bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circadian Rhythms of Perineuronal Net Composition
Authors: Pantazopoulos Harry , Gisabella Barbara , Rexrode Lindsay , Benefield David , Yildiz Emrah , Seltzer Phoebe , Valeri Jake , Chelini Gabriele , Reich Anna , Ardelt Magdalena , Berretta Sabina 
Published: April 2020

ABSTRACTPerineuronal Nets (PNNs) are extracellular matrix (ECM) structures that envelop neurons and regulate synaptic functions. Long thought to be stable structures, PNNs have been recently shown to respond dynamically during learning, potentially regulating the formation of new synapses. We postulated that PNNs vary during sleep, a period of active synaptic modification. Notably, PNN components are cleaved by matrix proteases such as the protease cathepsin-S. This protease is diurnally expressed in the mouse cortex, coinciding with dendritic spine density rhythms. Thus, cathepsin-S may contribute to PNN remodeling during sleep, mediating synaptic reorganization. These studies were designed to test the hypothesis that PNN numbers vary in a diurnal manner in the rodent and human brain, as well as in a circadian manner in the rodent brain, and that these rhythms are disrupted by sleep deprivation. In mice, we observed diurnal and circadian rhythms of PNNs labeled with the lectin wisteria floribunda agglutinin (WFA+PNNs) in several brain regions involved in emotional memory processing. Sleep deprivation prevented the daytime decrease of WFA+ PNNs and enhances fear memory extinction. Diurnal rhythms of cathepsin-S expression in microglia were observed in the same brain regions, opposite to PNN rhythms. Finally, incubation of mouse sections with cathepsin-S eliminated PNN labeling. In humans, WFA+PNNs showed a diurnal rhythm in the amygdala and thalamic reticular nucleus (TRN). Our results demonstrate that PNNs vary in a circadian manner and this is disrupted by sleep deprivation. We suggest that rhythmic modification of PNNs may contribute to memory consolidation during sleep.
FastSK: Fast Sequence Analysis with Gapped String Kernels
Authors: Blakely Derrick , Collins Eamon , Singh Ritambhara , Norton Andrew , Lanchantin Jack , Qi Yanjun 
Published: April 2020

AbstractGappedk-mer kernels with Support Vector Machines (gkm-SVMs) have achieved strong predictive performance on regulatory DNA sequences on modestly-sized training sets. However, existing gkm-SVM algorithms suffer from slow kernel computation time, as they depend exponentially on the sub-sequence feature-length, number of mismatch positions, and the task’s alphabet size. In this work, we introduce a fast and scalable algorithm for calculating gappedk-mer string kernels. Our method, named FastSK, uses a simplified kernel formulation that decomposes the kernel calculation into a set of independent counting operations over the possible mismatch positions. This simplified decomposition allows us to devise a fast Monte Carlo approximation that rapidly converges. FastSK can scale to much greater feature lengths, allows us to consider more mismatches, and is performant on a variety of sequence analysis tasks. On 10 DNA transcription factor binding site (TFBS) prediction datasets, FastSK consistently matches or outperforms the state-of-the-art gkmSVM-2.0 algorithms in AUC, while achieving average speedups in kernel computation of ∼100× and speedups of ∼800× for large feature lengths. We further show that FastSK outperforms character-level recurrent and convolutional neural networks across all 10 TFBS tasks. We then extend FastSK to 7 English-language medical named entity recognition datasets and 10 protein remote homology detection datasets. FastSK consistently matches or outperforms these baselines. Our algorithm is available as a Python package and as C++ source code1.
Circuit mechanisms underlying chronic epilepsy in a mouse model of focal cortical malformation
Authors: Yang Weiguo , Williams Anthony , Sun Qian-Quan 
Published: April 2020

HighlightsEctopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons is a key component of the hyperexcitable circuitryDisrupted E/I balance was located far away from cortical malformationsDendritic inhibition from somatostatin interneurons play a key role in epileptogenesisClosed-loop optogenetic stimulation to activate remainder somatostatin interneurons irreversibly stops the spontaneous spike-wave discharges in vivo.In BriefYang et al. report abnormal synaptic reorganization in an epileptogenesis zone in a mouse model of cortical malformation. The authors further demonstrate that spontaneous spike-wave discharges can be curbed by selectively activating somatostatin interneurons using close-loop fiber optogenetic stimulation to a small cortical region away from the microgyrus.SummaryHow aberrant neural circuits contribute to chronic epilepsy remains unclear. Using a mouse model of focal cortical malformation with spontaneous seizures, we dissected the circuit mechanisms underlying epileptogenesis. Spontaneous and optogenetically induced hyperexcitable burstsin vivowere present in a cortical region distal to (> 1mm) freeze-lesion induced microgyrus, instead of a region near it. ChR2-assisted circuit mapping revealed ectopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons as a key component of the hyperexcitable circuitry. This disrupted balance between excitation and inhibition was prominent in the cortical region distal to the microgyrus. Consistently, the synapses of both parvalbumin-positive interneurons (PV) and somatostatin-positive interneurons (SOM) to pyramidal neurons were maladaptive in a layer- and site-specific fashion. Finally, closed-loop optogenetic stimulation of SOM, but not PV, terminated spontaneous spike-wave discharges. Together, these results demonstrate highly site- and cell-type specific synaptic reorganization underlying chronic cortical epilepsy and provide insights into potential treatment strategies for this devastating neurological disorder.
Electrical Oscillations of Isolated Brain Microtubules
Authors: Gutierrez Brenda C. , Cantiello Horacio F. , del Rocío Cantero María 
Published: April 2020

