bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability
Authors: Jang Grace N , MacIver M Bruce 
Published: May 2021

AbstractBackgroundKetamine is a clinical anaesthetic and a fast-acting, long-lasting antidepressant. Ketamine is known for its antagonistic actions on N-methyl-D-aspartate (NMDA) receptors, but mechanisms leading to antidepression are not clear. The present study examined synaptic, neuronal and circuit-level loci, the duration of ketamine’s actions, and the involvement of NMDA receptors in these actions.MethodsExtracellular evoked field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant (10 μM) and anaesthetic (350 μM) concentrations. Effects of NMDA receptor antagonists, DL-2-Amino-5-phosphonovaleric acid (APV) and MK-801, γ-aminobutyric acid (GABA) receptor antagonist bicuculline, and a potassium channel blocker tetraethylammonium (TEA) were also studied.ResultsKetamine decreased population spike (PS) amplitudes during application, but a long-lasting increase in PS amplitudes was seen during washout of ketamine. While the acute effects of ketamine were reversed by bicuculline, the washout increase was not altered. This long-term increase was statistically significant (p<0.01, Wilcoxon Rank Test), sustained for >2 hours, and involved postsynaptic mechanisms. A similar, long-lasting effect was produced by MK-801 but was only partially evident with APV, demonstrating the importance of channel block downstream of NMDA receptors. Furthermore, TEA produced a lasting excitability increase, indicating possible involvement of potassium channel block in ketamine’s long-term effects.ConclusionsThis is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anaesthesia, while increased excitatory transmission contributes to its antidepressant effects.Published AbstractsSociety for Neuroscience Annual Meeting 2019Association of University Anesthesiologists Annual Meeting 2020International Anesthesia Research Society Annual Meeting 2020The Science of Consciousness Conference 2020International Society for Anaesthetic Pharmacology Annual Meeting 2020Western Anesthesia Residents Conference 2021Association of University Anesthesiologists Annual Meeting 2021International Anesthesia Research Society Annual Meeting 2021
Expansion and contraction of resource allocation in sensory bottlenecks
Authors: Edmondson Laura R , Rodríguez Alejandro Jiménez , Saal Hannes P 
Published: May 2021

AbstractTopographic sensory representations often do not scale proportionally to the size of their input regions, with some expanded and others contracted. In vision, the foveal representation is magnified cortically, as are the fingertips in touch. What principles drive this allocation, and how should receptor density, e.g. the high innervation of the fovea or the fingertips, and stimulus statistics, e.g. the higher contact frequencies on the fingertips, contribute? Building on work in efficient coding, we address this problem using linear models that maximize information transmission through decorrelation. We introduce a sensory bottleneck to impose constraints on resource allocation and derive the optimal neural allocation. We find that bottleneck width is a crucial factor in resource allocation, inducing either expansion or contraction. Both receptor density and stimulus statistics affect allocation and jointly determine convergence for wider bottlenecks. Furthermore, we show a close match between the predicted and empirical cortical allocations in a well-studied model system, the star-nosed mole. Overall, our results suggest that the strength of cortical magnification depends on resource limits.
Lecture-based, problem-based, digital problem-based and distance learning on knowledge improvement in medical education: a meta-analysis
Authors: Sun Jiangming 
Published: May 2021

AbstractProblem-based learning (PBL), an educational approach well applied in education, was believed as a deep method that can promote problem solving, and critical thinking. Varies implementation of PBL across different settings were introduced. How to objectively evaluate knowledge effectiveness of PBLs remains a challenge. The present study is aiming to systematically investigate the knowledge improvement between types of PBL in medical education. Our meta-analysis showed that distance learning using digital PBL could be a good alternative to traditional learning in medical education.
Development of the visual white matter pathways mediates development of electrophysiological responses in visual cortex
Authors: Caffarra Sendy , Joo Sung Jun , Bloom David , Kruper John , Rokem Ariel , Yeatman Jason D. 
Published: May 2021

