bluuebunny/crossref_metadata_2025 huggingface dataset:
SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer
Authors: Perone Ylenia , Farrugia Aaron J. , Rodríguez-Meira Alba , Győrffy Balázs , Ion Charlotte , Uggetti Andrea , Chronopoulos Antonios , Marrazzo Pasquale , Faronato Monica , Shousha Sami , Davies Claire , Steel Jennifer H. , Patel Naina , del Rio Hernandez Armando , Coombes Charles , Pruneri Giancarlo , Lim Adrian , Calvo Fernando , Magnani Luca
Published: May 2019

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.
Maritime Continent water cycle regulates low-latitude chokepoint of global ocean circulation
Authors: Lee Tong , Fournier Séverine , Gordon Arnold L. , Sprintall Janet
Published: May 2019

The Maritime Continent (MC) is a low-latitude chokepoint of the world oceans with the Indonesian throughflow (ITF) linking the Indo-Pacific oceans, influencing global ocean circulation, climate, and biogeochemistry. While previous studies suggested that South-China-Sea freshwaters north of the MC intruding the Indonesian Seas weaken the ITF during boreal winter, the impact of the MC water cycle on the ITF has not been investigated. Here we use ocean-atmosphere-land satellite observations to reveal the dominant contribution of the MC monsoonal water cycle to boreal winter−spring freshening in the Java Sea through local precipitation and runoff from Kalimantan, Indonesia. We further demonstrate that the freshening corresponds to a reduced southward pressure gradient that would weaken the ITF. Therefore, the MC water cycle plays a critical role regulating ITF seasonality. The findings have strong implications to longer-term variations of the ITF associated with the variability and change of Indo-Pacific climate and MC water cycle.
Sox17 is required for endothelial regeneration following inflammation-induced vascular injury
Authors: Liu Menglin , Zhang Lianghui , Marsboom Glenn , Jambusaria Ankit , Xiong Shiqin , Toth Peter T. , Benevolenskaya Elizaveta V. , Rehman Jalees , Malik Asrar B.
Published: May 2019

Repair of the endothelial cell barrier after inflammatory injury is essential for tissue fluid homeostasis and normalizing leukocyte transmigration. However, the mechanisms of endothelial regeneration remain poorly understood. Here we show that the endothelial and hematopoietic developmental transcription factor Sox17 promotes endothelial regeneration in the endotoxemia model of endothelial injury. Genetic lineage tracing studies demonstrate that the native endothelium itself serves as the primary source of endothelial cells repopulating the vessel wall following injury. We identify Sox17 as a key regulator of endothelial cell regeneration using endothelial-specific deletion and overexpression of Sox17. Endotoxemia upregulates Hypoxia inducible factor 1α, which in turn transcriptionally activates Sox17 expression. We observe that Sox17 increases endothelial cell proliferation via upregulation of Cyclin E1. Furthermore, endothelial-specific upregulation of Sox17 in vivo enhances lung endothelial regeneration. We conclude that endotoxemia adaptively activates Sox17 expression to mediate Cyclin E1-dependent endothelial cell regeneration and restore vascular homeostasis.
Initial state of DNA-Dye complex sets the stage for protein induced fluorescence modulation
Authors: Rashid Fahad , Raducanu Vlad-Stefan , Zaher Manal S. , Tehseen Muhammad , Habuchi Satoshi , Hamdan Samir M.
Published: May 2019

Protein-induced fluorescence enhancement (PIFE) is a popular tool for characterizing protein-DNA interactions. PIFE has been explained by an increase in local viscosity due to the presence of the protein residues. This explanation, however, denies the opposite effect of fluorescence quenching. This work offers a perspective for understanding PIFE mechanism and reports the observation of a phenomenon that we name protein-induced fluorescence quenching (PIFQ), which exhibits an opposite effect to PIFE. A detailed characterization of these two fluorescence modulations reveals that the initial fluorescence state of the labeled mediator (DNA) determines whether this mediator-conjugated dye undergoes PIFE or PIFQ upon protein binding. This key role of the mediator DNA provides a protocol for the experimental design to obtain either PIFQ or PIFE, on-demand. This makes the arbitrary nature of the current experimental design obsolete, allowing for proper integration of both PIFE and PIFQ with existing bulk and single-molecule fluorescence techniques.
Femtosecond time-resolved two-photon photoemission studies of ultrafast carrier relaxation in Cu2O photoelectrodes
Authors: Borgwardt Mario , Omelchenko Stefan T. , Favaro Marco , Plate Paul , Höhn Christian , Abou-Ras Daniel , Schwarzburg Klaus , van de Krol Roel , Atwater Harry A. , Lewis Nathan S. , Eichberger Rainer , Friedrich Dennis
Published: May 2019

