bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optoribogenetic control of regulatory RNA molecules
Authors: Pilsl Sebastian , Morgan Charles , Choukeife Moujab , Möglich Andreas , Mayer Günter 
Published: July 2020

AbstractShort regulatory RNA molecules underpin gene expression and govern cellular state and physiology. To establish a novel layer of control over these processes, we generated chimeric regulatory RNAs that interact reversibly and light-dependently with the light-oxygen-voltage photoreceptor PAL. By harnessing this interaction, the function of micro RNAs (miRs) and short hairpin (sh) RNAs in mammalian cells can be regulated in spatiotemporally precise manner. The underlying strategy is generic and can be adapted to near-arbitrary target sequences. Owing to full genetic encodability, it establishes unprecedented optoribogenetic control of cell state and physiology. The method stands to facilitate the non-invasive, reversible and spatiotemporally resolved study of regulatory RNAs and protein function in cellular and organismal environments.
Genes Encoding ACE2, TMPRSS2 and Related Proteins Mediating SARS-CoV-2 Viral Entry are Upregulated with Age in Human Cardiomyocytes
Authors: Robinson Emma L. , Alkass Kanar , Bergmann Olaf , Maguire Janet J. , Roderick H. Llewelyn , Davenport Anthony P. 
Published: July 2020

AbstractAge is an independent risk factor for adverse outcome in patients following COVID-19 infection. We hypothesised that differential expression of genes encoding proteins proposed to be required for entry of SARS-Cov-2 in aged compared to younger cardiomyocytes might contribute to the susceptibility of older individuals to COVID-19-associated cardiovascular complications.We generated strand-specific RNA-sequencing libraries from RNA isolated from flow-sorted cardiomyocyte nuclei from left ventricular tissue. RNASeq data were compared between five young (19-25yr) and five older (63-78yr) Caucasian males who had not been on medication or exhibited evidence of cardiovascular disease post-mortem.Expression of relevant genes encodingACE2, TMPRSS2, TMPRS11D, TMPRS11E, FURIN, CTSL, CTSBandB0AT1/SLC6A19were upregulated in aged cardiomyocytes and the combined relative cardiomyocyte expression of these genes correlated positively with age. Genes encoding proteins in the RAAS and interferon/interleukin pathways were also upregulated such asACE, AGTR1, MAS1andIL6R.Our results highlight SARS-CoV-2 related genes that have higher expression in aged compared with young adult cardiomyocytes. These data may inform studies using selective enzyme inhibitors/antagonists, available as experimental compounds or clinically approved drugs e.g. remdesivir that has recently been rapidly accepted for compassionate use, to further understand the contribution of these pathways in human cardiomyocytes to disease outcome in COVID-19 patients.
Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice
Authors: Henzi Anna , Senatore Assunta , Lakkaraju Asvin KK , Scheckel Claudia , Mühle Jonas , Reimann Regina , Sorce Silvia , Schertler Gebhard , Toyka Klaus V , Aguzzi Adriano 
Published: July 2020

AbstractThe adhesion G-protein coupled receptor Adgrg6 (formerly Gpr126) is instrumental in the development, maintenance and repair of peripheral nervous system myelin. The prion protein (PrP) is a potent activator of Adgrg6 and could be used as a potential therapeutic agent in treating peripheral demyelinating and dysmyelinating diseases. We designed a dimeric Fc-fusion protein comprising the myelinotrophic domain of PrP (FT2Fc), which activated Adgrg6 in vitro and exhibited favorable pharmacokinetic properties for in vivo treatment of peripheral neuropathies. While chronic FT2Fc treatment elicited specific transcriptomic changes in the sciatic nerves of PrP knockout mice, no amelioration of the peripheral demyelinating neuropathy was detected. Instead, RNA sequencing of sciatic nerves revealed downregulation of cytoskeletal and sarcomere genes, akin to the gene expression changes seen in myopathic skeletal muscle of PrP overexpressing mice. These results call for caution when devising myelinotrophic therapies based on PrP-derived Adgrg6 ligands. While our treatment approach was not successful, Adgrg6 remains an attractive therapeutic target to be addressed in other disease models or by using different biologically active Adgrg6 ligands.Summary blurbA dimeric prion protein ligand activates Adgrg6 but fails to induce pro-myelination signaling upon chronic treatment in a mouse model of peripheral demyelination.
Loss of Ubiquitin Ligase STUB1 Amplifies IFNγ-R1/JAK1 Signaling and Sensitizes Tumors to IFNγ
Authors: Apriamashvili Georgi , Vredevoogd David W. , Krijgsman Oscar , Bleijerveld Onno B. , Ligtenberg Maarten A. , de Bruijn Beaunelle , Boshuizen Julia , Altimari Daniela D’Empaire , Visser Nils L. , Londino James D. , Altelaar Maarten , Peeper Daniel S. 
Published: July 2020

