bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ketamine Modulates the Neural Correlates of Reward Processing in Unmedicated Patients in Remission from Depression
Authors: Kotoula Vasileia , Stringaris Argyris , Mackes Nuria , Mazibuko Ndabezinhle , Hawkins Peter.C.T , Furey Maura , Curran H Valerie , Mehta Mitul.A. 
Published: December 2020

AbstractKetamine as an antidepressant improves anhedonia, a pernicious symptom of depression as early as 2h post-infusion. The effects of ketamine on anhedonia are thought to be exerted via actions on reward-related brain areas—yet, these actions remain largely unknown. This study examines ketamine’s effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported. In order to identify brain areas that are modulated by the drug per se and are not linked to symptom changes, we have recruited 37 participants who remitted from depression and were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned while performing a monetary reward task and we examined ketamine’s effects on pre-defined brain areas that are part of the reward circuit. An overall effect of ketamine was observed during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, upon the receipt of smaller rewards and the levels of (2R,6R)-HNK, 2h post-infusion, significantly correlated with the activation observed in the ventral tegmental area (VTA) for that contrast. These findings demonstrate that ketamine can produce detectable changes in reward-related brain areas, 2h after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback.
Distinct impact of IgG subclass and Fc-FcγR interaction on autoantibody pathogenicity in different IgG4-mediated diseases
Authors: Bi Yanxia , Su Jian , Zhou Shengru , Zhao Yingjie , Zhang Yan , Zhang Huihui , Liu Mingdong , Zhou Aiwu , Pan Meng , Zhao Yiming , Li Fubin 
Published: December 2020

AbstractIgG4 is the least potent human IgG subclass for the FcγR-mediated antibody effector function and is considered anti-inflammatory in the context of prolonged inflammation and allergic responses. Paradoxically, IgG4 is also the dominant IgG subclass of pathogenic autoantibodies in IgG4-mediated diseases. Here we show that the IgG subclass and Fc-FcγR interaction have a distinct impact on the pathogenic function of autoantibodies in different IgG4-mediated diseases. While IgG4 and its weak Fc-FcγR interaction have an ameliorative role in the pathogenicity of anti-ADAMTS13 autoantibodies isolated from thrombotic thrombocytopenic purpura (TTP) patients, they have an unexpected exacerbating effect on anti-Dsg1 autoantibody pathogenicity in pemphigus foliaceus (PF) models. Strikingly, a non-pathogenic anti-Dsg1 antibody variant optimized for FcγR-mediated effector function can attenuate the skin lesions induced by pathogenic anti-Dsg1 antibodies by promoting the clearance of dead keratinocytes. These studies suggest that IgG effector function contributes to the clearance of autoantibody-Ag complexes, which is harmful in TTP, but beneficial in PF and may provide new therapeutic opportunity.
A generic, scalable, and rapid TR-FRET –based assay for SARS-CoV-2 antigen detection
Authors: Rusanen Juuso , Kareinen Lauri , Szirovicza Leonora , Uğurlu Hasan , Levanov Lev , Jääskeläinen Anu , Ahava Maarit , Kurkela Satu , Saksela Kalle , Hedman Klaus , Vapalahti Olli , Hepojoki Jussi 
Published: December 2020