AbstractMicrotubules (MTs) are important cytoskeletal structures engaged in a number of specific cellular activities, including vesicular traffic and motility, cell division, and information transfer within neuronal processes. MTs also are highly charged polyelectrolytes. Recent in vitro electrophysiological studies indicate that different brain MT structures, including two-dimensional (2D) sheets (MT sheets) and bundles, generate highly synchronous electrical oscillations. However, no information has been heretofore available as to whether isolated MTs also engage in electrical oscillations, despite the fact that taxol-stabilized isolated MTs are capable of amplifying electrical signals. Herein we tested the effect of voltage clamping on the electrical properties of isolated non-taxol stabilized brain MTs. Electrical oscillations were observed on application of holding potentials between ±200 mV that responded accordingly with changes in amplitude and polarity. Frequency domain spectral analysis of time records from isolated MTs disclosed a richer oscillatory response as compared to that observed in voltage clamped MT sheets from the same preparation. The data indicate that isolated brain MTs are electrical oscillators that behave as “ionic-based” transistors whose activity may be synchronized in higher MT structures. The ability of MTs to generate, propagate, and amplify electrical signals may have important implications in neuronal computational capabilities.Significance StatementMicrotubules (MTs) are important cytoskeletal structures engaged in a number of specific cellular activities. Recent in vitro electrophysiological studies indicate that different brain MT structures generate highly synchronous electrical oscillations. However, no information is available as to whether isolated MTs also engage in electrical oscillations. In the present study, we provide evidence that non-taxol stabilized isolated MTs generated electrical oscillations with richer frequency spectrum as compared to MT sheets. Thus, structured MT complexes may render more coherent responses at given oscillatory frequencies, suggesting entrainment in combined MT structures. The present study provides to our knowledge the first experimental evidence for electrical oscillations of single brain MTs.
Lymph Node Morphology in Stage II Colorectal Cancer
Authors: Greenwood Annabelle , Keating John , Kenwright Diane , Shekouh Ali , Dalzell Alex , Dennett Elizabeth , Danielson Kirsty 
Published: April 2020

ABSTRACTBackgroundColorectal cancer is one of the leading causes of cancer-associated morbidity and mortality worldwide. The local anti-tumour immune response is particularly important for patients with stage II where the tumour-draining lymph nodes have not yet succumbed to tumour spread. The lymph nodes allow for the expansion and release of B cell compartments such as primary follicles and germinal centres. A variation in this anti-tumour immune response may influence the observed clinical heterogeneity in stage II patients.AimThe aim of this study was to explore tumour-draining lymph node histomorphological changes and tumour pathological risk factors including the immunomodulatory microRNA-21 (miR-21) in a small cohort of stage II CRC.MethodsA total of 23 stage II colorectal cancer patients were included. Tumour and normal mucosa samples were analysed for miR-21 expression levels and B-cell compartments were quantified from Haematoxylin and Eosin slides of lymph nodes. These measures were compared to clinicopathological risk factors such as perforation, bowel obstruction, T4 stage and high-grade.ResultsWe observed greater follicle density in patients with a lower tumour T stage and higher germinal centre density in patients with higher pre-operative carcinoembryonic antigen levels. Trends were also detected between tumours with deficiency in mismatch repair proteins, lymphatic invasion and both the density and size of B-cell compartments. Lastly, elevated tumour miR-21 was associated with decreased follicle and germinal centre size.ConclusionVariation in B-cell compartments of tumour-draining lymph nodes is associated with clinicopathological risk factors in stage II CRC patients.What does this paper add to the literature?This study demonstrates the variability of tumour draining lymph node morphological features in stage II CRC patients. This provides new scope for biomarker discovery in stage II CRC patients which is a research priority for this patient group.
What happens on islands, doesn’t stay on islands: Patterns of synchronicity in mosquito nuisance and host-seeking activity between a mangrove island and adjacent coastal development
Authors: Johnson Brian J. , Manby Russell , Devine Gregor J. 
Published: April 2020