AbstractDespite the success of immune checkpoint blockade (ICB) most patients fail to respond durably, in part owing to reduced interferon gamma (IFNγ) sensitivity. Thus, elevating tumor IFNγ-receptor 1 (IFNγ-R1) expression to enhance IFNγ-mediated cytotoxicity is of potential clinical interest. Here, we show that increased IFNγ-R1 expression sensitizes tumors to IFNγ-mediated killing. To unveil the largely undefined mechanism governing IFNγ-R1 expression, we performed a genome-wide CRISPR/Cas9 screen for suppressors of its cell surface abundance. We uncovered STUB1 as key mediator of proteasomal degradation of the IFNγ-R1/JAK1 complex. STUB1 inactivation amplified IFNγ signaling, thereby sensitizing to cytotoxic T cells, but also inducing PD-L1. STUB1 loss in a rational combination with PD-1 blockade strongly inhibited melanomasin vivo. Clinically corroborating these results, aSTUB1-KO gene signature was strongly associated with anti-PD-1 response. These results uncover STUB1 as pivotal regulator of IFNγ tumor signaling and provide a rationale for its inhibition combined with anti-PD-1.
Beware of White Matter Hyperintensities Causing Systematic Errors in Grey Matter Segmentations!
Authors: Dadar Mahsa , Potvin Olivier , Camicioli Richard , Duchesne Simon ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2020

AbstractIntroductionVolumetric estimates of subcortical and cortical structures, extracted from T1-weighted MRIs, are widely used in many clinical and research applications. Here, we investigate the impact of the presence of white matter hyperintensities (WMHs) onFreeSurfergrey matter (GM) structure volumes and its possible bias on functional relationships.MethodsT1-weighted images from 1077 participants (4321 timepoints) from the Alzheimer’s Disease Neuroimaging Initiative were processed withFreeSurferversion 6.0.0. WMHs were segmented using a previously validated algorithm on either T2-weighted or Fluid-attenuated inversion recovery (FLAIR) images. Mixed effects models were used to assess the relationships between overlapping WMHs and GM structure volumes and overal WMH burden, as well as to investigate whether such overlaps impact associations with age, diagnosis, and cognitive performance.ResultsParticipants with higher WMH volumes had higher overalps with GM volumes of bilateral caudate, cerebral cortex, putamen, thalamus, pallidum, and accumbens areas (P < 0.0001). When not corrected for WMHs, caudate volumes increased with age (P < 0.0001) and were not different between cognitively healthy individuals and age-matched probable Alzheimer’s disease patients. After correcting for WMHs, caudate volumes decreased with age (P < 0.0001), and Alzheimer’s disease patients had lower caudate volumes than cognitively healthy individuals (P < 0.01). Uncorrected caudate volume was not associated with ADAS13 scores, whereas corrected lower caudate volumes were significantly associated with poorer cognitive performance (P < 0.0001).ConclusionsPresence of WMHs leads to systematic inaccuracies in GM segmentations, particularly for the caudate, which can also change clinical associations. While specifically measured for theFreesurfertoolkit, this problem likely affects other algorithms.
Divergent strategies to reduce stomatal pore index during water deficit in perennial angiosperms
Authors: Mano Noel Anthony , Lopez Santiago Franco , Mickelbart Michael V. 
Published: July 2020