ABSTRACTThe ongoing COVID-19 pandemic has seen an unprecedented increase in the demand for rapid and reliable diagnostic tools, leaving many laboratories scrambling for resources. We present a fast and simple method for the detection of SARS-CoV-2 in nasopharyngeal swabs. The method is based on the detection of SARS-CoV-2 nucleoprotein (NP) and S protein (SP) via time-resolved Förster resonance energy transfer (TR-FRET) with donor- and acceptor-labeled polyclonal anti-NP and -SP antibodies. Using recombinant proteins and cell culture-grown SARS-CoV-2 the limits of detection were established as 25 pg of NP or 20 infectious viral units (i.u.), and 875 pg of SP or 625 i.u. of SARS-CoV-2. Testing RT-PCR positive (n=48, with cycle threshold [Ct] values from 11 to 30) or negative (n=96) nasopharyngeal swabs, we showed that the assay yields positive results for all samples with Ct values of <25 and a single RT-PCR negative sample. We determined the presence of infectious virus in the RT-PCR-positive nasopharyngeal swabs by virus isolation, and observed a strong association between the presence of infectious virus and a positive antigen test result. The NP-based assay showed 97.4% (37/38) sensitivity and 100% (10/10) specificity in comparison with virus isolation, and 77.1% (37/48) and 99.0% (95/96) in comparison with SARS-CoV-2 RT-PCR. The assay is performed in a buffer that neutralizes SARS-CoV-2 infectivity and is relatively simple to set up as an “in-house” test. The assay principle as such is applicable to other viral infections, and could also be readily adapted to a massively high throughput testing format.
Excess deaths associated with the Iranian COVID-19 epidemic: a province-level analysis
Authors: Ghafari Mahan , Kadivar Alireza , Katzourakis Aris 
Published: December 2020

AbstractBackgroundThe number of publicly reported deaths from COVID-19 may underestimate the true death toll from the epidemic as they rely on provisional data that are often incomplete or omit undocumented deaths from COVID-19. In addition, these reports may be subject to significant under-reporting due to a limited testing capacity of a country to identify suspect cases. This study estimated the number of seasonal excess deaths attributable to the COVID-19 epidemic in 31 provinces of Iran.MethodsWe gathered the nationwide and provincial time series of the seasonal all-cause mortality data from spring 2015 to summer 2020 (21 March 2015 to 21 September 2020), in accordance with the Solar Hijri (SH) calendar, from the National Organization for Civil Registration (NOCR). We estimated the expected number of seasonal deaths for each province using a piecewise linear regression model which we established based on the mortality figures for the previous years and considered any significant deviations from the expectation during winter, spring, and summer of 2020 to be directly associated with COVID-19.ResultsOur analysis shows that from the start of winter to the end of summer (from 22 December 2019 to 21 September 2020), there were a total of 58.9K (95%CI: 46.9K - 69.5K) excess deaths across all 31 provinces with 27% (95%CI: 20% - 34%) estimated nationwide exposure to SARS-CoV-2. In particular, 2 provinces in the central and northern Iran, namely Qom and Golestan, had the highest level of exposure with 57% (95%CI: 44% - 69%) and 56% (95%CI: 44% - 69%), respectively, while another 27 provinces had significant levels of excess mortality in at least one season with >20% population-level exposure to the virus. We also detected unexpectedly high levels of excess mortality during fall 2019 (from 23 September to 21 December 2019) across 18 provinces. Our findings suggest that this spike cannot be a result of an early cryptic transmission of COVID-19 across the country and is also inconsistent with the molecular phylogenetics estimates for the start of the pandemic and its arrival to Iran. However, in the absence of appropriate surveillance data for detecting severe acute respiratory infections we were unable to make a determination as to what caused the spike in fall 2019.Conflict of InterestNone.
Light-dependent induction ofEdn2expression and attenuation of retinal pathology by endothelin receptor antagonists inProminin-1- deficient mice
Authors: Kobayashi Yuka , Watanabe Shizuka , Shirai Manabu , Yamashiro Chiemi , Ogata Tadahiko , Higashijima Fumiaki , Yoshimoto Takuya , Hayano Takahide , Asai Yoshiyuki , Sasai Noriaki , Kimura Kazuhiro 
Published: December 2020

AbstractRetinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. TheProminin-1gene (Prom1) is a causative gene for RP and MD, andProm1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration inProm1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression ofEdn2was also induced by light stimulation inProm1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis inProm1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.
Population genomics of the emerging forest pathogenNeonectria neomacrospora
Authors: Nielsen Knud Nor , Gopalakrishnan Shyam , Korneliussen Thorfinn Sand , Skovrind Mikkel , Sirén Kimmo , Petersen Bent , Sicheritz-Pontén Thomas , Thomsen Iben M. , Gilbert M. Thomas P. , Hansen Ole Kim 
Published: December 2020