AbstractThe latency of neural responses in the visual cortex changes systematically across the lifespan. Here we test the hypothesis that development of visual white matter pathways mediates maturational changes in the latency of visual signals. Thirty-eight children participated in a cross-sectional study including diffusion MRI and MEG sessions. During the MEG acquisition, participants performed a lexical decision and a fixation task on words presented at varying levels of contrast and noise. For all stimuli and tasks, early evoked fields were observed around 100 ms after stimulus onset (M100), with slower and lower amplitude responses for low as compared to high contrast stimuli. The optic radiations and optic tracts were identified in each individual’s brain based on diffusion MRI tractography. The diffusion properties of the optic radiations predicted M100 responses, especially for high contrast stimuli. Higher optic radiation fractional anisotropy (FA) values were associated with faster and larger M100 responses. Over this developmental window, the M100 responses to high contrast stimuli became faster with age and the optic radiation FA mediated this effect. These findings suggest that the maturation of the optic radiations over childhood accounts for individual variations observed in the developmental trajectory of visual cortex responses.
A novel bacteriophage with broad host-range against Clostridioides difficile ribotype 078 elucidates the phage receptor
Authors: Whittle M.J , Bilverstone T.W , van Esveld R.J , Lücke A.C. , Lister M.M , Kuehne S.A , Minton N.P 
Published: May 2021

AbstractBacteriophage represent a promising option for the treatment of Clostridioides difficile (formerly Clostridium difficile) infection (CDI), which at present relies on conventional antibiotic therapy. The specificity of bacteriophages should prevent the dysbiosis of the colonic microbiota associated with the treatment of CDI with antibiotics. Whilst numerous phages have been isolated, none have been characterised with broad host-range activity towards PCR ribotype (RT) 078 C. difficile strains despite their considerable relevance to medicine and agriculture. In this study, we isolated four novel C. difficile Myoviruses: ΦCD08011, ΦCD418, ΦCD1801 and ΦCD2301. Their characterisation revealed that each was comparable with other C. difficile phages described in the literature, with the exception of ΦCD1801 which exhibited a broad host-range activity towards RT 078, infecting 15/16 (93.8%) of the clinical isolates tested. In order for wild-type phages to be exploited in the effective treatment of CDI, an optimal phage cocktail must be assembled that provides broad coverage against all C. difficile RTs. In an attempt to advance these efforts, we conducted a series of fundamental experiments that identified the C. difficile SlpA, the major constituent of the C. difficile surface-layer (S-layer), as the phage receptor. Thus, we demonstrated that ΦCD1801 could only bind to RT 012 or RT 027 strains in the presence of a plasmid-borne S-layer cassette corresponding to RT 078. Armed with this information, efforts should now be directed towards the isolation of phages with broad host-range activity against each of the fourteen described S-layer cassette types which could form the basis of an effective cocktail active against a wide range of C. difficile isolates.ImportanceResearch into phage therapy has seen a resurgence in recent years owing to growing concerns regarding antimicrobial resistance. Phage research for potential therapy against Clostridium difficile infection (CDI) is in its infancy, where an optimal “one size fits all” phage cocktail is yet to be derived. The pursuit thus far, has aimed to find phages with the broadest possible host-range. Although, for C. difficile strains belonging to certain PCR ribotypes (RTs), in particular RT 078, phages with broad-host range activity are yet to be discovered. In this study, we isolate 4 novel Myoviruses including ΦCD1801, which exerts the broadest host-range activity towards RT 078 reported in the literature. Through the application of ΦCD1801 to robust binding assays, we elucidate SlpA as the phage receptor on the bacterial cell surface. Our finding suggests that an optimal “one size fits all” combinatorial phage cocktail, could theoretically comprise 14 phages, each targeting one of the 14 described S-layer cassettes of C. difficile.
COVID-19 testing among children, parental preferences for testing venues and acceptability of school-based testing: a survey of US parents
Authors: Teasdale Chloe A. , Borrell Luisa N. , Shen Yanhan , Kimball Spencer , Rinke Michael L. , Fleary Sasha A. , Nash Denis 
Published: May 2021

