bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insight into the autosomal-dominant inheritance pattern of SOD1-associated ALS from native mass spectrometry
Authors: Cveticanin Jelena , Mondal Tridib , Meiering Elizabeth M. , Sharon Michal , Horovitz Amnon 
Published: July 2020

AbstractAbout 20% of all familial amyotrophic lateral sclerosis (ALS) cases are associated with mutations in superoxide dismutase (SOD1), a homodimeric protein. The disease has an autosomal-dominant inheritance pattern. It is, therefore, important to determine whether wild-type and mutant SOD1 subunits self-associate randomly or preferentially. A measure for the extent of bias in subunit association is the coupling constant determined in a double-mutant cycle type analysis. Here, cell lysates containing co-expressed wild-type and mutant SOD1 subunits were analyzed by native mass spectrometry to determine these coupling constants. Strikingly, we find a linear positive correlation between the coupling constant and the duration of the disease. Our results indicate that inter-subunit communication and a preference for heterodimerization greatly increase the disease severity.
DeepMIB: User-friendly and open-source software for training of deep learning network for biological image segmentation
Authors: Belevich Ilya , Jokitalo Eija 
Published: July 2020

AbstractDeep learning approaches are highly sought after solutions for coping with large amounts of collected datasets and are expected to become an essential part of imaging workflows. However, in most cases, deep learning is still considered as a complex task that only image analysis experts can master. DeepMIB addresses this problem and provides the community with a user-friendly and open-source tool to train convolutional neural networks and apply them to segment 2D and 3D light and electron microscopy datasets.
Spatial coupling between DNA replication and mismatch repair inCaulobacter crescentus
Authors: Chai Tiancong , Terrettaz Céline , Collier Justine 
Published: July 2020

ABSTRACTThe DNA mismatch repair (MMR) process detects and corrects replication errors in organisms ranging from bacteria to humans. In most bacteria, it is initiated by MutS detecting mismatches and MutL nicking the mismatch-containing DNA strand. Here, we show that MMR reduces the appearance of rifampicin resistances more than a 100-fold in theCaulobacter crescentus Alphaproteobacterium. Using fluorescently-tagged and functional MutS and MutL proteins, live cell microscopy experiments showed that MutS is usually associated with the replisome during the whole S-phase of theC. crescentuscell cycle, while MutL displays an apparently more dynamic association with the replisome. Thus, MMR components appear to use a 1D-scanning mode to search for rare mismatches, although the spatial association between MutS and the replisome is dispensible under standard growth conditions. Conversely, the spatial association of MutL with the replisome appears as critical for MMR inC. crescentus, suggesting a model where the β-sliding clamp licences the endonuclease activity of MutL right behind the replication fork where mismatches are generated. The spatial association between MMR and replisome components may also play a role in speeding up MMR and/or in recognizing which strand needs to be repaired in a variety ofAlphaproteobacteria.
Chromatin-contact atlas reveals disorder-mediated protein interactions and moonlighting chromatin-associated RBPs
Authors: Rafiee Mahmoud-Reza , Zagalak Julian A , Sidorov Sviatoslav , Steinhauser Sebastian , Davey Karen , Ule Jernej , Luscombe Nicholas M 
Published: July 2020

AbstractRNA-binding proteins (RBPs) play diverse roles in regulating co-transcriptional RNA-processing and chromatin functions, but our knowledge of the repertoire of chromatin-associated RBPs (caRBPs) and their interactions with chromatin remains limited. Here, we developed SPACE (Silica Particle Assisted Chromatin Enrichment) to isolate global and regional chromatin components with high specificity and sensitivity, and SPACEmap to identify the chromatin-contact regions in proteins. Applied to mouse embryonic stem cells, SPACE identified 1,459 chromatin-associated proteins, ∼48% of which are annotated as RBPs, indicating their dual roles in chromatin and RNA-binding. Additionally, SPACEmap stringently verified chromatin-binding of 404 RBPs and identified their chromatin-contact regions. Notably, SPACEmap showed that about half of the caRBPs bind to chromatin by intrinsically disordered regions (IDRs). Studying SPACE and total proteome dynamics from mES cells grown in 2iL and serum medium indicates significant correlation (R = 0.62). One of the most dynamic caRBPs is Dazl, which we find co-localized with PRC2 at transcription start sites of genes that are distinct from Dazl mRNA binding. Dazl and other PRC2-colocalised caRBPs are rich in intrinsically disordered regions (IDRs), which could contribute to the formation and regulation of phase-separated PRC condensates. Together, our approach provides an unprecedented insight into IDR-mediated interactions and caRBPs with moonlighting functions in native chromatin.
SETD2 deficiency impairs β-catenin destruction complex to facilitate renal cell carcinoma formation
Authors: Rao Hanyu , Li Xiaoxue , Liu Min , Liu Jing , Feng Wenxin , Xu Jin , Gao Wei-Qiang , Li Li 
Published: July 2020