Cuprous oxide (Cu2O) is a promising material for solar-driven water splitting to produce hydrogen. However, the relatively small accessible photovoltage limits the development of efficient Cu2O based photocathodes. Here, femtosecond time-resolved two-photon photoemission spectroscopy has been used to probe the electronic structure and dynamics of photoexcited charge carriers at the Cu2O surface as well as the interface between Cu2O and a platinum (Pt) adlayer. By referencing ultrafast energy-resolved surface sensitive spectroscopy to bulk data we identify the full bulk to surface transport dynamics for excited electrons rapidly localized within an intrinsic deep continuous defect band ranging from the whole crystal volume to the surface. No evidence of bulk electrons reaching the surface at the conduction band level is found resulting into a substantial loss of their energy through ultrafast trapping. Our results uncover main factors limiting the energy conversion processes in Cu2O and provide guidance for future material development.
Publisher Correction: Multicolor multiscale brain imaging with chromatic multiphoton serial microscopy
Authors: Abdeladim Lamiae , Matho Katherine S. , Clavreul Solène , Mahou Pierre , Sintes Jean-Marc , Solinas Xavier , Arganda-Carreras Ignacio , Turney Stephen G. , Lichtman Jeff W. , Chessel Anatole , Bemelmans Alexis-Pierre , Loulier Karine , Supatto Willy , Livet Jean , Beaurepaire Emmanuel
Published: May 2019

Affiliation 4 incorrectly read ‘University of the Basque Country (Ikerbasque), University of the Basque Country and Donostia International Physics Center, San Sebastian 20018, Spain.’

Also, the affiliations of Ignacio Arganda-Carreras with ‘IKERBASQUE, Basque Foundation for Science, Bilbao, 48013, Spain’ and ‘Donostia International Physics Center (DIPC), San Sebastian, 20018, Spain’ were inadvertently omitted.

Additionally, the third sentence of the first paragraph of the Results section entitled ‘Multicontrast organ-scale imaging with ChroMS microscopy’ incorrectly read ‘For example, one can choose lambda1 = 850 and lambda2 = 110 nm for optimal two-photon excitation of blue and red chromophores.’. The correct version reads ‘lambda2 = 1100 nm’ instead of ‘lambda2 = 110 nm’. These errors have now been corrected in the PDF and HTML versions of the Article.
A comparison of exercise interventions from bed rest studies for the prevention of musculoskeletal loss
Authors: Konda Nagarjun N. , Karri Rama S. , Winnard Andrew , Nasser Mona , Evetts Simon , Boudreau Eilis , Caplan Nick , Gradwell David , Velho Rochelle M.
Published: May 2019

Musculoskeletal loss in actual or simulated microgravity occurs at a high rate. Bed rest studies are a reliable ground-based spaceflight analogue that allow for direct comparison of intervention and control participants. The aim of this review was to investigate the impact of exercise compared to no intervention on bone mineral density (BMD) and muscle cross-sectional area (muscle CSA) in bed rest studies relative to other terrestrial models. Eligible bed rest studies with healthy participants had an intervention arm with an exercise countermeasure and a control arm. A search strategy was implemented for MEDLINE. After screening, eight studies were identified for inclusion. Interventions included resistive exercise (RE), resistive vibration exercise (RVE), flywheel resistive exercise, treadmill exercise with lower body negative pressure (LBNP) and a zero-gravity locomotion simulator (ZLS). Lower limb skeletal sites had the most significant BMD losses, particularly at the hip which reduced in density by 4.59% (p < 0.05) and the tibial epiphysis by 6% (p < 0.05). Exercise attenuated bone loss at the hip and distal tibia compared to controls (p < 0.05). Muscle CSA changes indicated that the calf and quadriceps were most affected by bed rest. Exercise interventions significantly attenuated loss of muscle mass. ZLS, LBNP treadmill and RE significantly attenuated bone and muscle loss at the hip compared to baseline and controls. Despite exercise intervention, high rates of bone loss were still observed. Future studies should consider adding bisphosphonates and pharmacological/nutrition-based interventions for consideration of longer-duration missions. These findings correlate to terrestrial bed rest settings, for example, stroke or spinal-injury patients.
Identification of an early cell fate regulator by detecting dynamics in transcriptional heterogeneity and co-regulation during astrocyte differentiation
Authors: Ando Tatsuya , Kato Ryuji , Honda Hiroyuki
Published: May 2019

There are an increasing number of reports that characterize the temporal behavior of gene expression at the single-cell level during cell differentiation. Despite accumulation of data describing the heterogeneity of biological responses, the dynamics of gene expression heterogeneity and its regulation during the differentiation process have not been studied systematically. To understand transcriptional heterogeneity during astrocyte differentiation, we analyzed single-cell transcriptional data from cells representing the different stages of astrocyte differentiation. When we compared the transcriptional variability of co-expressed genes between the undifferentiated and differentiated states, we found that there was significant increase in transcriptional variability in the undifferentiated state. The genes showing large changes in both “variability” and “correlation” between neural stem cells (NSCs) and astrocytes were found to be functionally involved in astrocyte differentiation. We determined that these genes are potentially regulated by Ascl1, a previously known oscillatory gene in NSCs. Pharmacological blockade of Ntsr2, which is transcriptionally co-regulated with Ascl1, showed that Ntsr2 may play an important role in the differentiation from NSCs to astrocytes. This study shows the importance of characterizing transcriptional heterogeneity and rearrangement of the co-regulation network between different cell states. It also highlights the potential for identifying novel regulators of cell differentiation that will further increase our understanding of the molecular mechanisms underlying the differentiation process.
A sea-level plateau preceding the Marine Isotope Stage 2 minima revealed by Australian sediments
Authors: Ishiwa Takeshige , Yokoyama Yusuke , Okuno Jun’ichi , Obrochta Stephen , Uehara Katsuto , Ikehara Minoru , Miyairi Yosuke
Published: May 2019