Summary⍰ Modulation of stomatal development may be an acclimation response to low water availability. However, stomatal development plasticity has been assessed in very few species.⍰ We quantified leaf anatomy traits, including stomatal index (SI), density (SD), size (SS), and pore index (SPI), in response to water-deficit stress in river birch (Betula nigraL.), eastern redbud (Cercis canadensisL.), and silver maple (Acer saccharinumL.).⍰ Birch and redbud, but not maple, had reduced SPI in response to water deficit. The mechanism by which SPI reduction occurred (via SD or SS) varied among species and with severity of water stress. Despite reduced SPI in birch and redbud, anatomical changes were relatively small and had a minor to no effect on the theoretical maximum stomatal conductance. Furthermore, gas-exchange rates were equivalent to well-watered plants following media re-irrigation.⍰ In some tree species, stomatal development is downregulated in response to water deficit conditions. Stomatal development plasticity is facilitated by smaller or fewer stomata, depending upon the species and the intensity of the stress. Water-deficit-induced plasticity in stomatal development is species-specific, likely due to species adaptation to ecological niches.
Pomegranate: 2D segmentation and 3D reconstruction for fission yeast and other radially symmetric cells
Authors: Baybay Erod Keaton , Esposito Eric , Hauf Silke 
Published: July 2020

AbstractThree-dimensional (3D) segmentation of cells in microscopy images is crucial to accurately capture signals that extend across optical sections. Using brightfield images for segmentation has the advantage of being minimally phototoxic and leaving all other channels available for signals of interest. However, brightfield images only readily provide information for two-dimensional (2D) segmentation. In radially symmetric cells, such as fission yeast and many bacteria, this 2D segmentation can be computationally extruded into the third dimension. However, current methods typically make the simplifying assumption that cells are straight rods. Here, we report Pomegranate, a pipeline that performs the extrusion into 3D using spheres placed along the topological skeletons of the 2D-segmented regions. The diameter of these spheres adapts to the cell diameter at each position. Thus, Pomegranate accurately represents radially symmetric cells in 3D even if cell diameter varies and regardless of whether a cell is straight, bent or curved. We have tested Pomegranate on fission yeast and demonstrate its ability to 3D segment wild-type cells as well as classical size and shape mutants. The pipeline is available as macro for the open-source image analysis software Fiji/ImageJ. 2D segmentations created within or outside Pomegranate can serve as input, thus making this a valuable extension to the image analysis portfolio already available for fission yeast and other radially symmetric cell types.
Evolutionary dynamics of sex-biased genes expressed in cricket brains and gonads
Authors: Whittle Carrie A. , Kulkarni Arpita , Extavour Cassandra G. 
Published: July 2020

AbstractSex-biased gene expression, particularly sex-biased expression in the gonad, has been linked to rates of protein sequence evolution (nonsynonymous to synonymous substitutions, dN/dS) in animals. However, in insects, sex-biased expression studies remain centered on a few holometabolous species, and moreover, other major tissue types such as the brain remain underexplored. Here, we studied sex-biased gene expression and protein evolution in a hemimetabolous insect, the cricketGryllus bimaculatus. We generated novel male and female RNA-seq data for two sexual tissue types, the gonad and somatic reproductive system, and for two core components of the nervous system, the brain and ventral nerve cord. From a genome-wide analysis, we report several core findings. Firstly, testis-biased genes had accelerated evolution, as compared to ovary-biased and unbiased genes, which was associated with positive selection events. Secondly, while sex-biased brain genes were much less common than for the gonad, they exhibited a striking tendency for rapid protein evolution, an effect that was stronger for the female than male brain. Further, some sex-biased brain genes were linked to sexual functions and mating behaviors, which we suggest may have accelerated their evolution via sexual selection. Thirdly, a tendency for narrow cross-tissue expression breadth, suggesting low pleiotropy, was observed for sex-biased brain genes, suggesting relaxed purifying selection, which we speculate may allow enhanced freedom to evolve adaptive protein functional changes. The findings of rapid evolution of testis-biased genes and male and female-biased brain genes are discussed with respect to pleiotropy, positive selection, and the mating biology of this cricket.
Tau forms oligomeric complexes on microtubules that are distinct from pathological oligomers in disease
Authors: Gyparaki M. T. , Arab A. , Sorokina E. M. , Santiago-Ruiz A. N. , Bohrer C. H. , Xiao J. , Lakadamyali M. 
Published: July 2020