AbstractClear cell renal cell carcinoma (ccRCC) is a largely incurable disease that is highly relevant to epigenetic regulation including histone modification and DNA methylation. SET domain–containing 2 (SETD2) is a predominant histone methyltransferase catalyzing the trimethylation of histone H3 Lysine 36 (H3K36me3) and its mutations are highly relevant to clear cell renal cell carcinoma (ccRCC). However, its physiology role in ccRCC remains largely unexplored. Here we report that Setd2 deletion impairs the β-catenin destruction complex to facilitate ccRCC formation in a c-MYC-generated polycystic kidney disease (PKD) model, which can be relieved by an inhibitor of β-catenin-responsive transcription. Clinically, SETD2 loss is widely observed in ccRCC samples, and negatively correlated with expression of some members of β-catenin destruction complex, but positively correlated with the activation of Wnt/β-catenin signaling. Our findings thus highlight a previously unrecognized role of SETD2-mediated H3K36me3 modification in regulation of Wnt/β-catenin pathway in ccRCC.SummaryOur findings for the first time reveal a previously unrecognized role of the SETD2-mediated H3K36me3 modification in regulation of the Wnt/β-catenin pathway in ccRCC and shed light on the molecular mechanisms underlying the formation of renal cell carcinoma with epigenetic disorders.
Impact of urolithiasis and hydronephrosis on acute kidney injury in patients with urinary tract infection
Authors: Hsiao Chih-Yen , Chen Tsung-Hsien , Lee Yi-Chien , Wang Ming-Cheng 
Published: July 2020

AbstractBackgroundUrolithiasis is a common cause of urinary tract obstruction and urinary tract infection (UTI). This study aimed to identify whether urolithiasis with or without hydronephrosis has an impact on acute kidney injury (AKI) in patients with UTI.Methods and findingsThis retrospective study enrolled hospitalized UTI patients who underwent imaging in an acute care setting from January 2006 to April 2019. Of the 1113 participants enrolled, 191 (17.2%) had urolithiasis and 76 (6.8%) had ureteral stone complicated with hydronephrosis. Multivariate logistic regression analysis showed that in UTI patients with urolithiasis, the presence of ureteral stone with concomitant hydronephrosis was an independent risk factor for AKI (odds ratio [OR] 2.345, 95% confidence interval [CI] 1.128–4.876, P = 0.023). In addition, urolithiasis was associated with an increased risk for AKI (OR 2.484, 95% CI 1.398–4.415, P = 0.002) in UTI patients without hydronephrosis.ConclusionThe presence of ureteral stone with hydronephrosis increases the risk for AKI of UTI patients with urolithiasis, and urolithiasis remains a risk factor of AKI in UTI patients without hydronephrosis.
Gold nanocarriers for transport of oligonucleotides across brain endothelial cells
Authors: Fatima Nayab , Gromnicova Radka , Loughlin Jane , Sharrack Basil , Male David 
Published: July 2020