AbstractIn a national survey of 2,074 US parents conducted in March 2021, 35.9% reported their youngest child had been tested at least once for COVID-19. Parents’ preferred testing venue choice was the pediatrician’s office. Only half of parent surveyed (50.6%) reported that they would allow their child to be tested for COVID-19 at school/daycare if it was required.
Using a two-stage convolutional neural network to rapidly identify tiny herbivorous beetles in the field
Authors: Takimoto Hironori , Sato Yasuhiro , Nagano Atsushi J. , Shimizu Kentaro K. , Kanagawa Akihiro 
Published: May 2021

ABSTRACTRecently, deep convolutional neural networks (CNN) have been adopted to help beginners identify insect species from field images. However, the application of these methods on the identification of tiny congeneric species moving across heterogeneous background remains difficult. To enable rapid and automatic identification in the field, we customized a method involving real-time object detection of two Phyllotreta beetles. We first performed data augmentation using transformations, syntheses, and random erasing of the original images. We then proposed a two-stage method for the detection and identification of small insects based on CNN, where YOLOv4 and EfficientNet were used as a region proposal network and a re-identification method, respectively. Evaluation of the model revealed that one-step object detection by YOLOv4 alone was not precise (Precision = 0.55) when classifying two species of flea beetles and background objects. In contrast, the two-step CNNs improved the precision (Precision = 0.89) with moderate accuracy (F-measure = 0.55) and acceptable speed (ca. 5 frames per second for full HD images) of detection and identification of insect species in the field. Although real-time identification of tiny insects remains a challenge in the field, our method aids in improving small object detection on a heterogeneous background.
Dynamics of repair and regeneration of adult zebrafish respiratory gill tissue after cryoinjury
Authors: Ramel Marie-Christine , Progatzky Fränze , Rydlova Anna , Wane Madina , Schymeinsky Jürgen , Williams Cara , Jung Birgit , Lamb Jonathan , Thomas Matthew J , Bugeon Laurence , Dallman Margaret J. 
Published: May 2021

AbstractThe study of respiratory tissue damage and repair is critical to understand not only the consequences of respiratory tissue exposure to infectious agents, irritants and toxic chemicals, but also to comprehend the pathogenesis of chronic inflammatory lung diseases. To gain further insights into these processes, we developed a gill cryoinjury model in the adult zebrafish. Time course analysis showed that cryoinjury of the gills triggered an inflammatory response, extensive cell death and collagen deposition at the site of injury. However, the inflammation was rapidly resolved, collagen accumulation dissipated and by 3 weeks after injury the affected gill tissue had begun to regenerate. RNA seq analysis of cryoinjured gills, combined with a comparison of zebrafish heart cryoinjury and caudal fin resection datasets, highlighted the differences and similarities of the transcriptional programmes deployed in response to injury in these three zebrafish models. Comparative RNA seq analysis of cryoinjured zebrafish gills with mouse pulmonary fibrosis datasets also identified target genes, including the understudied FIBIN, as differentially expressed in the two species. Further mining, including of human datasets, suggests that FIBIN may contribute to the successful resolution of tissue damage without fibrosis.
Quantitation of tizoxanide in multiple matrices to support cell culture, animal and human research
Authors: Neary Megan , Arshad Usman , Tatham Lee , Pertinez Henry , Box Helen , Rajoli Rajith KR , Valentijn Anthony , Sharp Joanne , Rannard Steve P , Biagini Giancarlo A , Curley Paul , Owen Andrew 
Published: May 2021

