pathways and stimulate strong Th1 and Th17 responses. In mice this fusion vaccine, designated GI-19007, was immunogenic and elicited strong gamma interferon (IFN-) and interleukin-17 (IL-17) responses; despite this, they displayed minimal prophylactic activity in mice that were subsequently infected with a virulent clinical strain. In contrast, in a therapeutic model in the guinea pig, GI-19007 significantly reduced the lung bacterial load and reduced lung pathology, particularly in terms of secondary lesion development, while significantly improving survival in one-third of these animals. In further studies in which guinea pigs were vaccinated with BCG before challenge, therapeutic vaccination with GI-19007 initially improved survival versus that of animals given BCG alone, although this protective effect was gradually lost at around 400 days after challenge. Given its apparent ability to substantially limit bacterial dissemination within and from the lungs, GI-19007 potentially can be used to limit lung damage as well as facilitating chemotherapeutic regimens in infected individuals.

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.

The first Biograph Vision PET/CT system (Siemens Healthineers) was installed at the University Medical Center Groningen. Improved performance of this system could allow for a reduction in activity administration or scan duration. This study evaluated the effects of reduced scan duration in oncologic ¹⁸F-FDG PET imaging on quantitative and subjective imaging parameters and its influence on clinical image interpretation. Methods: Patients referred for a clinical PET/CT scan were enrolled in this study, received a weight-based ¹⁸F-FDG injected activity, and underwent list-mode PET acquisition at 180 s per bed position (s/bp). Acquired PET data were reconstructed using the vendor-recommended clinical reconstruction protocol (hereafter referred to as "clinical"), using the clinical protocol with additional 2-mm gaussian filtering (hereafter referred to as "clinical+G2"), and—in conformance with European Association of Nuclear Medicine Research Ltd. (EARL) specifications—using different scan durations per bed position (180, 120, 60, 30, and 10 s). Reconstructed images were quantitatively assessed for comparison of SUVs and noise. In addition, clinically reconstructed images were qualitatively evaluated by 3 nuclear medicine physicians. Results: In total, 30 oncologic patients (22 men, 8 women; age: 48–88 y [range], 67 ± 9.6 y [mean ± SD]) received a single weight-based (3 MBq/kg) ¹⁸F-FDG injected activity (weight: 45–123 kg [range], 81 ± 15 kg [mean ± SD]; activity: 135–380 MBq [range], 241 ± 47.3 MBq [mean ± SD]). Significant differences in lesion SUV_max were found between the 180-s/bp images and the 30- and 10-s/bp images reconstructed using the clinical protocols, whereas no differences were found in lesion SUV_peak. EARL-compliant images did not show differences in lesion SUV_max or SUV_peak between scan durations. Quantitative parameters showed minimal deviation (~5%) in the 60-s/bp images. Therefore, further subjective image quality assessment was conducted using the 60-s/bp images. Qualitative assessment revealed the influence of personal preference on physicians’ willingness to adopt the 60-s/bp images in clinical practice. Although quantitative PET parameters differed minimally, an increase in noise was observed. Conclusion: With the Biograph Vision PET/CT system for oncologic ¹⁸F-FDG imaging, scan duration or activity administration could be reduced by a factor of 3 or more with the use of the clinical+G2 or the EARL-compliant reconstruction protocol.

Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for noninvasively visualizing these cells in a living organism. 1-(2'-deoxy-2'-¹⁸F-fluoroarabinofuranosyl) cytosine (¹⁸F-FAC) is a PET radiotracer that measures deoxyribonucleoside salvage and accumulates preferentially in immune cells. We hypothesized that ¹⁸F-FAC PET could noninvasively image brain-infiltrating leukocytes. Methods: Healthy mice were imaged with ¹⁸F-FAC PET to quantify if this radiotracer crosses the blood–brain barrier (BBB). Experimental autoimmune encephalomyelitis (EAE) is a mouse disease model with brain-infiltrating leukocytes. To determine whether ¹⁸F-FAC accumulates in brain-infiltrating leukocytes, EAE mice were analyzed with ¹⁸F-FAC PET, digital autoradiography, and immunohistochemistry, and deoxyribonucleoside salvage activity in brain-infiltrating leukocytes was analyzed ex vivo. Fingolimod-treated EAE mice were imaged with ¹⁸F-FAC PET to assess if this approach can monitor the effect of an immunomodulatory drug on brain-infiltrating leukocytes. PET scans of individuals injected with 2-chloro-2'-deoxy-2'-¹⁸F-fluoro-9-β-d-arabinofuranosyl-adenine (¹⁸F-CFA), a PET radiotracer that measures deoxyribonucleoside salvage in humans, were analyzed to evaluate whether ¹⁸F-CFA crosses the human BBB. Results: ¹⁸F-FAC accumulates in the healthy mouse brain at levels similar to ¹⁸F-FAC in the blood (2.54 ± 0.2 and 3.04 ± 0.3 percentage injected dose per gram, respectively) indicating that ¹⁸F-FAC crosses the BBB. EAE mice accumulate ¹⁸F-FAC in the brain at 180% of the levels of control mice. Brain ¹⁸F-FAC accumulation localizes to periventricular regions with significant leukocyte infiltration, and deoxyribonucleoside salvage activity is present at similar levels in brain-infiltrating T and innate immune cells. These data suggest that ¹⁸F-FAC accumulates in brain-infiltrating leukocytes in this model. Fingolimod-treated EAE mice accumulate ¹⁸F-FAC in the brain at 37% lower levels than control-treated EAE mice, demonstrating that ¹⁸F-FAC PET can monitor therapeutic interventions in this mouse model. ¹⁸F-CFA accumulates in the human brain at 15% of blood levels (0.08 ± 0.01 and 0.54 ± 0.07 SUV, respectively), indicating that ¹⁸F-CFA does not cross the BBB in humans. Conclusion: ¹⁸F-FAC PET can visualize brain-infiltrating leukocytes in a mouse MS model and can monitor the response of these cells to an immunomodulatory drug. Translating this strategy into humans will require exploring additional radiotracers.

OBJECTIVE

To report U.S. national population-based rates and trends in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) among adults, in both the emergency department (ED) and inpatient settings.

Symmetric division of stem cells positive for gastrin receptor CCK2R is linked to gastric cancer.