AbstractTreatment of diseases that affect the CNS by gene therapy requires delivery of oligonucleotides to target cells within the brain. As the blood brain barrier prevents movement of large biomolecules, current approaches involve direct injection of the oligonucleotides, which is invasive and may have only a localised effect. The aim of this study was to investigate the potential of 2 nm galactose-coated gold nanoparticles (NP-Gal) as a delivery system of oligonucleotides across brain endothelium.DNA oligonucleotides of different types were attached to NP-Gal by the place exchange reaction and were characterised by EMSA (electrophoretic mobility shift assay). Several nanoparticle formulations were created, with single-or double-stranded (20nt or 40nt) DNA oligonucleotides, or with different amounts of DNA attached to the carriers. These nanocarriers were applied to transwell cultures of human brain endothelium in vitro (hCMEC/D3 cell-line) or to a 3D-hydrogel model of the blood-brain barrier including astrocytes. Transfer rates were measured by quantitative electron microscopy for the nanoparticles and qPCR for DNA.Despite the increase in nanoparticle size caused by attachment of oligonucleotides to the NP-Gal carrier, the rates of endocytosis and transcytosis of nanoparticles were both considerably increased when they carried an oligonucleotide cargo. Carriers with 40nt dsDNA were most efficient, accumulating in vesicles, in the cytosol and beneath the basal membrane of the endothelium. The oligonucleotide cargo remained attached to the nanocarriers during transcytosis and the transport rate across the endothelial cells was increased at least 50fold compared with free DNA. The nanoparticles entered the extracellular matrix and were taken up by the astrocytes in biologically functional amounts.Attachment of DNA confers a strong negative charge to the nanoparticles which may explain the enhanced binding to the endothelium and transcytosis by both vesicular transport and the transmembrane/cytosol pathway. These gold nanoparticles have the potential to transport therapeutic amounts of nucleic acids into the CNS.
Alternative isoforms of KDM2A and KDM2B lysine demethylases negatively regulate canonical Wnt signaling
Authors: Lađinović Dijana , Pinkas Daniel , Raška Otakar , Liška František , Raška Ivan , Vacík Tomáš 
Published: July 2020

AbstractA precisely balanced activity of canonical Wnt signaling is essential for a number of biological processes and its perturbation leads to developmental defects or diseases. Here, we demonstrate that alternative isoforms of the KDM2A and KDM2B lysine demethylases have the ability to negatively regulate canonical Wnt signaling. These KDM2A and KDM2B isoforms (KDM2A-SF and KDM2B-SF) lack the N-terminal demethylase domain, but they are able to bind to activated promoters in order to repress them. We have observed that KDM2A-SF and KDM2B-SF bind to and repress the promoters of AXIN2 and CYCLIN D1, two canonical Wnt signaling target genes. Moreover, KDM2A-SF and KDM2B-SF can repress a Wnt-responsive luciferase reporter. The transcriptional repression mediated by KDM2A-SF and KDM2B-SF, but also by KDM2A-LF, is dependent on their DNA binding domain, while the N-terminal demethylase domain is dispensable for this process. Surprisingly, KDM2B-LF is unable to repress both the endogenous promoters and the luciferase reporter. Finally, we show that both KDM2A-SF and KDM2B-SF are able to interact with TCF7L1, one of the transcriptional mediators of canonical Wnt signaling. KDM2A-SF and KDM2B-SF are thus likely to affect the transcription of the TCF7L1 target genes also through this interaction.
Effect of cultivation system on quality changes in durum wheat grain and flour produced in North-Eastern Europe
Authors: Banach Joanna K. , Majewska Katarzyna , Żuk-Gołaszewska Krystyna 
Published: July 2020

AbstractGrain of the highest hardness was produced from durum wheat grown without the growth regulator, at the lowest sowing density (350 seeds m-2) and nitrogen fertilization dose of 80 kg ha-1. The highest values L* and b* were determined in the grain of wheat cultivated without additional agrotechnical measures (growth regulator and nitrogen fertilization). Study results, supported by correlation analysis, indicated that high-quality grain with desired flour quality parameters (extraction rate, granulation and lightness) can be produced from spring durum wheat grown without the growth regulator and at medium doses of nitrogen fertilization. Additionally, this variant of applied cultivation system can reduce costs of durum wheat production and contamination of the natural environment.
Putative linear motifs mediate the trafficking to apical and basolateral membranes
Authors: Dobson Laszlo , Zeke András , Szekeres Levente , Langó Tamás , Tusnády Gábor 
Published: July 2020