Further understanding of past climate requires a robust estimate of global ice volume fluctuations that in turn rely on accurate global sea-level reconstructions. An advantage of Marine Isotope Stage 2 (MIS 2) is the availability of suitable material for radiocarbon dating to allow comparison of sea-level data with other paleoclimatic proxies. However, the number and accuracy of sea-level records during MIS 2 is currently lacking. Here we present the history of MIS 2 eustatic sea-level change as recorded in the Bonaparte Gulf, northwestern Australia by reconstructing relative sea level and then modeling glacial isostatic adjustment. The isostatically-corrected global sea-level history indicates that sea-level plateaued from 25.9 to 20.4 cal kyr BP (modeled median probability) prior reaching its minimum (19.7 to 19.1 cal kyr BP). Following the plateau, we detect a 10-m global sea-level fall over ~1,000 years and a short duration of the Last Glacial Maximum (global sea-level minimum; 19.7 to 19.1 cal kyr BP). These large changes in ice volume over such a short time indicates that the continental ice sheets never reached their isostatic equilibrium during the Last Glacial Maximum.
v-P2O5 micro-clustering in P-doped silica studied by a first-principles Raman investigation
Authors: Giacomazzi Luigi , Martin-Samos L. , Alessi A. , Richard N. , Boukenter A. , Ouerdane Y. , Girard S. , Valant M. , De Gironcoli S.
Published: May 2019

Synthetic vitreous silica is currently the preferred material for the production of optical fibres because of the several excellent properties of this glass, e.g. high transmission in the visible and IR domains, high mechanical strength, chemical durability, and ease of doping with various materials. For instance, fiber lasers and amplifiers exploit the light amplification properties provided by rare-earth ions employed as dopants in the core of silica-based optical fibers. The structure and composition of the nearest neighbor shell surrounding rare-earth ions in silica-based optical fibers and amplifiers have been intensively debated in the last decade. To reduce aggregation effects between rare-earth ions, co-dopants such as phosphorus and aluminium are added as structural modifiers; phosphorus-doping, in particular, has proved to be very efficient in dissolving rare-earth ions. In this work, we provide further insights concerning the embedding of P atoms into the silica network, which may be relevant for explaining the ease of formation of a phosphorus pentoxide nearest-neighbor shell around a rare-earth dopant. In particular, by means of first-principles calculations, we discuss alternative models for an irradiation (UV, x–, γ-rays) induced paramagnetic center, i.e. the so called room-temperature phosphorus-oxygen-hole center, and its precursors. We report that the most likely precursor of a room-temperature phosphorus-oxygen-hole center comprises of a micro-cluster of a few (at least two) neighboring phosphate tetrahedra, and correspondingly that the occurrence of isolated [(O-)2P(=O)2]− units is unlikely even at low P-doping concentrations. In fact, this work predicts that the symmetric stretching of P=O bonds in isolated [(O-)2P(=O)2]− units appears as a Raman band at a frequency of ~1110 cm−1, and only by including at least another corner-sharing phosphate tetrahedron, it is shown to shift to higher frequencies (up to ~40 cm−1) due to the shortening of P=O bonds, thereby leading to an improved agreement with the observed Raman band located at ~1145 cm−1.
Author Correction: Infection with the Makona variant results in a delayed and distinct host immune response compared to previous Ebola virus variants
Authors: Versteeg Krista , Menicucci Andrea R. , Woolsey Courtney , Mire Chad E. , Geisbert Joan B. , Cross Robert W. , Agans Krystle N. , Jeske Daniel , Messaoudi Ilhem , Geisbert Thomas W.
Published: May 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Diet quality and depression risk in a Japanese population: the Japan Public Health Center (JPHC)-based Prospective Study
Authors: Okubo Ryo , Matsuoka Yutaka J. , Sawada Norie , Mimura Masaru , Kurotani Kayo , Nozaki Shoko , Shikimoto Ryo , Tsugane Shoichiro
Published: May 2019

The association of overall diet quality based on the Japanese Food Guide Spinning Top with risk of depression is not known. This prospective cohort study aimed to determine whether higher adherence to the Japanese food guide reduced the risk of depression. Of 12,219 residents enrolled at baseline, we extracted 1,112 participants who completed a 5-year follow-up (1995) and participated in a mental health screening (2014–2015). Diet quality was scored based on adherence to the Japanese food guide and the ratio of white to red meat according to the Alternative Healthy Index and ranged from 0 (worst) to 80 (best). We calculated odds ratios and 95% confidence intervals for current psychiatrist-diagnosed depression per quartile of total score and of eight component scores with the lowest quartile as reference. Mean age of the participants was 73 years and 59% were women. Total diet quality score was not significantly associated with risk of depression 20 years after the baseline assessment. Among the eight components on the diet quality score, there was a significantly reduced risk for the highest quartile of the white to red meat ratio score. In conclusion, our results do not indicate that higher adherence to the Japanese food guide prevents depression.
Confidence as a diagnostic tool for perceptual aftereffects
Authors: Gallagher Regan M. , Suddendorf Thomas , Arnold Derek H.
Published: May 2019

