bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypothalamic dopamine neurons control sensorimotor behavior by modulating brainstem premotor nuclei
Authors: Barrios Joshua P. , Wang Wei-Chun , England Roman , Reifenberg Erica , Douglass Adam D.
Published: July 2020

Dopamine (DA)-producing neurons are critically involved in the production of motor behaviors in multiple circuits that are conserved from basal vertebrates to mammals. While there is increasing evidence that DA neurons in the hypothalamus play a locomotor role, their precise contributions to behavior and the circuit mechanisms by which they are achieved remain unclear. Here we demonstrate thattyrosine hydroxylase 2-expressing (th2+) DA neurons in the zebrafish hypothalamus fire phasic bursts of activity to acutely promote swimming and modulate audiomotor behaviors on fast timescales. Their anatomy and physiology reveal two distinct functional DA modules within the hypothalamus. The first comprises an interconnected set of cerebrospinal fluid-contacting DA nuclei surrounding the third ventricle, which lack distal projections outside of the hypothalamus and influence locomotion through unknown means. The second includes neurons in the preoptic nucleus, which send long-range projections to targets throughout the brain, including the mid- and hindbrain, where they activate premotor circuits involved in swimming and sensorimotor integration. These data suggest a broad regulation of motor behavior by DA neurons within multiple hypothalamic nuclei and elucidate a novel functional mechanism for the preoptic DA neurons in the initiation of movement.
A synthetic kinematic index of trunk displacement conveying the overall motor condition in Parkinson’s disease
Authors: Lopez Emahnuel Troisi , Minino Roberta , Sorrentino Pierpaolo , Rucco Rosaria , Carotenuto Anna , Agosti Valeria , Tafuri Domenico , Manzo Valentino , Liparoti Marianna , Sorrentino Giuseppe
Published: July 2020

BACKGROUND

Parkinson’s disease (PD) is characterized by motor impairment, affecting quality of life and increasing fall risk, due to ineffective postural control. To this day, the diagnosis remains based on clinical approach. Similarly, motor evaluation is based on heterogeneous, operator-dependent observational criteria. A synthetic, replicable index to quantify motor impairment is still lacking. In this paper, we build upon the idea that the trunk is crucial in balance control. Hence, we have designed a new measure of postural stability which assesses the trunk displacement in relation to the center of mass, that we named trunk displacement index (TDI).

METHODS

Twenty-three PD patients and twenty-three healthy controls underwent clinical (UPDRS-III) and motor examination (3D gait analysis). The TDI was extracted from kinematic measurements using a stereophotogrammetric system. A correlation analysis was performed to assess the relationship of TDI with typical gait parameters, to verify its biomechanical value, and UPDRS-III, to observe its clinical relevance. Finally, its sensitivity was measured, comparing pre- and post-L-DOPA subclinical intake.

RESULTS

The TDI showed significant correlations with many gait parameters, including both velocity and stability characteristics of gait, and with the UPDRS-III. Finally, the TDI resulted capable in discriminating between off and on state in PD, whereas typical gait parameters failed two show any difference between those two conditions.

CONCLUSIONS

Our results suggest that the TDI may be considered a highly sensitive biomechanical index, reflecting the overall motor condition in PD, and provided of clinical relevance due to the correlation with the clinical evaluation.
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

About 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

Deep 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

The 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

RNA-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

Clear 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.

Our 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

Background

Urolithiasis 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 findings

This 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.

Conclusion

The 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

Treatment 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

A 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

Grain 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

Cell 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.
A common molecular mechanism for cognitive deficits and craving in alcoholism
Authors: Meinhardt Marcus W. , Pfarr Simone , Rohleder Cathrin , Vengeliene Valentina , Barroso-Flores Janet , Hoffmann Rebecca , Meinhardt Manuela L. , Paul Elisabeth , Hansson Anita C. , Köhr Georg , Meier Nils , von Bohlen und Halbach Oliver , Bell Richard L. , Endepols Heike , Neumaier Bernd , Schönig Kai , Bartsch Dusan , Spanagel Rainer , Sommer Wolfgang H.
Published: July 2020

Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. The medial prefrontal cortex, a key brain region for executive control, is prone to alcohol-induced neuroadaptations. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. Here using a bi-directional neuromodulation approach we demonstrate a causal link for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we generated a phenotype of reduced cognitive flexibility and excessive alcohol-seeking. Conversely, restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. Also targeting mGluR2 pharmacologically reduced relapse behavior. Finally, we developed a FDG-PET biomarker to identify those individuals that respond to mGluR2-based interventions. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving, and provide a personalized mGluR2-mechanism-based intervention strategy for medication development of alcoholism.
Acute stress impairs reward learning in men
Authors: Carvalheiro Joana , Conceição Vasco A. , Mesquita Ana , Seara-Cardoso Ana
Published: July 2020

Acute 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

The 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

Recent 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

Sequencing 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

Healthy 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

A 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.
An increase in dendritic plateau potentials is associated with experience-dependent cortical map reorganization
Authors: Pages Stéphane , Chenouard Nicolas , Chéreau Ronan , Kouskoff Vladimir , Gambino Frédéric , Holtmaat Anthony
Published: July 2020

The organization of sensory maps in the cerebral cortex depends on experience, which drives homeostatic and long-term synaptic plasticity of cortico-cortical circuits. In the mouse primary somatosensory cortex (S1) afferents from the higher-order, posterior medial thalamic nucleus (POm) gate synaptic plasticity in layer (L) 2/3 pyramidal neurons via disinhibition and the production of dendritic plateau potentials. Here we address whether these thalamocortically mediated responses play a role in whisker map plasticity in S1. We find that trimming all but two whiskers causes a partial fusion of the representations of the two spared whiskers, concomitantly with an increase in the occurrence of POm-driven, N-methyl-D-aspartate receptor (NMDAR)-dependent plateau potentials. Blocking the plateau potentials restores the archetypical organization of the sensory map. Our results reveal a novel mechanism for experience-dependent cortical map plasticity in which higher-order thalamocortically mediated plateau potentials facilitate the fusion of normally segregated cortical representations.
Liquid-liquid phase separation driven compartmentalization of reactive nucleoplasm
Authors: Laghmach Rabia , Potoyan Davit A
Published: July 2020

The nucleus of eukaryotic cells harbors active and out of equilibrium environments conducive to diverse gene regulatory processes. On a molecular scale, gene regulatory processes take place within hierarchically compartmentalized sub-nuclear bodies. While the impact of nuclear structure on gene regulation is widely appreciated, it has remained much less clear whether and how gene regulation is impacting nuclear order itself. Recently, the liquid-liquid phase separation emerged as a fundamental mechanism driving the formation of biomolecular condensates, including membrane-less organelles, chromatin territories, and transcriptional domains. The transience and environmental sensitivity of biomolecular condensation are strongly suggestive of kinetic gene-regulatory control of phase separation. To better understand kinetic aspects controlling biomolecular phase-separation, we have constructed a minimalist model of the reactive nucleoplasm. The model is based on the Cahn-Hilliard formulation of ternary protein-RNA-nucleoplasm components coupled to non-equilibrium and spatially dependent gene expression. We find a broad range of kinetic regimes through an extensive set of simulations where the interplay of phase separation and reactive timescales can generate heterogeneous multi-modal gene expression patterns. Furthermore, the significance of this finding is that heterogeneity of gene expression is linked directly with the heterogeneity of length-scales in phase-separated condensates.
Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing
Authors: Leibowitz Mitchell L. , Papathanasiou Stamatis , Doerfler Phillip A. , Blaine Logan J. , Yao Yu , Zhang Cheng-Zhong , Weiss Mitchell J. , Pellman David
Published: July 2020

Genome editing has promising therapeutic potential for genetic diseases and cancer (1, 2). However, the most practicable current approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of structural chromosomal abnormalities. Here, we show that a catastrophic mutational process called chromothripsis is a previously unappreciated consequence of CRISPR-Cas9-mediated DSBs. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer (3–6). Using model cell systems and a genome editing protocol similar to ones in clinical trials (7) (NCT03655678,NCT03745287) we show that CRISPR-Cas9-mediated DNA breaks generate abnormal nuclear structures—micronuclei and chromosome bridges—that trigger chromothripsis. Chromothripsis is an on-target toxicity that may be minimized by cell manipulation protocols or screening but cannot be completely avoided in many genome editing applications.
Overexpression of HLA class I predominantly on alpha cell in at risk individuals for type 1 diabetes
Authors: Benkahla Mehdi A. , Sabouri Somayeh , Kiosses William B. , Rajendran Sakthi , Quesada-Masachs Estefania , von Herrath Matthias
Published: July 2020