AbstractCell polarity refers to the asymmetric organisation of cellular components in various cells. Epithelial cells are the best known examples of polarized cells, featuring apical and basolateral membrane domains. Despite huge efforts, the exact rules governing the protein distribution in such domains are still elusive. In this study we examined linear motifs accumulating in these parts and based on the results we prepared ‘Classical’ and Convolutional Neural Networks to classify human transmembrane proteins localizing into apical/basolateral membranes. Asymmetric expression of drug transporters results in vectorial drug transport, governing the pharmacokinetics of numerous substances, yet the data on how proteins are sorted in epithelial cells is very scattered. The provided dataset may offer help to experimentalists to characterize novel molecular targets to regulate transport processes more precisely.
Acute stress impairs reward learning in men
Authors: Carvalheiro Joana , Conceição Vasco A. , Mesquita Ana , Seara-Cardoso Ana 
Published: July 2020

AbstractAcute stress is ubiquitous in everyday life, but the extent to which acute stress affects how people learn from the outcomes of their choices is still poorly understood. Here, we investigate how acute stress impacts reward and punishment learning in men using a reinforcement-learning task. Sixty-two male participants performed the task whilst under stress and control conditions. We observed that acute stress impaired participants’ choice performance towards monetary gains, but not losses. To unravel the mechanism(s) underlying such impairment, we fitted a reinforcement-learning model to participants’ trial-by-trial choices. Computational modeling indicated that under acute stress participants learned more slowly from positive prediction errors — when the outcomes were better than expected — consistent with stress-induced dopamine disruptions. Such mechanistic understanding of how acute stress impairs reward learning is particularly important given the pervasiveness of stress in our daily life and the impact that stress can have on our wellbeing and mental health.
Orienting auditory attention in time: Lateralized alpha power reflects spatio-temporal filtering
Authors: Wöstmann Malte , Maess Burkhard , Obleser Jonas 
Published: July 2020

AbstractThe deployment of neural alpha (8-12 Hz) lateralization in service of spatial attention is well-established: Alpha power increases in the cortical hemisphere ipsilateral to the attended hemifield, and decreases in the contralateral hemisphere, respectively. Much less is known about humans’ ability to deploy such alpha lateralization in time, and to thus exploit alpha power as a spatio-temporal filter. Here we show that spatially lateralized alpha power does signify - beyond the direction of spatial attention - the distribution of attention in time and thereby qualifies as a spatio-temporal attentional filter. Participants (N= 20) selectively listened to spoken numbers presented on one side (left vs right), while competing numbers were presented on the other side. Key to our hypothesis, temporal foreknowledge was manipulated via a visual cue, which was either instructive and indicated the to-be-probed number position (70% valid) or neutral. Temporal foreknowledge did guide participants’ attention, as they recognized numbers from the to-be-attended side more accurately following valid cues. In the magnetoencephalogram (MEG), spatial attention to the left versus right side induced lateralization of alpha power in all temporal cueing conditions. Modulation of alpha lateralization at the 0.8-Hz presentation rate of spoken numbers was stronger following instructive compared to neutral temporal cues. Critically, we found stronger modulation of lateralized alpha power specifically at the onsets of temporally cued numbers. These results suggest that the precisely timed hemispheric lateralization of alpha power qualifies as a spatio-temporal attentional filter mechanism susceptible to top-down behavioural goals.
XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature
Authors: Yurchenko Andrey A. , Padioleau Ismael , Matkarimov Bakhyt T. , Soulier Jean , Sarasin Alain , Nikolaev Sergey 
Published: July 2020

ABSTRACTRecent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). However, the genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyzed a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observed an average of 25-fold increase of mutation rates in XP-C vs. sporadic leukemia which we presume leads to its elevated incidence and early appearance. In all XP-C tumors predominant mutational process is characterized by a distinct mutational signature, highlighting a specific mutational pattern in the context of GG-NER deficiency. We observed a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients leading to internal cancers.
A high-qualityde novogenome assembly from a single parasitoid wasp
Authors: Ye Xinhai , Yang Yi , Tian Zhaoyang , Xu Le , Yu Kaili , Xiao Shan , Yin Chuanlin , Xiong Shijiao , Fang Qi , Chen Hu , Li Fei , Ye Gongyin 
Published: July 2020