Perceptual judgements are, by nature, a product both of sensation and the cognitive processes responsible for interpreting and reporting subjective experiences. Changed perceptual judgements may thus result from changes in how the world appears (perception), or subsequent interpretation (judgement). This ambiguity has led to persistent debates about how to interpret changes in decision-making, and if higher-order cognitions can change how the world looks, or sounds, or feels. Here we introduce an approach that can help resolve these ambiguities. In three motion-direction experiments, we measured perceptual judgements and subjective confidence. We show that each measure is sensitive to sensory information and can index sensory adaptation. Each measure is also sensitive to decision biases, but response bias impacts the central tendency of decision and confidence distributions differently. Our findings show that subjective confidence, when measured in addition to perceptual decisions, can supply important diagnostic information about the cause of aftereffects.
Platelet function in HIV plus dengue coinfection associates with reduced inflammation and milder dengue illness
Authors: Hottz Eugenio D. , Quirino-Teixeira Anna Cecíllia , Valls-de-Souza Rogério , Zimmerman Guy A. , Bozza Fernando A. , Bozza Patrícia T.
Published: May 2019

HIV-infected subjects under virological control still exhibit a persistent proinflammatory state. Thus, chronic HIV infection changes the host homeostasis towards an adapted immune response that may affect the outcome of coinfections. However, little is known about the impact of HIV infection on inflammatory amplification and clinical presentation in dengue. Platelets have been shown to participate in immune response in dengue and HIV. We hypothesized that altered platelet responses in HIV-infected subjects may contribute to altered inflammatory milieu and disease progression in dengue. We prospectively followed a cohort of 84 DENV-infected patients of whom 29 were coinfected with HIV under virological control. We report that dengue and HIV coinfection progress with reduced inflammation and milder disease progression with lower risk of vascular instability. Even though the degree of thrombocytopenia and platelet activation were similar between dengue-infected and HIV plus dengue-coinfected patients, plasma levels of the platelet-derived chemokines RANTES/CCL5 and PF4/CXCL4 were lower in coinfection. Consistently, platelets from coinfected patients presented defective secretion of the stored-chemokines PF4 and RANTES, but not newly synthesized IL-1β, when cultured ex vivo. These data indicate that platelets from HIV-infected subjects release lower levels of chemokines during dengue illness, which may contribute to milder clinical presentation during coinfection.
Simultaneous Quantitation of Cationic and Non-ionic Contrast Agents in Articular Cartilage Using Synchrotron MicroCT Imaging
Authors: Saukko Annina E. A. , Turunen Mikael J. , Honkanen Miitu K. M. , Lovric Goran , Tiitu Virpi , Honkanen Juuso T. J. , Grinstaff Mark W. , Jurvelin Jukka S. , Töyräs Juha
Published: May 2019

Early diagnosis of acute cartilage injuries enables monitoring of disease progression and improved treatment option planning to prevent post-traumatic osteoarthritis. In contrast-enhanced computed tomography (CECT), the changes in cationic agent diffusion within the tissue reflect cartilage degeneration. The diffusion in degenerated cartilage depends on proteoglycan (PG) content and water content, but each having an opposite effect on diffusion, thus compromising the diagnostic sensitivity. To overcome this limitation, we propose the simultaneous imaging of cationic (sensitive to PG and water contents) and non-ionic (sensitive to water content) agents. In this study, quantitative dual-energy CT (QDECT) imaging of two agents is reported for the first time at clinically feasible imaging time points. Furthermore, this is the first time synchrotron microCT with monochromatic X-rays is employed in cartilage CECT. Imaging was conducted at 1 and 2 h post contrast agent immersion. Intact, PG-depleted, and mechanically injured + PG-depleted cartilage samples (n = 33) were imaged in a mixture of cationic (iodine-based CA4+) and non-ionic (gadolinium-based gadoteridol) agents. Concurrent evaluation of CA4+ and gadoteridol partitions in cartilage is accomplished using QDECT. Subsequent normalization of the CA4+ partition with that of the gadoteridol affords CA4+ attenuations that significantly correlate with PG content – a key marker of OA.
Microbiota alter metabolism and mediate neurodevelopmental toxicity of 17β-estradiol
Authors: Catron Tara R. , Swank Adam , Wehmas Leah C. , Phelps Drake , Keely Scott P. , Brinkman Nichole E. , McCord James , Singh Randolph , Sobus Jon , Wood Charles E. , Strynar Mark , Wheaton Emily , Tal Tamara
Published: May 2019

Estrogenic chemicals are widespread environmental contaminants associated with diverse health and ecological effects. During early vertebrate development, estrogen receptor signaling is critical for many different physiologic responses, including nervous system function. Recently, host-associated microbiota have been shown to influence neurodevelopment. Here, we hypothesized that microbiota may biotransform exogenous 17-βestradiol (E2) and modify E2 effects on swimming behavior. Colonized zebrafish were continuously exposed to non-teratogenic E2 concentrations from 1 to 10 days post-fertilization (dpf). Changes in microbial composition and predicted metagenomic function were evaluated. Locomotor activity was assessed in colonized and axenic (microbe-free) zebrafish exposed to E2 using a standard light/dark behavioral assay. Zebrafish tissue was collected for chemistry analyses. While E2 exposure did not alter microbial composition or putative function, colonized E2-exposed larvae showed reduced locomotor activity in the light, in contrast to axenic E2-exposed larvae, which exhibited normal behavior. Measured E2 concentrations were significantly higher in axenic relative to colonized zebrafish. Integrated peak area for putative sulfonated and glucuronidated E2 metabolites showed a similar trend. These data demonstrate that E2 locomotor effects in the light phase are dependent on the presence of microbiota and suggest that microbiota influence chemical E2 toxicokinetics. More broadly, this work supports the concept that microbial colonization status may influence chemical toxicity.
Rim-to-Disc Ratio Outperforms Cup-to-Disc Ratio for Glaucoma Prescreening
Authors: Kumar J. R. Harish , Seelamantula Chandra Sekhar , Kamath Yogish Subraya , Jampala Rajani
Published: May 2019