ABSTRACTThe fungal pathogenNeonectria neomacrosporais of increasing concern in Europe where, within the last decade, it has caused substantial damage to forest stands and ornamental trees of the genusAbies(Mill.). Using whole-genome sequencing of a comprehensive collection of isolates, we show the extent of three major clades withinN. neomacrospora, which most likely diverged around the end of the last Ice Age. We find it likely that the current European epidemic ofN. neomacrosporawas founded from a population belonging to the east North American clade. All European isolates (1957-2019) had a common evolutionary history, but substantial and asymmetrical gene flow from the larger American source population could be detected. The European population shows multiple signs of having gone through a bottleneck and subsequent population expansion.
DNA metabarcoding provides insights into the diverse diet of a dominant suspension feeder, the giant plumose anemoneMetridium farcimen
Authors: Wells Christopher D. , Paulay Gustav , Nguyen Bryan N. , Leray Matthieu 
Published: December 2020

ABSTRACTBenthic suspension feeders have significant impacts on plankton communities by depleting plankton or modifying composition of the plankton through prey selectivity. Quantifying diets of planktivorous animals can be difficult because plankton are frequently microscopic, may lack diagnostic characters, and are digested at variable rates. With DNA metabarcoding, the identification of gut contents has become faster and more accurate, and the technique allows for higher taxonomic resolution-n while also identifying rare and highly degraded items that would otherwise not be detected. We used DNA metabarcoding to examine the diet of the giant plumose anemoneMetridium farcimen,a large, abundant, competitively-dominant anemone on subtidal rock surfaces and floating docks in the northeast Pacific Ocean. Gut contents of 12 individuals were compared to 80- and 330-μm filtered plankton samples collected one hour prior between 0.02 and 1.5 km from the anemones. The objectives of this study were to determine ifM. farcimenhas a selective diet and compare our findings with traditional gut content analyses.Metridium farcimencaptured a wider range of prey than previously suspected and metabarcoding found many more taxa than traditional sampling techniques. Gut contents were less diverse than 80-μm filtered plankton samples, but more diverse than 330-μm filtered plankton samples. The diet of the anemones was 52% arthropods with a surprisingly high relative abundance of an ant (10%) that has mating flights in August when this study was conducted. The gut contents ofM. farcimenlikely include all prey that it can detect and that cannot escape. There were no overrepresented taxa in the gut contents compared to the plankton but there were underrepresented taxa. This study highlights the usefulness of the metabarcoding method in identifying prey within the gut of planktivorous animals and the significant terrestrial input into marine food webs.
Ambiguous support for extra-tropical accelerated diversification of rosids
Authors: Gamisch Alexander 
Published: December 2020

AbstractSun et al.1used a comprehensive phylogenetic and a locality based climatic dataset to examine how past climates have driven diversification across 17 orders of rosids. They concluded that tropical rosids diversify slower than the (younger) non-tropical counterparts in part due to a strong negative relationship between paleo-temperature and diversification (i.e. higher diversification rates under lower temperatures). Their conclusions are based on tip rates (derived from BAMM2; DR3) and correlations with current temperature (e-SIM4) or binary tropicality data sets (BAMM/STRAPP5; FiSSE6) as well as tree-wide estimates of diversification with paleo-temperature (BAMM; RPANDA7) or tropicality (BiSSE8; HiSSE9). Here, I highlight several inconsistencies in their diversification analyses as well as a systematic error pertaining to the RPANDA model selection procedure, which, together with several minor technical issues, weaken the support for Sun et al.’s1conclusions. A re-analysis of their BiSSE/HiSSE and RPANDA analyses are performed.
A massively multi-scale approach to characterising tissue architecture by synchrotron micro-CT applied to the human placenta
Authors: Tun W. M. , Poologasundarampillai G. , Bischof H. , Nye G. , King O. N. F. , Basham M. , Tokudome Y. , Lewis R. M. , Johnstone E. D. , Brownbill P. , Darrow M. , Chernyavsky I. L. 
Published: December 2020