AbstractCoastal development is expanding globally in response to mass human migration, yet urban planning guidelines often overlook the problems that human encroachment on or near coastal mosquito habitat may cause. This study aimed at elucidating the frequency and magnitude of dispersal of highly vagile saltmarsh mosquitoes from productive off-shore bay islands to adjacent coastal human developments. Inter-population dynamics and daily host-seeking activity of saltmarsh mosquitoes were monitored daily at 15-minute intervals within a productive bay island and adjacent coastal development in southeast Queensland, Australia, using emerging smart trap technology over a 2-month period of high mosquito activity. The regulation of mosquito dispersal and host-seeking activity by local environmental factors, e.g. temperature, relative humidity and hourly wind patterns, were also investigated. The data show that the primary saltmarsh mosquitoesAedes vigilax(Skuse) andCulex sitiens(Wiedemann) disperse from offshore breeding sites to neighboring mainland areas in high numbers and in highly synchronized waves despite unfavorable wind patterns and the need to traverse a considerable expanse (ca. 1.4 km) of open water. Patterns of host-seeking activity within each site were also remarkably similar despite notable differences in the local environment demonstrating a consistency in host-seeking activity across disparate habitats. These findings demonstrate that distant saltmarsh habitats, including offshore breeding sites, are likely to be primary sources of mosquito nuisance for coastal housing developments. This observation highlights the need to develop new planning and regulatory guidelines that alert urban planners to the risks of encroaching on habitats close to the sources of highly vagile mosquito species.
Inspecting abundantly expressed genes in male strobili in sugi (Cryptomeria japonica D. Don) via a highly accurate cDNA assembly
Authors: Wei Fu-Jin , Ueno Saneyoshi , Ujino-Ihara Tokuko , Saito Maki , Tsumura Yoshihiko , Higuchi Yuumi , Hirayama Satoko , Iwai Junji , Hakamata Tetsuji , Moriguchi Yoshinari 
Published: April 2020

AbstractSugi (Cryptomeria japonica D. Don) is an important conifer used for afforestation in Japan. The field of functional genomics is rapidly developing. The genomics of this gymnosperm species is currently being studied. Although its genomic size is 11 Gbps, it is still too large to assemble well within a short period of time. Transcriptomics is the one another approach to address this. Moreover, it is a necessary step in obtaining the complete genomic data. Here we designed a three stages assembling workflow using the de novo transcriptome assembly tools, Oases and Trinity. The three stages in transcriptomics are independent assembly, automatic and semi-automatic integration, and refinement by filtering out potential contamination. We found a set of 49,795 cDNA and an equal number of translated proteins (CJ3006NRE). According to the benchmark of BUSCO, 87.01 % were complete genes, including very high “Complete and single-copy” genes–78.47%. Compared to other full-length cDNA resources, the extent of the coverage in CJ3006NRE suggests that it may be used as the standard for further studies. When two tissue-specific libraries were compared, principal component analysis (PCA) showed that there were significant differences between male strobili and leaf and bark sets. The highest three upregulated transcription factors stood out as orthologs to angiosperms. The identified signature-like domain of the transcription factors demonstrated the accuracy of the assembly. Based on the evaluation of different resources, we demonstrate that our transcriptome assembly output is valuable and useful for further studies in functional genomics and evolutionary biology.
The time of strong actomyosin binding depends on electrostatic interactions within the force generating region in human cardiac myosin
Authors: Gargey Akhil , Iragavarapu Shiril Bhardwaj , Grdzelishvili Alexander V. , Nesmelov Yuri E. 
Published: April 2020

AbstractTwo single mutations, R694N and E45Q, were introduced in the beta isoform of human cardiac myosin to remove permanent salt bridges E45:R694 and E98:R694 in the force-generating region of myosin head. Beta isoform-specific bridges E45:R694 and E98:R694 were discovered in the molecular dynamics simulations of the alpha and beta myosin isoforms. Alpha and beta isoforms exhibit different kinetics, ADP dissociates slower from actomyosin containing beta myosin isoform, therefore, beta myosin stays strongly bound to actin longer. We hypothesize that the electrostatic interactions in the force-generating region modulate affinity of ADP to actomyosin, and therefore, the time of the strong actomyosin binding. Wild type and the mutants of the myosin head construct (1-843 amino acid residues) were expressed in differentiated C2C12cells, and duration of the strongly bound state of actomyosin was characterized using transient kinetics spectrophotometry. All myosin constructs exhibited a fast rate of ATP binding to actomyosin and a slow rate of ADP dissociation, showing that ADP release limits the time of the strongly bound state of actomyosin. Mutant R694N showed faster rate of ADP release from actomyosin, compared to the wild type and the E45Q mutant, thus confirming that electrostatic interactions within the force-generating region of human cardiac myosin regulate ADP release and the duration of the strongly bound state of actomyosin.
Nanopore metagenomic sequencing of influenza virus directly from respiratory samples: diagnosis, drug resistance and nosocomial transmission
Authors: Xu Yifei , Lewandowski Kuiama , Downs Louise O , Kavanagh James , Hender Thomas , Lumley Sheila , Jeffery Katie , Foster Dona , Sanderson Nicholas D , Vaughan Ali , Morgan Marcus , Vipond Richard , Carroll Miles , Peto Timothy , Crook Derrick , Walker A Sarah , Matthews Philippa C , Pullan Steven T 
Published: April 2020