We present a novel and fully automated fundus image processing technique for glaucoma prescreening based on the rim-to-disc ratio (RDR). The technique accurately segments the optic disc and optic cup and then computes the RDR based on which it is possible to differentiate a normal fundus from a glaucomatous one. The technique performs a further categorization into normal, moderate, or severely glaucomatous classes following the disc-damage-likelihood scale (DDLS). To the best of our knowledge, this is the first engineering attempt at using RDR and DDLS to perform glaucoma severity assessment. The segmentation of the optic disc and cup is based on the active disc, whose parameters are optimized to maximize the local contrast. The optimization is performed efficiently by means of a multiscale representation, accelerated gradient-descent, and Green’s theorem. Validations are performed on several publicly available databases as well as data provided by manufacturers of some commercially available fundus imaging devices. The segmentation and classification performance is assessed against expert clinician annotations in terms of sensitivity, specificity, accuracy, Jaccard, and Dice similarity indices. The results show that RDR based automated glaucoma assessment is about 8% to 10% more accurate than a cup-to-disc ratio (CDR) based system. An ablation study carried out considering the ground-truth expert outlines alone for classification showed that RDR is superior to CDR by 5.28% in a two-stage classification and about 3.21% in a three-stage severity grading.
Novel CMKLR1 Inhibitors for Application in Demyelinating Disease
Authors: Kumar Vineet , LaJevic Melissa , Pandrala Mallesh , Jacobo Sam A. , Malhotra Sanjay V. , Zabel Brian A.
Published: May 2019

Small molecules that disrupt leukocyte trafficking have proven effective in treating patients with multiple sclerosis (MS). We previously reported that chemerin receptor chemokine-like receptor 1 (CMKLR1) is required for maximal clinical and histological experimental autoimmune encephalomyelitis (EAE); and identified CMKLR1 small molecule antagonist 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) that significantly suppressed disease onset in vivo. Here we directly compared α-NETA versus FDA-approved MS drug Tecfidera for clinical efficacy in EAE; characterized key safety/toxicity parameters for α-NETA; identified structure-activity relationships among α-NETA domains and CMKLR1 inhibition; and evaluated improved α-NETA analogs for in vivo efficacy. α-NETA proved safe and superior to Tecfidera in suppressing clinical EAE. In addition, we discovered structurally differentiated α-NETA analogs (primarily ortho- or para-methoxy substitutions) with significantly improved target potency in vitro and improved efficacy in vivo. These findings suggest that α-NETA-based CMKLR1 inhibitors may prove safe and effective in treating demyelinating diseases and potentially other autoimmune disorders.
Reconstruction of larval origins based on genetic relatedness and biophysical modeling
Authors: Segura-García I. , Garavelli L. , Tringali M. , Matthews T. , Chérubin L. M. , Hunt J. , Box S. J.
Published: May 2019

The assessment of the mechanisms and patterns of larval connectivity between geographically separated populations leads to a better understanding of benthic marine population dynamics, especially in commercially valuable species. This study investigated for the first time the fine-scale temporal genetic variability of new settlers and their origins in a benthic marine organism with one of the longest pelagic larval phases, the Caribbean spiny lobster (Panulirus argus). We genotyped newly settled postlarvae in the Florida Keys and adults of spiny lobster from the Florida Keys and throughout the Caribbean Sea. We identified strong larval connectivity between Dominican Republic, Belize, Nicaragua, the Florida Keys, and West-Florida. The larval dispersal modeling suggests that Florida’s lobster population could receive recruits from within and from other areas outside its state and national maritime boundaries. The genetic analyses refine the oceanographic model indicating that the connectivity patterns described could also result from unknown parental populations sourcing adults and postlarvae in different spawning seasons to the Florida Keys. We discuss the importance of small temporal scales to identify patterns in larval export. Our findings are significant on two levels. From the larval dispersal perspective, genetic results and biophysical modeling identify patterns of gene flow enhancing persistence of local populations. From an economic and fishery perspective, P. argus is the most important commercial species in the Caribbean and our results inform how considering larval source and sink dynamics across international boundaries could improve management plans at local, national, and regional levels.
The Reprimo gene family member, reprimo-like (rprml), is required for blood development in embryonic zebrafish
Authors: Stanic Karen , Reig German , Figueroa Ricardo J. , Retamal Pedro A. , Wichmann Ignacio A. , Opazo Juan C. , Owen Gareth I. , Corvalán Alejandro H. , Concha Miguel L. , Amigo Julio D.
Published: May 2019