AbstractTau is a microtubule-associated protein, which promotes neuronal microtubule assembly and stability. Accumulation of tau into insoluble aggregates known as neurofibrillary tangles (NFTs) is a pathological hallmark of several neurodegenerative diseases. The current hypothesis is that small, soluble oligomeric tau species preceding NFT formation cause toxicity. However, thus far visualizing the spatial distribution of tau monomers and oligomers inside cells under physiological or pathological conditions has not been possible. Here, using single molecule localization microscopy (SMLM), we show that,in vivo, tau forms small oligomers on microtubules under physiological conditions. These physiological oligomers are distinct from those found in cells exhibiting tau aggregation and could be pre-cursors of aggregated tau in pathology. Further, using an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct tau aggregate species. Our work elucidates tau’s nanoscale composition under physiological and pathological conditionsin vivo.
Ultra-accurate Microbial Amplicon Sequencing Directly from Complex Samples with Synthetic Long Reads
Authors: Callahan Benjamin J , Grinevich Dmitry , Thakur Siddhartha , Balamotis Michael A , Yehezkel Tuval Ben 
Published: July 2020

AbstractOut of the many pathogenic bacterial species that are known, only a fraction are readily identifiable directly from a complex microbial community using standard next generation DNA sequencing technology. Long-read sequencing offers the potential to identify a wider range of species and to differentiate between strains within a species, but attaining sufficient accuracy in complex metagenomes remains a challenge. Here, we describe and analytically validate LoopSeq, a commercially-available synthetic long-read (SLR) sequencing technology that generates highly-accurate long reads from standard short reads. LoopSeq reads are sufficiently long and accurate to identify microbial genes and species directly from complex samples. LoopSeq applied to full-length 16S rRNA genes from known strains in a microbial community perfectly recovered the full diversity of full-length exact sequence variants in a known microbial community. Full-length LoopSeq reads had a per-base error rate of 0.005%, which exceeds the accuracy reported for other long-read sequencing technologies. 18S-ITS and genomic sequencing of fungal and bacterial isolates confirmed that LoopSeq sequencing maintains that accuracy for reads up to 6 kilobases in length. Analysis of rinsate from retail meat samples demonstrated that LoopSeq full-length 16S rRNA synthetic long-reads could accurately classify organisms down to the species level, and could differentiate between different strains within species identified by the CDC as potential foodborne pathogens. The order-of-magnitude improvement in both length and accuracy over standard Illumina amplicon sequencing achieved with LoopSeq enables accurate species-level and strain identification from complex and low-biomass microbiome samples. The ability to generate accurate and long microbiome sequencing reads using standard short read sequencers will accelerate the building of quality microbial sequence databases and removes a significant hurdle on the path to precision microbial genomics.
Notch controls arterialization by regulating the cell cycle and not differentiation
Authors: Luo Wen , Garcia-Gonzalez Irene , Fernandez-Chacon Macarena , Casquero-Garcia Veronica , Benedito Rui 
Published: July 2020

AbstractArteries are thought to be formed by the induction of a highly conserved arterial genetic program in a subset of vessels experiencing an increase in pulsatile and oxygenated blood flow. Both VEGF and Notch signalling have been shown to be essential for the initial steps of arterial specification. Here, we combined inducible genetic mosaics and transcriptomics to modulate and understand the function of these signalling pathways on cell proliferation, arterial-venous differentiation and mobilization. We observed that endothelial cells with high VEGF or Notch signalling are not genetically pre-determined and can form both arteries and veins. Importantly, cells completely lacking the Notch-Rbpj transcriptional activator complex can form arteries when the Myc-dependent metabolic and cell-cycle activity is suppressed. Thus, arterial development does not require the induction of a Notch-dependent arterial differentiation program, but rather the timely suppression of the endothelial metabolism and cell-cycle, a process preceding arterial mobilization and complete differentiation.
Joint Detection of Serum IgM/IgG Antibody is An Important Key to Clinical Diagnosis of SARS-COV-2 Infection
Authors: Hu Fang , Shang Xiaoling , Chen Meizhou , Zhang Changliang 
Published: July 2020

AbstractBackgroundThis study was aimed to investigate the application of SARS- COV-2 IgM and IgG antibodies in diagnosis of COVID-19 infection.MethodThis study enrolled a total of 178 patients at Huangshi Central Hospital from January to February, 2020. Among them, 68 patients were SARS-COV-2 infected confirmed with nucleic acid test (NAT) and CT imaging. 9 patients were in the suspected group (NAT negative) with fever and other respiratory symptoms. 101 patients were in the control group with other diseases and negative to SARS-COV-2 infection. After serum samples were collected, SARS-COV-2 IgG and IgM antibodies were tested by chemiluminescence immunoassay (CLIA) for all patients.ResultsThe specificity of serum IgM and IgG antibodies to SARS-COV-2 were 99.01% (100/101) and 96.04% (97/101) respectively, and the sensitivity were 88.24% (60/68) and 97.06% (66/68) respectively. The combined detection rate of SARS-COV-2 IgM and IgG antibodies were 98.53% (67/68).ConclusionCombined detection of serum SARS-COV-2 IgM and IgG antibodies had better sensitivity compared with single IgM or IgG test, which can be used as an important diagnostic tool for SARS-COV-2 infection and a screening tool of potential SARS-COV-2 carriers in clinics, hospitals and accredited scientific laboratory.
Accuracy of online symptom checkers and the potential impact on service utilisation
Authors: Ceney Adam , Tolond Stephanie , Glowinski Andrzej , Marks Ben , Swift Simon , Palser Tom 
Published: July 2020

