bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-faceted Semantic Clustering With Text-derived Phenotypes
Authors: Slater Luke T , Williams John A , Karwath Andreas , Fanning Hilary , Ball Simon , Schofield Paul , Hoehndorf Robert , Gkoutos Georgios V
Published: May 2021

Identification of ontology concepts in clinical narrative text enables the creation of phenotype profiles that can be associated with clinical entities, such as patients or drugs. Constructing patient phenotype profiles using formal ontologies enables their analysis via semantic similarity, in turn enabling the use of background knowledge in clustering or classification analyses. However, traditional semantic similarity approaches collapse complex relationships between patient phenotypes into a unitary similarity scores for each pair of patients. Moreover, single scores may be based only on matching terms with the greatest information content (IC), ignoring other dimensions of patient similarity. This process necessarily leads to a loss of information in the resulting representation of patient similarity, and is especially apparent when using very large text-derived and highly multi-morbid phenotype profiles. Moreover, it renders finding a biological explanation for similarity very difficult; the black box problem. In this article, we explore the generation of multiple semantic similarity scores for patients based on different facets of their phenotypic manifestation, which we define through different sub-graphs in the Human Phenotype Ontology. We further present a new methodology for deriving sets of qualitative class descriptions for groups of entities described by ontology terms. Leveraging this strategy to obtain meaningful explanations for our semantic clusters alongside other evaluation techniques, we show that semantic clustering with ontology-derived facets enables the representation, and thus identification of, clinically relevant phenotype relationships not easily recoverable using overall clustering alone. In this way, we demonstrate the potential of faceted semantic clustering for gaining a deeper and more nuanced understanding of text-derived patient phenotypes.
A whole system approach to increasing children’s physical activity in a multi-ethnic UK city: a process evaluation protocol
Authors: Hall Jennifer , Bingham Daniel D , Seims Amanda , Dogra Sufyan Abid , Burkhardt Jan , Nobles James , McKenna Jim , Bryant Maria , Barber Sally E , Daly-Smith Andy
Published: May 2021

Background

Engaging in regular physical activity requires continued complex decision-making in varied and dynamic individual, social and structural contexts. Widespread shortfalls of physical activity interventions suggests the complex underlying mechanisms of change are not yet fully understood. More insightful process evaluations are needed to design and implement more effective approaches. This paper describes the protocol for a process evaluation of the JU:MP programme, a whole systems approach to increasing physical activity in children and young people aged 5-14 years in North Bradford, UK.

Methods

This process evaluation, underpinned by realist philosophy, aims to understand the development and implementation of the JU:MP programme and the mechanisms by which JU:MP influences physical activity in children and young people. It also aims to explore behaviour change across wider policy, strategy and neighbourhood systems. A mixed method data collection approach will include semi-structured interview, observation, documentary analysis, surveys, and participatory evaluation methods including reflections and ripple effect mapping.

Discussion

Not only is this an innovative approach to process evaluation but it will also feed into iterative programme development to generate evidence-based practice and deliver practice-based evidence. This paper advances knowledge regarding the development of process evaluations for evaluating systems interventions, and emphasises the importance of process evaluation.
Fast and Accurate Estimation of Gas-Phase Entropy from the Molecular Surface Curvature
Authors: Venkatraman Vishwesh , Roy Amitava
Published: May 2021

Estimating entropy is crucial for understanding and modifying biological systems, such as protein-ligand binding. Current computational methods to estimate entropy require extensive, or at times prohibitively extensive, computational resources. This article presents SHAPE (SHape-based Accurate Predictor of Entropy), a new method that estimates the gas-phase entropy of small molecules purely from their surface geometry. The gas-phase entropy of small molecules can be computed in ≈0.01 CPU hours with run time complexity of, whereNais the number of atoms. The accuracy of SHAPE is within 1 − 2% of computationally expensive quantum mechanical or molecular mechanical calculations. We further show that the inclusion of gas-phase entropy, estimated using SHAPE, improves the rank-order correlation between binding affinity and binding score from 0.18 to 0.40. The speed and accuracy of SHAPE make it well-suited for inclusion in molecular docking or QSAR (quantitative structure-activity relationships) methods.