The Reprimo gene family comprises a group of single-exon genes for which their physiological function remains poorly understood. Heretofore, mammalian Reprimo (RPRM) has been described as a putative p53-dependent tumor suppressor gene that functions at the G2/M cell cycle checkpoint. Another family member, Reprimo-like (RPRML), has not yet an established role in physiology or pathology. Importantly, RPRML expression pattern is conserved between zebrafish and human species. Here, using CRISPR-Cas9 and antisense morpholino oligonucleotides, we disrupt the expression of rprml in zebrafish and demonstrate that its loss leads to impaired definitive hematopoiesis. The formation of hemangioblasts and the primitive wave of hematopoiesis occur normally in absence of rprml. Later in development there is a significant reduction in erythroid-myeloid precursors (EMP) at the posterior blood island (PBI) and a significant decline of definitive hematopoietic stem/progenitor cells (HSPCs). Furthermore, loss of rprml also increases the activity of caspase-3 in endothelial cells within the caudal hematopoietic tissue (CHT), the first perivascular niche where HSPCs reside during zebrafish embryonic development. Herein, we report an essential role for rprml during hematovascular development in zebrafish embryos, specifically during the definitive waves of hematopoiesis, indicating for the first time a physiological role for the rprml gene.
Symptom trajectories in patients with panic disorder in a primary care intervention: Results from a randomized controlled trial (PARADISE)
Authors: Lukaschek Karoline , Hiller Thomas S. , Schumacher Ulrike , Teismann Tobias , Breitbart Jörg , Brettschneider Christian , König Hans-Helmut , Margraf Jürgen , Gensichen Jochen
Published: May 2019

This analysis aims to identify and characterize symptom trajectories in primary care patients with panic disorder with/without agoraphobia (PD/AG) who participated in a primary care team based training involving elements of cognitive behavioural therapy (CBT). Growth Mixture Modeling was used to identify different latent classes of change in patients with PD/AG (N = 176) who underwent treatment including CBT elements. We identified three patient classes with distinct similar trajectories. Class 1 (n = 58, mean age: 46.2 years ± 13.4 years, 81% women) consisted of patients with an initially high symptom burden, but symptoms declined constantly over the intervention period. Symptoms of patients in class 2 (n = 89, mean age: 44.2 years ± 14.5 years, 67.4% women) declined rapidly at the beginning, then patients went into a plateau-phase. The third class (n = 29, mean age: 47.0 years ± 12.4 years, 65.5% women) was characterized by an unstable course and had the worse outcome. Our findings show that only a minority did not respond to the treatment. To identify this minority and refer to a specialist would help patients to get intensive care in time.
Key nutritional factors and interactions during larval development of pikeperch (Sander lucioperca)
Authors: El Kertaoui Najlae , Lund Ivar , Assogba Hospice , Domínguez David , Izquierdo Maria S. , Baekelandt Sébastien , Cornet Valérie , Mandiki Syaghalirwa N. M. , Montero Daniel , Kestemont Patrick
Published: May 2019

The effects of 8 nutritional variables (Ca/P, Eicosapentaenoic acid (20:5n-3) + Docosahexaenoic acid (22:6n − 3) (EPA + DHA), Arachidonic acid (20:4n − 6) (ARA), Se, vitamins E, C, D and A) were investigated to identify their respective importance and interactions in pikeperch larval development. In this respect, two modalities (low and high levels) of each variable were tested through a fractional factorial experimental design allowing a reduction from 256 (28) to 16 (28 – 4) experimental units. Survival was significantly higher in larvae fed a high Ca/P diet while larval growth was significantly lower in larvae fed the same diet variant, associated with a higher incidence of kyphosis and pectoral anomalies in these larvae. Lordosis and scoliosis seemed to be mostly affected by dietary long chain polyunsaturated fatty acids (LC-PUFAs). A significant interaction was shown between n-3 LC-PUFA and vitamin C on jaw anomalies, while myocyte-specific enhancer factor 2C (mef2c) gene expression correlated positively with dietary vitamin C increment. Results also demonstrated an effect of the different nutrients and their interactions on the activity levels of digestive enzymatic activities. The results of the present study highlight the importance of the interactions between Ca/P, LC-PUFAs and vitamins C and E, suggesting their essential roles as key nutritional factors influencing pikeperch larval development.
Acoustic Focusing Enhancement In Fresnel Zone Plate Lenses
Authors: Tarrazó-Serrano Daniel , Pérez-López Sergio , Candelas Pilar , Uris Antonio , Rubio Constanza
Published: May 2019

The development of flat acoustic lenses for different applications such as biomedical engineering is a topic of great interest. Flat lenses like Fresnel Zone Plates (FZPs) are capable of focusing energy beams without the need of concave or convex geometries, which are more difficult to manufacture. One of the possible applications of these type of lenses is tumor ablation through High Intensity Focused Ultrasound (HIFU) therapies with real time Magnetic Resonance Imaging (MRI) monitoring. In order to be MRI compatible, the FZP material cannot have electromagnetic interaction. In this work, a Phase-Reversal FZP (PR-FZP) made of Polylactic Acid (PLA) manufactured with a commercial 3D printer is proposed as a better, more efficient and MRI compatible alternative to conventional Soret FZPs. Phase-Reversal lenses, unlike traditional FZPs, take advantage of all the incident energy by adding phase compensation regions instead of pressure blocking regions. The manufactured PR-FZP achieves 21.9 dB of focal gain, which increases the gain compared to a Soret FZP of its same size by a factor of 4.0 dB. Both numerical and experimental results are presented, demonstrating the improved focusing capabilities of these types of lenses.
Atmospheric Circulation Patterns Associated with Extreme United States Floods Identified via Machine Learning
Authors: Schlef Katherine E. , Moradkhani Hamid , Lall Upmanu
Published: May 2019