ABSTRACTMulti-scale structural assessment of biological soft tissue is challenging but essential to gain insight into structure-function relationships of tissue/organ. Using the human placenta as an example, this study brings together sophisticated sample preparation protocols, advanced imaging, and robust, validated machine-learning segmentation techniques to provide the first massively multi-scale and multi-domain information that enables detailed morphological and functional analyses of both maternal and fetal placental domains. Finally, we quantify the scale-dependent error in morphological metrics of heterogeneous placental tissue, estimating the minimal tissue scale needed in extracting meaningful biological data. The developed protocol is beneficial for high-throughput investigation of structure-function relationships in both normal and diseased placentas, allowing us to optimise therapeutic approaches for pathological pregnancies. In addition, the methodology presented is applicable in characterisation of tissue architecture and physiological behaviours of other complex organs with similarity to the placenta, where an exchange barrier possesses circulating vascular and avascular fluid spaces.
High-resolution radioluminescence microscopy of FDG uptake in an engineered 3D tumor-stoma model
Authors: Khan Syamantak , Kim Sungwoo , Yang Yunzhi Peter , Pratx Guillem 
Published: December 2020

AbstractPURPOSEThe increased glucose metabolism of cancer cells is the basis for18F-fluorodeoxyglucose positron emission tomography (FDG-PET). However, due to its coarse image resolution, PET is unable to resolve the metabolic role of cancer-associated stroma, which often influences the metabolic reprogramming of a tumor. This study investigates the feasibility of imaging engineered 3D tumor models with high resolution using FDG.METHODMulticellular tumor spheroids (A549 lung adenocarcinoma) were co-cultured with GFP-expressing human umbilical vein endothelial cells (HUVECs) within an artificial extracellular matrix to mimic a tumor and its surrounding stroma. The tumor model was constructed as a thin 3D layer over a transparent CdWO4 scintillator plate to allow high-resolution imaging of the cultured cells. The radioluminescence signal was collected by a highly sensitive microscope and camera. Fluorescence microscopy was performed in the same instrument to localize endothelial and tumor cells.RESULTSSimultaneous brightfield and fluorescence imaging, co-localized with radioluminescence signal, provided high-resolution information on FDG accumulation in the engineered tissue. The microvascular stromal compartment took up a large fraction of FDG, comparable to the tumor spheroids. In vitro gamma counting also revealed that both A549 and HUVEC cells were highly glycolytic and characterized by rapid FDG-uptake kinetics.CONCLUSIONOur study demonstrates the feasibility of imaging FDG distribution in tumor and stromal components separately with high spatial resolution in engineeredin vitrotumor models. Our imaging method is safe, simple, rapid, and can be easily used for otherin vitrocancer models, surgical tissue slices, and tumor biopsies to interrogate PET radiotracer uptake at high resolution.
Structural basis for piRNA-targeting
Authors: Anzelon Todd A. , Chowdhury Saikat , Hughes Siobhan M. , Xiao Yao , Lander Gabriel C. , MacRae Ian J. 
Published: December 2020

SummaryPiwi proteins use PIWI-interacting RNAs (piRNAs) to identify and silence the transposable elements (TEs) pervasively found in animal genomes. The Piwi targeting mechanism is proposed to be similar to targeting by Argonaute proteins, which employ microRNA (miRNA) guides to repress cellular mRNAs, but has not been characterized in detail. We present cryo-EM structures of a Piwi-piRNA complex with and without target RNAs and analysis of target recognition. Resembling Argonaute, Piwi identifies targets using the piRNA seed-region. However, Piwi creates a much weaker seed so that prolonged target association requires further piRNA-target pairing. Beyond the seed, Piwi creates wide central cleft wide for unencumbered piRNA-target pairing, enabling long-lived Piwi-piRNA-target interactions that are tolerant of mismatches. Piwi ensures targeting fidelity by blocking propagation of the piRNA-target duplex in the absence of faithful seed pairing, and by requiring extended piRNA-target pairing to reach an endonucleolytically active conformation. This mechanism allows Piwi to minimize off-targeting cellular mRNAs and adapt piRNA sequences to evolving genomic threats.
Paradoxical effects of cigarette smoke and COPD on SARS-CoV2 infection and disease
Authors: Tomchaney M. , Contoli M. , Mayo J. , Baraldo S. , Shuaizhi L. , Cabel CR. , Bull DA. , Lick S. , Malo J. , Knoper S. , Kim SS. , Tram J. , Rojas-Quintero J. , Kraft M. , Ledford J. , Tesfaigzi Y. , Martinez F.D. , Thorne C. A. , Kheradmand F. , Campos S. K. , Papi A. , Polverino F. 
Published: December 2020