Human leukocyte antigens of class-I (HLA-I) molecules are hyper-expressed in insulin-containing islets (ICI) of type 1 diabetic (T1D) donors. This study investigated the HLA-I expression in autoantibody positive (AAB+) donors and more closely defined its intra-islet and intracellular localization as well as proximity to infiltrating CD8 T cells with high-resolution confocal microscopy. We found HLA-I hyper-expression had already occurred prior to clinical diagnosis of T1D in islets of AAB+ donors. Interestingly, throughout all stages of disease, HLA-I was mostly expressed by alpha cells. Hyper-expression in AAB+ and T1D donors was associated with intra-cellular accumulation in the Golgi. Proximity analysis showed a moderate but significant correlation between HLA-I and infiltrating CD8 T cells only in ICI of T1D donors, but not in AAB+ donors. These observations not only demonstrate a very early, islet-intrinsic immune-independent increase of HLA-I during diabetes pathogenesis, but also point towards a role for alpha cells in T1D.

Human leukocyte antigens of class-I (HLA-I) are hyper-expressed in insulin-containing islets of type 1 diabetic (T1D) donors. This study finds HLA-I hyper-expression occurs prior to clinical diagnosis of T1D in islets of autoantibody-positive donors and mostly expressed by alpha cells.
Spontaneous alpha-band amplitude predicts subjective visibility but not discrimination accuracy during high-level perception
Authors: Samaha Jason , LaRocque Joshua J. , Postle Bradley R.
Published: July 2020

Near-threshold perception is a paradigm case of perceptual reports diverging from reality – perception of an unchanging stimulus can vacillate from undetected to clearly perceived. Among the many factors that predict whether a stimulus will reach awareness, the amplitude of low-frequency brain oscillations - particularly in the alpha frequency band (8-13 Hz) - has emerged as a reliable predictor of trial-to-trial variability in perceptual decisions. Analysis grounded in signal detection theory suggest that strong prestimulus alpha oscillations diminish subjective perception without affecting the accuracy or sensitivity (d’) of perceptual decisions. These results, coupled with recent studies on sensory responses, point to an inhibitory influence of alpha-band amplitude on early visuocortical activity. The findings to date have been based on simple, low-level visual stimuli, which warrant a focus on early visual processing. However, the physiology of alpha in higher-level visual areas is known to be distinct from early visual cortex, with evidence indicating that alpha amplitude in the inferior temporal (IT) cortex is excitatory (rather than inhibitory, as in early visual cortex). Here, we addressed the question of how spontaneous oscillatory amplitude impacts subjective and objective aspects of perception using a high-level perceptual decision task. Human observers completed a near-threshold face/house discrimination task with subjective visibility ratings while electroencephalograms (EEG) were recorded. Using a single-trial multiple regression analysis, we found that spontaneous fluctuations in pre-stimulus alpha-band amplitude were negatively related to visibility ratings but did not predict trial-by-trial accuracy. These results suggest that the inhibitory influence of prestimulus alpha activity in early visual cortex, rather than the excitatory influence of alpha in IT, comes to bias high-level perceptual reports. Our findings provide further evidence that ongoing alpha amplitude dissociates subjective and objective measures of visual perception.
Photochemical NOT Gate for DNA Computing
Authors: Emanuelson Cole , Bardhan Anirban , Deiters Alexander
Published: July 2020

DNA-based Boolean logic gates (AND, OR and NOT) can be assembled into complex computational circuits that generate an output signal in response to specific patterns of oligonucleotide inputs. However, the fundamental nature of NOT gates, which convert the absence of an input into an output, makes their implementation within DNA-based circuits difficult. Premature execution of a NOT gate before completion of its upstream computation introduces an irreversible error into the circuit. We developed a novel DNA gate design utilizing photocaging groups that prevents gate function until irradiation at a certain time-point. Optical activation provides temporal control over circuit performance by preventing premature computation and is orthogonal to all components of DNA computation devices. Using this approach, we designed NAND and NOR logic gates that respond to synthetic microRNA inputs. We further demonstrate the utility of the NOT gate within multi-layer circuits in response to a specific pattern of four microRNAs.
Roles of motor on-rate and cargo mobility in intracellular transport
Authors: Bovyn Matthew J. , Reddy Babu J.N. , Gross Steven P. , Allard Jun F.
Published: July 2020