ABSTRACTBackgroundInfluenza virus presents a significant challenge to public health by causing seasonal epidemics and occasional pandemics. Nanopore metagenomic sequencing has the potential to be deployed for near-patient testing, providing rapid diagnosis of infection, rationalising antimicrobial therapy, and supporting interventions for infection control. This study aimed to evaluate the applicability of this sequencing approach as a routine laboratory test for influenza in clinical settings.MethodsWe conducted Nanopore metagenomic sequencing for 180 respiratory samples from a UK hospital during the 2018/19 influenza season, and compared results to routine molecular diagnostic testing. We investigated drug resistance, genetic diversity, and nosocomial transmission using influenza sequence data.ResultsMetagenomic sequencing was 83% (75/90) sensitive and 93% (84/90) specific for detecting influenza A viruses compared with the diagnostic standard (Cepheid Xpress/BioFire FilmArray Respiratory Panel). We identified a H3N2 genome with the oseltamivir resistant S331R mutation in the NA protein, potentially associated with the emergence of a distinct intra-subtype reassortant. Whole genome phylogeny refuted suspicions of a transmission cluster in the infectious diseases ward, but identified two other clusters that likely reflected nosocomial transmission, associated with a predominant strain circulating in the community. We also detected a range of other potentially pathogenic viruses and bacteria from the metagenome.ConclusionNanopore metagenomic sequencing can detect the emergence of novel variants and drug resistance, providing timely insights into antimicrobial stewardship and vaccine design. Generation of full genomes can contribute to the investigation and management of nosocomial outbreaks.
Cancer cell elimination by cytotoxic T cell cooperation and additive damage
Authors: Weigelin Bettina , den Boer Annemieke Th. , Wagena Esther , Broen Kelly , Dolstra Harry , de Boer Rob J , Figdor Carl G. , Textor Johannes , Friedl Peter 
Published: April 2020

SummaryCytotoxic T lymphocytes (CTL) eliminate tumor target cells in an antigen and cell-contact dependent manner. Lethal hit delivery occurs as a rapid and binary, “yes/no” process when immunogenicity is very high1–3, howeverin vivoCTL often fail to kill solid tumor cells during 1:1 conjugations4–6. Using long-term time-lapse microscopy in three distinct tumor cytotoxicity models and statistical modeling, we here show that migrating CTL transit between target cells and initiate apoptosis by a series of sublethal interactions (‘additive cytotoxicity’), while individual conjugations rarely induced apoptosis. Sublethal damage included perforin-dependent membrane pore formation, nuclear lamina rupture and DNA damage, and these events resolved within minutes to hours. In immunogenic B16F10 melanoma tumorsin vivo, frequent serial engagements and sublethal hit delivery of CTL was largely confined to interstitial niches in the invasion front, resulting in eradication of invading tumor cells. Thus, additive cytotoxicity is a probabilistic process achieved by a series of CTL-target cell engagements and sublethal events. The need for additive “hits” has implications for the topographic mechanisms of elimination or immune evasion of tumor cells and microenvironmental regulation of CTL accumulation and cooperation by targeted therapy.
Expanding the depth and sensitivity of cross-link identification by differential ion mobility using FAIMS
Authors: Schnirch Lennart , Nadler-Holly Michal , Siao Siang-Wun , Frese Christian K. , Viner Rosa , Liu Fan 
Published: April 2020

AbstractIn cross-linking mass spectrometry, the depth and sensitivity is often limited by the low abundance of cross-links compared to non-cross-linked peptides in the digestion mixture. To improve the identification efficiency of low abundant cross-links, here we present a gas-phase separation strategy using high field asymmetric waveform ion mobility spectrometry (FAIMS) coupled to the Orbitrap Tribrid mass spectrometers. By enabling an additional peptide separation step in gas phase using the FAIMS device, we increase the number of cross-link identification by 23% for a medium complex sample and 56% for strong cation exchange-fractionated HEK293 cell lysate. Furthermore, we show that for medium complex samples, FAIMS enables the collection of single-shot cross-linking data with comparable depth to the corresponding sample fractionated by chromatography-based approaches. Altogether, we demonstrate FAIMS is highly beneficial for XL-MS studies by expanding the proteome coverage of cross-links while improving the efficiency and confidence of cross-link identification.