AbstractSequencing and assembling a genome with a single individual have several advantages, such as lower heterozygosity and easier sample preparation. However, the amount of genomic DNA of some small sized organisms might not meet the standard DNA input requirement for current sequencing pipelines. Although few studies sequenced a single small insect with about 100 ng DNA as input, it may still be challenging for many small organisms to obtain such amount of DNA from a single individual. Here, we use 20 ng DNA as input, and present a high-quality genome assembly for a single haploid male parasitoid wasp (Habrobracon hebetor) using Nanopore and Illumina. Because of the low input DNA, a whole genome amplification (WGA) method is used before sequencing. The assembled genome size is 131.6 Mb with a contig N50 of 1.63 Mb. A total of 99% Benchmarking Universal Single-Copy Orthologs are detected, suggesting the high level of completeness of the genome assembly. Genome comparison betweenH. hebetorand its relativeBracon brevicornisshows a high-level genome synteny, indicating the genome ofH. hebetoris highly accurate and contiguous. Our study provides an example forde novoassembling a genome from ultra-low input DNA, and will be used for sequencing projects of small sized species and rare samples, haploid genomics as well as population genetics of small sized species.
Adaptation of reach action to a novel force-field is not predicted by acuity of dynamic proprioception in either older or younger adults
Authors: Kitchen Nick M. , Miall R Chris 
Published: July 2020

AbstractHealthy ageing involves degeneration of the neuromuscular system which impacts movement control and proprioception. Yet the relationship between these sensory and motor deficits in upper limb reaching has not been examined in detail. Recently, we reported that age-related proprioceptive deficits were unrelated to accuracy in rapid arm movements, but whether this applied in motor tasks more heavily dependent on proprioceptive feedback was not clear. To address this, we have tested groups of younger and older adults on a force-field adaptation task under either full or limited visual feedback conditions and examined how performance related to dynamic proprioceptive acuity. Adaptive performance was similar between the age groups, regardless of visual feedback condition, although older adults showed increased after-effects. Physically inactive individuals made larger systematic (but not variable) proprioceptive errors, irrespective of age. However, dynamic proprioceptive acuity was unrelated to adaptation and there was no consistent evidence of proprioceptive recalibration with adaptation to the force-field for any group. Finally, in spite of clear age-dependent loss of spatial working memory capacity, we found no relationship between memory capacity and adaptive performance or proprioceptive acuity. Thus, non-clinical levels of deficit in dynamic proprioception, due to age or physical inactivity, do not affect force-field adaptation, even under conditions of limited visual feedback that might require greater proprioceptive control.
Solid-state NMR spectroscopy identifies three classes of lipids inC. neoformansmelanized cell walls and whole fungal cells
Authors: Chrissian Christine , Camacho Emma , Kelly John E. , Wang Hsin , Casadevall Arturo , Stark Ruth E. 
Published: July 2020

AbstractA primary virulence-associated trait of the opportunistic fungal pathogenCryptococcus neoformansis the production of melanin pigments that are deposited into the cell wall and interfere with the host immune response. Previously, our solid-state NMR studies of isolated melanized cell walls (melanin ‘ghosts’) revealed that the pigments are strongly associated with lipids, but their identities, origins, and potential roles were undetermined. Herein, we exploited spectral editing techniques to identify and quantify the lipid molecules associated with pigments in melanin ghosts. The lipid profiles were remarkably similar in wholeC. neoformanscells, grown under either melanizing or non-melanizing conditions; triglycerides (TGs), sterol esters (SEs) and polyisoprenoids (PPs) were the major constituents. Although no quantitative differences were found between melanized and non-melanized cells, melanin ghosts were relatively enriched in SEs and PPs. In contrast to lipid structures reported during early stages of fungal growth in nutrient-rich media, variants found herein could be linked to nutrient stress, cell aging, and subsequent production of substances that promote chronic fungal infections. The fact that TGs and SEs are the typical cargo of lipid droplets suggests that these organelles could be connected toC. neoformansmelanin synthesis. Moreover, the discovery of PPs is intriguing because dolichol is a well-established constituent of human neuromelanin. The presence of these lipid species even in non-melanized cells suggests that they could be produced constitutively under stress conditions in anticipation of melanin synthesis. These findings demonstrate thatC. neoformanslipids are more varied compositionally and functionally than previously recognized.