Molecular motors like kinesin are critical for cellular organization and biological function including in neurons. There is detailed understanding of how they move and how factors such as applied force and the presence of microtubule-associated proteins can alter this single-motor travel. In order to walk, the cargo-motor complex must first attach to a microtubule. This attachment process is less studied. Here, we use a combination of single-molecule bead experiments, modeling, and simulation to examine how cargos with kinesin-1 bind to microtubules. In experiment, we find that increasing cargo size and environment viscosity both signficantly slow cargo binding time. We use modeling and simulation to examine how the single motor on rate translates to the on rate of the cargo. Combining experiment and modeling allows us to estimate the single motor on rate as 100 s−1. This is a much higher value than previous estimates. We attribute the difference between our measurements and previous estimates to two factors: first, we are directly measuring initial motor attachment (as opposed to re-binding of a second motor) and second, the theoretical framework allows us to account for missed events (i.e. binding events not detected by the experiments due to their short duration). This indicates that the mobility of the cargo itself, determined by its size and interaction with the cytoplasmic environment, play a previously underestimated role in determining intracellular transport kinetics.
Development of a data-driven COVID-19 prognostication tool to inform triage and step-down care for hospitalised patients in Hong Kong: A population-based cohort study
Authors: Tsui Eva L.H. , Lui Carrie S.M. , Woo Pauline P.S. , Cheung Alan T.L. , Lam Peggo K.W. , Tang Van T.W. , Yiu C.F. , Wan C.H. , Lee Libby H.Y.
Published: July 2020

Background

This is the first study on prognostication in an entire cohort of laboratory-confirmed COVID-19 patients in the city of Hong Kong. Prognostic tool is essential in the contingency response for the next wave of outbreak. This study aims to develop prognostic models to predict COVID-19 patients’ clinical outcome on day 1 and day 5 of hospital admission.

Methods

We did a retrospective analysis of a complete cohort of 1,037 COVID-19 laboratory-confirmed patients in Hong Kong as of 30 April 2020, who were admitted to 16 public hospitals with their data sourced from an integrated electronic health records system. It covered demographic information, chronic disease(s) history, presenting symptoms as well as the worst clinical condition status, biomarkers’ readings and Ct value of PCR tests on Day-1 and Day-5 of admission. The study subjects were randomly split into training and testing datasets in a 8:2 ratio. Extreme Gradient Boosting (XGBoost) model was used to classify the training data into three disease severity groups on Day-1 and Day-5.

Results

The 1,037 patients had a mean age of 37.8 (SD±17.8), 53.8% of them were male. They were grouped under three disease outcome: 4.8% critical/serious, 46.8% stable and 48.4% satisfactory. Under the full models, 30 indicators on Day-1 and Day-5 were used to predict the patients’ disease outcome and achieved an accuracy rate of 92.3% and 99.5%. With a trade-off between practical application and predictive accuracy, the full models were reduced into simpler models with seven common specific predictors, including the worst clinical condition status (4-level), age group, and five biomarkers, namely, CRP, LDH, platelet, neutrophil/lymphocyte ratio and albumin/globulin ratio. Day-1 model’s accuracy rate, macro- and micro-averaged sensitivity and specificity were 91.3%, 84.9%-91.3% and 96.0%-95.7% respectively, as compared to 94.2%, 95.9%-94.2% and 97.8%-97.1% under Day-5 model.