AbstractObjectivesThe aims of this study are firstly to investigate the diagnostic and triage performance of symptom checkers, secondly to assess their potential impact on healthcare utilisation and thirdly to investigate for variation in performance between systems.SettingPublicly available symptom checkersParticipantsPublicly available symptom-checkers were identified. A standardised set of 50 clinical vignettes was developed and systematically run through each system by a non-clinical researcher.Primary and secondary outcome measuresSystem accuracy was assessed by measuring the percentage of times the correct diagnosis was a) listed first, b) within the top five diagnoses listed and c) listed at all. The safety of the disposition advice was assessed by comparing it with national guidelines for each vignette.ResultsTwelve tools were identified and included. Mean diagnostic accuracy of the systems was poor, with the correct diagnosis being listed first on 37.7% (Range 22.2 to 72.0%) of occasions and present in the top five diagnoses on 51.0% (Range 22.2 to 84.0%). 51.0% of systems suggested additional resource utilisation above that recommended by national guidelines (range 18.0% to 61.2%). Both diagnostic accuracy and appropriate resource recommendation varied substantially between systems.ConclusionsThere is wide variation in performance between available symptom checkers and overall performance is significantly below what would be accepted in any other medical field, though some do achieve a good level of accuracy and safety of disposition. External validation and regulation are urgently required to ensure these public facing tools are safe.Strengths and LimitationsData collection was undertaken by non-clinically trained staff to replicate patient behaviour and there was random sampling to test the inter-rater reliabilityClinical vignettes were agreed by a clinical team consisting of a GP, a pharmacist and a hospital emergency care consultantCurrent UK guidelines were used to assess service utilisation. Where symptom checkers were developed outside of the UK the disposition advice may be unlikely to be aligned due to different jurisdictionsThis research was a limited indirect study on the variety of terms and language patients might use in their interactions with these systemsThere was no assessment of how a clinician would diagnose and triage a patient presenting with the vignette symptoms
High excess mortality during the COVID-19 outbreak in Stockholm Region areas with young and socially vulnerable populations
Authors: Calderón-Larrañaga Amaia , Vetrano Davide L , Rizzuto Debora , Bellander Tom , Fratiglioni Laura , Dekhtyar Serhiy 
Published: July 2020

AbstractBackgroundWe aimed to describe the distribution of excess mortality (EM) during the first weeks of the COVID-19 outbreak in the Stockholm Region, Sweden, according to individual age and sex, and the sociodemographic contextMethodsWeekly all-cause mortality data were obtained from Statistics Sweden for the period 01/01/2015 to 17/05/2020. EM during the first 20 weeks of 2020 was estimated by comparing observed mortality rates with expected mortality rates during the five previous years (N=2,379,792). EM variation by socioeconomic status (tertiles of income, education, Swedish-born, gainful employment) and age distribution (share of 70+ year-old persons) was explored based on Demographic Statistics Area (DeSO) data.FindingsAn EM was first detected during the week of March 23-29 2020. During the peaking week of the epidemic (6-12 April 2020), an EM of 160% was observed: 211% in 80+ year-old women; 179% in 80+ year-old men. During the same week, the highest EM was observed for DeSOs with lowest income (171%), lowest education (162%), lowest share of Swedish-born (178%), and lowest share of gainfully employed (174%). There was a 1.2 to 1.7-fold increase in EM between those areas with a higher vs. lower proportion of young people.InterpretationLiving in areas with lower socioeconomic status and younger populations is linked to COVID-19 EM. These conditions might have facilitated the viral spread. Our findings add to the well-known biological vulnerability linked to increasing age, the relevance of the sociodemographic context when estimating the individual risk to COVID-19.FundingNone.