AbstractCurrently nitazoxanide is being assessed as a candidate therapeutic for SARS-CoV-2. Unlike many other candidates being investigated, tizoxanide (the active metabolite of nitazoxanide) plasma concentrations achieve antiviral levels after administration of the approved dose, although higher doses are expected to be needed to maintain these concentrations across the dosing interval in the majority of patients. Here an LC-MS/MS assay is described that has been validated in accordance with Food and Drug Administration (FDA) guidelines. Fundamental parameters have been evaluated, and these included accuracy, precision and sensitivity. The assay was validated for human plasma, mouse plasma and Dulbeccos Modified Eagles Medium (DMEM) containing varying concentrations of Foetal Bovine Serum (FBS). Matrix effects are a well-documented source of concern for chromatographic analysis, with the potential to impact various stages of the analytical process, including suppression or enhancement of ionisation. Therefore, a robustly validated LC-MS/MS analytical method is presented capable of quantifying tizoxanide in multiple matrices with minimal impact of matrix effects. The validated assay presented here was linear from 15.6ng/mL to 1000ng/mL. Accuracy and precision ranged between 102.2% and 113.5%, 100.1% and 105.4%, respectively. The presented assay here has applications in both pre-clinical and clinical research and may be used to facilitate further investigations into the application of nitazoxanide against SARS-CoV-2.
Activating P2Y1 receptors improves function in arteries with repressed autophagy
Authors: Cho Jae Min , Park Seul-Ki , Kwon Oh Sung , La Salle D. Taylor , Cerbie James , Fermoyle Caitlin C. , Morgan David , Nelson Ashley , Bledsoe Amber , Bharath Leena P. , Tandar Megan , Kunapuli Satya P. , Richardson Russell S. , Anandh Babu Pon Velayutham , Mookherjee Sohom , Kishore Bellamkonda K. , Wang Fei , Yang Tianxin , Boudina Sihem , Trinity Joel D. , Symons J. David 
Published: May 2021

AbstractObjectiveThe importance of endothelial cell (EC) autophagy to vascular homeostasis is evolving. Earlier we reported that purinergic 2Y1 receptor (P2Y1-R) activation rejuvenates shearstress induced nitric oxide (NO) generation in bovine aortic endothelial cells that is otherwise compromised after pharmacological and genetic autophagy repression. Here we determined the translational and functional relevance of these findings.Approach and ResultsFirst we assessed translational relevance using older humans and mice that exhibit blunted EC autophagy at rest together with impaired arterial function vs. appropriate controls. Rhythmic handgrip exercise elevated radial artery shear rate similarly in adult and older males for 60-min. Compared to baseline, autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs from adult but not older subjects. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older mice in response to 60-min treadmill-running. Next we questioned whether an inability to initiate EC autophagy precipitates arterial dysfunction. Age-associated reductions in intraluminal flow-mediated vasodilation observed in older vs. adult mice were recapitulated in arteries from adult mice by : (i) NO synthase inhibition; (ii) autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) P2Y1-R blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from : (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy.ConclusionsArterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs.
Comprehensive analysis of clustered mutations in cancer reveals recurrent APOBEC3 mutagenesis of ecDNA
Authors: Bergstrom Erik N. , Luebeck Jens , Petljak Mia , Bafna Vineet , Mischel Paul S. , Harris Reuben S. , Alexandrov Ludmil B. 
Published: May 2021

ABSTRACTClustered somatic mutations are common in cancer genomes with prior analyses revealing several types of clustered single-base substitutions, including doublet- and multi-base substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here, we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome sequenced cancers from 30 cancer types. While only 3.7% of substitutions and 0.9% of indels were found to be clustered, they contributed 8.4% and 6.9% of substitution and indel drivers, respectively. Multiple distinct mutational processes gave rise to clustered indels including signatures enriched in tobacco smokers and homologous-recombination deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, while the majority of multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, previously attributed to the activity of APOBEC3 deaminases, accounted for a large proportion of clustered substitutions. However, only 16.2% of omikli matched APOBEC3 patterns with experimental validation confirming additional mutational processes giving rise to omikli. Kataegis was generated by multiple mutational processes with 76.1% of all kataegic events exhibiting AID/APOBEC3-associated mutational patterns. Co-occurrence of APOBEC3 kataegis and extrachromosomal-DNA (ecDNA) was observed in 31% of samples with ecDNA. Multiple distinct APOBEC3 kataegic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kataegic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fueling the evolution of ecDNA.
Neural correlates and determinants of approach-avoidance conflict in the prelimbic prefrontal cortex
Authors: Fernandez-Leon J.A. , Engelke D.S. , Aquino-Miranda G. , Goodson A. , Rasheed M.N. , Do-Monte F.H. 
Published: May 2021