The massive socioeconomic impacts engendered by extreme floods provides a clear motivation for improved understanding of flood drivers. We use self-organizing maps, a type of artificial neural network, to perform unsupervised clustering of climate reanalysis data to identify synoptic-scale atmospheric circulation patterns associated with extreme floods across the United States. We subsequently assess the flood characteristics (e.g., frequency, spatial domain, event size, and seasonality) specific to each circulation pattern. To supplement this analysis, we have developed an interactive website with detailed information for every flood of record. We identify four primary categories of circulation patterns: tropical moisture exports, tropical cyclones, atmospheric lows or troughs, and melting snow. We find that large flood events are generally caused by tropical moisture exports (tropical cyclones) in the western and central (eastern) United States. We identify regions where extreme floods regularly occur outside the normal flood season (e.g., the Sierra Nevada Mountains due to tropical moisture exports) and regions where multiple extreme flood events can occur within a single year (e.g., the Atlantic seaboard due to tropical cyclones and atmospheric lows or troughs). These results provide the first machine-learning based near-continental scale identification of atmospheric circulation patterns associated with extreme floods with valuable insights for flood risk management.
Assessing local chlamydia screening performance by combining survey and administrative data to account for differences in local population characteristics
Authors: Green Nathan , Sherrard-Smith Ellie , Tanton Clare , Sonnenberg Pam , Mercer Catherine H. , White Peter J.
Published: May 2019

Reducing health inequalities requires improved understanding of the causes of variation. Local-level variation reflects differences in local population characteristics and health system performance. Identifying low- and high-performing localities allows investigation into these differences. We used Multilevel Regression with Post-stratification (MRP) to synthesise data from multiple sources, using chlamydia testing as our example. We used national probability survey data to identify individual-level characteristics associated with chlamydia testing and combined this with local-level census data to calculate expected levels of testing in each local authority (LA) in England, allowing us to identify LAs where observed chlamydia testing rates were lower or higher than expected, given population characteristics. Taking account of multiple covariates, including age, sex, ethnicity, student and cohabiting status, 5.4% and 3.5% of LAs had testing rates higher than expected for 95% and 99% posterior credible intervals, respectively; 60.9% and 50.8% had rates lower than expected. Residual differences between observed and MRP expected values were smallest for LAs with large proportions of non-white ethnic populations. London boroughs that were markedly different from expected MRP values (≥90% posterior exceedance probability) had actively targeted risk groups. This type of synthesis allows more refined inferences to be made at small-area levels than previously feasible.
Illumina and Nanopore methods for whole genome sequencing of hepatitis B virus (HBV)
Authors: McNaughton Anna L. , Roberts Hannah E. , Bonsall David , de Cesare Mariateresa , Mokaya Jolynne , Lumley Sheila F. , Golubchik Tanya , Piazza Paolo , Martin Jacqueline B. , de Lara Catherine , Brown Anthony , Ansari M. Azim , Bowden Rory , Barnes Eleanor , Matthews Philippa C.
Published: May 2019

Advancing interventions to tackle the huge global burden of hepatitis B virus (HBV) infection depends on improved insights into virus epidemiology, transmission, within-host diversity, drug resistance and pathogenesis, all of which can be advanced through the large-scale generation of full-length virus genome data. Here we describe advances to a protocol that exploits the circular HBV genome structure, using isothermal rolling-circle amplification to enrich HBV DNA, generating concatemeric amplicons containing multiple successive copies of the same genome. We show that this product is suitable for Nanopore sequencing as single reads, as well as for generating short-read Illumina sequences. Nanopore reads can be used to implement a straightforward method for error correction that reduces the per-read error rate, by comparing multiple genome copies combined into a single concatemer and by analysing reads generated from plus and minus strands. With this approach, we can achieve an improved consensus sequencing accuracy of 99.7% and resolve intra-sample sequence variants to form whole-genome haplotypes. Thus while Illumina sequencing may still be the most accurate way to capture within-sample diversity, Nanopore data can contribute to an understanding of linkage between polymorphisms within individual virions. The combination of isothermal amplification and Nanopore sequencing also offers appealing potential to develop point-of-care tests for HBV, and for other viruses.
Safety of low-dose subcutaneous recombinant interleukin-2: systematic review and meta-analysis of randomized controlled trials
Authors: Mahmoudpour Seyed Hamidreza , Jankowski Marius , Valerio Luca , Becker Christian , Espinola-Klein Christine , Konstantinides Stavros , Quitzau Kurt , Barco Stefano
Published: May 2019