ABSTRACTIntroductionHow cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severity is controversial. We investigated the protein and mRNA expression of SARS-CoV-2 entry receptor ACE2 and proteinase TMPRSS2 in lungs from COPD patients and controls, and lung tissue from mice exposed acutely and chronically to CS. Also, we investigated the effects of CS exposure on SARS-CoV-2 infection in human bronchial epithelial cells.MethodsIn Cohort 1, ACE2-positive cells were quantified by immunostaining in FFPE sections from both central and peripheral airways. In Cohort 2, we quantified pulmonary ACE2 protein levels by immunostaining and ELISA, and both ACE2 and TMPRSS2 mRNA levels by RT-qPCR. In C57BL/6 WT mice exposed to air or CS for up to 6 months, pulmonary ACE2 protein levels were quantified by triple immunofluorescence staining and ELISA. The effects of CS exposure on SARS-CoV-2 infection were evaluated after 72hr in vitro infection of Calu-3 cells. After SARS-CoV-2 infection, the cells were fixed for IF staining with dsRNA-specific J2 monoclonal Ab, and cell lysates were harvested for WB of viral nucleocapsid (N) protein. Supernatants (SN) and cytoplasmic lysates were obtained to measure ACE2 levels by ELISA.ResultsIn both human cohorts, ACE2 protein and mRNA levels were decreased in peripheral airways from COPD patients versus both smoker and NS controls, but similar in central airways. TMPRSS2 levels were similar across groups. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia versus air-exposed mice exposed to 3 and 6 months of CS. In Calu3 cells in vitro, CS-treatment abrogated infection to levels below the limit of detection. Similar results were seen with WB for viral N protein, showing peak viral protein synthesis at 72hr.ConclusionsACE2 levels were decreased in both bronchial and alveolar epithelial cells from uninfected COPD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-treatment did not affect ACE2 levels but potently inhibited SARS-CoV-2 replication in this in vitro model. These findings urge to further investigate the controversial effects of CS and COPD on SARS-CoV2 infection.
RIOK2 drives glioblastoma cell proliferation by modulating MYC through the RNA-binding protein IMP3
Authors: Chen Alexander S. , Marquez Jhomar , Boyd Nathaniel H. , Oh Se-Yeong , Gulbronson Riley , Hamilton Jamie A.G. , Legan Emily R. , Read Renee D. 
Published: December 2020

ABSTRACTGlioblastoma (GBM) is the most common primary malignant brain tumor and is resistant to current therapies. Here, using a combination of proteomic and genetic approaches in bothDrosophilaand human GBM models, we identify novel signaling effectors that act downstream of EGFR and PI3K signaling pathways, which drive GBM. Our results indicate that RIOK2, an atypical serine/threonine kinase, forms a complex with the RNA-binding protein, IMP3 (Imp inDrosophila), and that the dRIOK2/RIOK-Imp/IMP3 pathway is necessary for tumorigenesis. Furthermore, our results indicate that RIOK2 catalytic activity is important for neoplasia and recruits TORC2 to phosphorylate IMP3. Finally, the dRIOK2-Imp pathway regulates protein levels of dMyc, a known Imp target mRNA, and these key findings were recapitulated in human GBM models. Collectively, our data indicates that RIOK2 catalytic activity promotes the activation of TORC2 and recruitment of IMP3, which in turn, modulates MYC mRNA and protein levels to promote tumorigenesis.