ABSTRACTThe recollection of environmental cues associated with threat or reward allows animals to select the most appropriate behavioral responses. Neurons in the prelimbic cortex (PL) respond to both threat- and reward-associated cues. However, it remains unknown whether PL regulates threat-avoidance vs. reward-approaching responses when an animals’ decision depends on previously associated memories. Using a conflict model in which male Long-Evans rats retrieve memories of shock- and food-paired cues, we observed two distinct phenotypes during conflict: i) rats that continued to press a lever for food (Pressers); and ii) rats that exhibited a complete suppression in food seeking (Non-Pressers). Single-unit recordings revealed that increased risk-taking behavior in Pressers is associated with persistent food-cue responses in PL, and reduced spontaneous activity in PL glutamatergic (PLGLUT) neurons during conflict. Activating PLGLUT neurons in Pressers attenuated food-seeking responses in a neutral context, whereas inhibiting PLGLUT neurons in Non-Pressers reduced defensive responses and increased food approaching during conflict. Our results establish a causal role for PLGLUT neurons in mediating individual variability in memory-based risky decision making by regulating threat-avoidance vs. reward-approach behaviors.
Case study: Digital spatial profiling of metastatic clear cell carcinoma reveals intra-tumor heterogeneity in epithelial-mesenchymal gradient
Authors: Wang Duncan Yi-Te , Tan Tuan Zea , Tai Ya-Ting , Ye Jieru , Lin Wei-Chou , Wei Lin-Hung , Huang Ruby Yun-Ju 
Published: May 2021

AbstractIntrinsic intra-tumor heterogeneity (ITH) has been linked to worse patient outcomes. The development of spatial profiling technology has enabled the deciphering of ITH with multiple analysis readouts. Advanced ovarian clear cell carcinoma (OCCC), known to harbor ITH, is chemoresistant, poor prognostic, and possesses distinct molecular and histological characteristics. However, detailed spatial information of the nature of ITH within OCCC remains unclear. Here, we utilized the NanoString Digital spatial profiling (DSP) GeoMx platform to perform multiplex protein expression analysis on tumor samples of primary and colonic metastatic sites from one advanced OCCC patient. The spatial resolution revealed the existence of an epithelial-mesenchymal (EM) gradient within the metastatic tumor but not the primary tumor, and similar EM gradient was not observed within the primary tumor. The EM gradient exhibited a distinct pattern from the periphery to the core of the metastatic tumor. Compared to tumor cells at the primary site, there was an intermediate zone in between the tumor periphery and the tumor core in the colonic metastasis with differential expression patterns of pan-cytokeratin (PanCK), fibronectin (FN), smooth muscle actin (SMA), neural cell adhesion molecule (NCAM), integrin alpha X (ITGAX), and Ki-67. Our study provides the first spatially resolved in situ evidence of intermediate or hybrid EM states within the tumor samples of similar morphology. This not only demonstrates the promising applications of spatial profiling in precision medicine but also provides an unprecedented view of the EM gradient during the progression of cancer such as OCCC.
Spatial profiling of microbial communities by sequential FISH with error-robust encoding
Authors: Cao Zhaohui , Zuo Wenlong , Wang Lanxiang , Chen Junyu , Qu Zepeng , Jin Fan , Dai Lei 
Published: May 2021

AbstractSpatial analysis of microbiomes at single cell resolution with high multiplexity and accuracy has remained challenging. Here we present spatial profiling of a microbiome using sequential error-robust fluorescence in situ hybridization (SEER-FISH), a highly multiplexed and accurate imaging method that allows mapping of microbial communities at micron-scale. We show that multiplexity of RNA profiling in microbiomes can be increased significantly by sequential rounds of probe hybridization and dissociation. Combined with error-correction strategies, we demonstrate that SEER-FISH enables accurate taxonomic identification in complex microbial communities. Using microbial communities composed of diverse bacterial taxa isolated from plant rhizospheres, we show that SEER-FISH can quantify the abundance of each taxon and map microbial biogeography on roots. SEER-FISH should enable accurate spatial profiling of the ecology and function of complex microbial communities.