Standard-dose intravenous recombinant interleukin-2 (rIL-2) is indicated for the treatment of some subtypes of cancer; however, severe adverse events, including venous thromboembolism (VTE), may complicate its administration. Low-dose subcutaneous rIL-2 is being studied for the management of immune-mediated diseases, since it can modulate the immunological response by specifically targeting T regulatory (Treg) cells; importantly, it is supposed to cause fewer or no complications. In this systematic review and meta-analysis of phase II-III randomized controlled trials (RCTs), we investigated the safety of low-dose (<6 Million International Unit [MIU]/day) and ultra-low-dose (≤1 MIU/day) rIL-2 for severe adverse events (grade III-V) with a focus on VTE. Data of 1,321 patients from 24 RCTs were analysed: 661 patients were randomized to the rIL-2 arm (on top of standard of care) and 660 patients to standard of care alone or placebo. Two studies reported higher rates of thrombocytopenia in the low-dose rIL-2 arm. Ultra-low-dose rIL-2 was reported to be well tolerated in 6 studies with a negligible rate of severe adverse events. Symptomatic VTE events were not reported in any of the study arms (absolute risk difference 0% [95%CI −0.1%; +0.1%]). Our results may facilitate the study and introduction in clinical practice of low-dose rIL-2 for potentially new indications.
Ecological feedbacks stabilize a turf-dominated ecosystem at the southern extent of kelp forests in the Northwest Atlantic
Authors: Feehan Colette J. , Grace Sean P. , Narvaez Carla A.
Published: May 2019

Temperate marine ecosystems globally are undergoing regime shifts from dominance by habitat-forming kelps to dominance by opportunistic algal turfs. While the environmental drivers of shifts to turf are generally well-documented, the feedback mechanisms that stabilize novel turf-dominated ecosystems remain poorly resolved. Here, we document a decline of kelp Saccharina latissima between 1980 and 2018 at sites at the southernmost extent of kelp forests in the Northwest Atlantic and their replacement by algal turf. We examined the drivers of a shift to turf and feedback mechanisms that stabilize turf reefs. Kelp replacement by turf was linked to a significant multi-decadal increase in sea temperature above an upper thermal threshold for kelp survival. In the turf-dominated ecosystem, 45% of S. latissima were attached to algal turf rather than rocky substrate due to preemption of space. Turf-attached kelp required significantly (2 to 4 times) less force to detach from the substrate, with an attendant pattern of lower survival following 2 major wave events as compared to rock-attached kelp. Turf-attached kelp allocated a significantly greater percentage of their biomass to the anchoring structure (holdfast), with a consequent energetic trade-off of slower growth. The results indicate a shift in community dominance from kelp to turf driven by thermal stress and stabilized by ecological feedbacks of lower survival and slower growth of kelp recruited to turf.
Serum bilirubin level is a strong predictor for disability in activities in daily living (ADL) in Japanese elderly patients with diabetes
Authors: Inoguchi Toyoshi , Fukuhara Saki , Yamato Mayumi , Nakai Michikazu , Etoh Tomoaki , Masakado Mitsunori , Suehiro Satoshi , Umeda Fumio , Yamauchi Teruaki
Published: May 2019

Elderly patients with diabetes are at increased risk of frailty and disability in activities of daily living (ADL). Recent evidence has shown that oxidative stress is associated with these conditions. In this cross-sectional study, we aimed to assess whether serum level of bilirubin, a strong endogenous antioxidant, can predict ADL disability in elderly patients with diabetes. Forty elderly patients aged 70 years and older with diabetes and ADL disability and 158 elderly patients with diabetes and without ADL disability were continuously recruited. Multivariate logistic regression models showed that serum bilirubin level was a significant predictor for ADL disability. Receiver operating characteristic analysis showed that the area under the curve (AUC) of serum bilirubin level alone for ADL disability was 0.887 (95% CI 0.837–0.936, P < 0.001) and the cut-off value was 0.4 mg/dL (sensitivity = 88.0% and specificity = 65.0%). The predictive ability was further increased by the addition of age (AUC = 0.921) or addition of age, body mass index, red blood cell count, cerebrovascular disease and chronic renal failure (AUC = 0.953). In conclusion, low serum bilirubin level is a strong predictive biomarker for ADL disability in elderly patients with diabetes, and its clinical utility is suggested.
An Improved Grey Wolf Optimizer Based on Differential Evolution and Elimination Mechanism
Authors: Wang Jie-Sheng , Li Shu-Xia
Published: May 2019

The grey wolf optimizer (GWO) is a novel type of swarm intelligence optimization algorithm. An improved grey wolf optimizer (IGWO) with evolution and elimination mechanism was proposed so as to achieve the proper compromise between exploration and exploitation, further accelerate the convergence and increase the optimization accuracy of GWO. The biological evolution and the “survival of the fittest” (SOF) principle of biological updating of nature are added to the basic wolf algorithm. The differential evolution (DE) is adopted as the evolutionary pattern of wolves. The wolf pack is updated according to the SOF principle so as to make the algorithm not fall into the local optimum. That is, after each iteration of the algorithm sort the fitness value that corresponds to each wolf by ascending order, and then eliminate R wolves with worst fitness value, meanwhile randomly generate wolves equal to the number of eliminated wolves. Finally, 12 typical benchmark functions are used to carry out simulation experiments with GWO with differential evolution (DGWO), GWO algorithm with SOF mechanism (SGWO), IGWO, DE algorithm, particle swarm algorithm (PSO), artificial bee colony (ABC) algorithm and cuckoo search (CS) algorithm. Experimental results show that IGWO obtains the better convergence velocity and optimization accuracy.