Conclusions

Both Day-1 and Day-5 models can accurately predict the disease severity. Relevant clinical management could be planned according to the predicted patients’ outcome. The model is transformed into a simple online calculator to provide convenient clinical reference tools at the point of care, with an aim to inform clinical decision on triage and step-down care.
The consequences of adjustment, correction and selection in genome-wide association studies used for two-sample Mendelian randomization
Authors: Walker Venexia M , Harrison Sean , Carter Alice R , Gill Dipender , Tzoulaki Ioanna , Davies Neil M
Published: July 2020

Introduction

Genome-wide association studies (GWASs) often adjust for covariates, correct for medication use, or select on medication users. If these summary statistics are used in two-sample Mendelian randomization analyses, estimates may be biased. We used simulations to investigate how GWAS adjustment, correction and selection affects these estimates and performed an analysis in UK Biobank to provide an empirical example.

Methods

We simulated six GWASs: no adjustment for a covariate, correction for medication use, or selection on medication users; adjustment only; selection only; correction only; both adjustment and selection; and both adjustment and correction. We then ran two-sample Mendelian randomization analyses using these GWASs to evaluate bias. We also performed equivalent GWASs using empirical data from 306,560 participants in UK Biobank with systolic blood pressure as the exposure and body mass index as the covariate and ran two-sample Mendelian randomization with coronary heart disease as the outcome.

Results

The simulation showed that estimates from GWASs with selection can produce biased two-sample Mendelian randomization estimates. Yet, we observed relatively little difference between empirical estimates of the effect of systolic blood pressure on coronary artery disease across the six scenarios.

Conclusions

Given the potential for bias from using GWASs with selection on Mendelian randomization estimates demonstrated in our simulation, careful consideration before using this approach is warranted. However, based on our empirical results, using adjusted, corrected or selected GWASs is unlikely to make a large difference to two-sample Mendelian randomization estimates in practice.
Two New Models for Epidemics with Application to the COVID-19 Pandemic in the United States, Italy, and the United Kingdom
Authors: Roberts David H.
Published: July 2020

The Distributed Logistic Model and the Adaptive Logistic Model of epidemics are formulated and used to study the course of cases and deaths during the COVID-19 pandemic. The distributed model is designed to account for a spread of initiation times of hot spots across a country; it does especially well at capturing the initial and linear phases of epidemics. The adaptive model accounts for the development of social mitigation factors, and does especially well at capturing the declining phases of epidemics. The historical data for the U.S., Italy, and the U.K. are analyzed in detail. The parameters of the fits to the two models provide complementary information about the pandemic. The initial infection rate constant was r0 ≃ 0.29 day−1 for each country, and the effective infection rate constants evolved with time in essentially the same way for each. This suggests that mitigation effects were equally effective in all three countries. Analysis with the distributed model suggests that it took somewhat different times T for the epidemic to spread across each country, with T (US)≃ 50 days significantly greater than the T ‘s of Italy or the U.K. The mortality ratio in the U.S. was about 0.061 while in Italy and U.K. it was much larger at about 0.15.
Studies on the Biosorption Potential of Copper byRhizopus arrhizusBiomass
Authors: Chauhan Jyoti , Saini Ishan , Kaushik Prashant
Published: July 2020

Due to rapid industrialization and global urbanization, heavy metal pollution of water reservoirs is a severe environmental threat. Moreover, the removal of these heavy metal ions of copper from the wastewaters using conventional methods are costly, time taking, and less effective. Whereas, biosorption proved as a better alternative technique over the traditional methods for the removal of metal ions from the water bodies. Biological materials or biosorbents have been used for the adsorption of metal ions from the aquatic system. Therefore, Rhizopusarrhizus(living biomass) for the biosorption of copper (Cu) metal was used as biosorbent in the present investigation. The pH and temperature at which biosorption occurs are critical. In case ofR. arrhizusthe maximum adsorption was recorded at pH 7.0, and a temperature of 35°C.Whereas, the maximum adsorption capacity (Q value) of 100 mg biomass ofRhizopus arrhizuswas observed as 94.46 % at 80 ppm concentration. The maximum adsorption capacity of 200 mg biomass of test fungi was reported as 97.32 % at the metal concentration of 80 ppm. Maximum Q value (biosorption capacity, i.e. mg metal per g biosorbent) was 37.785 mg/g at an 80-ppm concentration in case of 100 mg biomass. In the case of 200 mg biomass, the maximum Q value was 19.464 mg/g observed at 80 ppm concentration. Overall, the present study showed that 100 mg and 200 mgRhizopus arrhizusbiomass acts as an excellent adsorbing material for the adsorption of Cu metal ions.