Abstract Figure
Using OPMs to measure neural activity in standing, mobile participants
Authors: Seymour Robert A. , Alexander Nicholas , Mellor Stephanie , O’Neill George C. , Tierney Tim M. , Barnes Gareth R. , Maguire Eleanor A.
Published: May 2021

Optically pumped magnetometer-based magnetoencephalography (OP-MEG) can be used to measure neuromagnetic fields while participants move in a magnetically shielded room. Head movements in previous OP-MEG studies have been up to 20 cm translation and ∼30° rotation in a sitting position. While this represents a step-change over stationary MEG systems, naturalistic head movement is likely to exceed these limits, particularly when participants are standing up. In this proof-of-concept study, we sought to push the movement limits of OP-MEG even further. Using a 90 channel (45-sensor) whole-head OP-MEG system and concurrent motion capture, we recorded auditory evoked fields while participants were: (i) sitting still, (ii) standing up and still, and (iii) standing up and making large natural head movements continuously throughout the recording – maximum translation 120 cm, maximum rotation 198°. Following pre-processing, movement artefacts were substantially reduced but not eliminated. However, upon utilisation of a beamformer, the M100 event-related field localised to primary auditory regions. Furthermore, the event-related fields from auditory cortex were remarkably consistent across the three conditions. These results suggest that a wide range of movement is possible with current OP-MEG systems. This in turn underscores the exciting potential of OP-MEG for recording neural activity during naturalistic paradigms that involve movement (e.g. navigation), and for scanning populations who are difficult to study with stationary MEG (e.g. young children).
The geometry of decision-making
Authors: Sridhar Vivek Hari , Li Liang , Gorbonos Dan , Nagy Máté , Schell Bianca R. , Sorochkin Timothy , Gov Nir S. , Couzin Iain D.
Published: May 2021

Choosing among spatially-distributed options is a central challenge for animals, from deciding among alternative potential food sources or refuges, to choosing with whom to associate. Using an integrated theoretical and experimental approach (employing immersive virtual reality), we consider the interplay between movement and vectorial integration during decision-making regarding two, or more, options in space. In computational models of this process we reveal the occurrence of spontaneous and abrupt “critical” transitions (associated with specific geometrical relationships) whereby organisms spontaneously switch from averaging vectorial information among, to suddenly excluding one, among the remaining options. This bifurcation process repeats until only one option—the one ultimately selected—remains. Thus we predict that the brain repeatedly breaks multi-choice decisions into a series of binary decisions in space-time. Experiments with fruit flies, desert locusts, and larval zebrafish reveal that they exhibit these same bifurcations, demonstrating that across taxa and ecological context, there exist fundamental geometric principles that are essential to explain how, and why, animals move the way they do.
Crucial Roles of Carotenoids as Bacterial Endogenous Defense System for Bacterial Radioresistance of Deinococcus radiodurans
Authors: Yang Qiao
Published: May 2021

Background

The central dogma of radiation biology is that the cytotoxic and mutagenic effects of radiation are principally the result of biological macromolecules (DNA, RNA, polysaccharides, proteins and lipids) damage caused during the course of irradiation. Previous studies on the radioresistance of the extremely radiation-resistant red-carotenoid-pigmented bacterium Deinococcus radiodurans have been focused on DNA repair system. However, relative little is known about the biochemical basis of the extraordinary recovery capacity of D. radiodurans for ionizing radiation and can include hundreds of DNA double-strand breaks.

Methodology/Principal Findings

Here we identified a novel carotenoid in D. radiodurans as ((all-E)-1’-hydroxy-3’,4’-didehydro-1’,2’,2,3-quahydro-β,ψ-carotene-4-one-1) and characterized the intracellular distribution of carotenoids. Following exposure to ionizing radiation, the wild-type parent of D. radiodurans survived much higher compared with radiation-sensitive colorless mutants screened by 60Co irradiation and by knockout of crtB or crtI genes for the carotenoid biosynthesis. Electron paramagnetic resonance spectroscopy analysis showed that two carotenoid can effectively scavenge radicals including superoxide anion (O2.−) and hydroxyl radical (.OH). Consistent results showing the substantial antioxidant abilities of the two carotenoids were obtained by UV-induction of bacteriophage λ method in vivo, and the detectable reaction potentials of two carotenoids with nitric oxide (NO) evaluated by ultraviolet-visible near-infrared ray (UV/vis/NIR) spectra assay.

Conclusions/Significance

Our findings support the idea that the degree of bacterial radioresistance of D. radiodurans is partly related to the levels of carotenoids in the cells. Carotenoids, as an important member of the structural and non-structural components of the cells, are endogenous scavengers of reactive oxygen species and can effectively quench radicals generated during irradiation. The current work suggests that carotenoids play a previously unrecognized protection role in the endogenous defense System (EDS) that facilitates the recovery from radiation injury. And we propose a complete model to elucidate the mechanisms of extreme radioresistance in this remarkable bacterium.
Early beta oscillations in multisensory association areas underlie crossmodal performance enhancement
Authors: Michail Georgios , Senkowski Daniel , Holtkamp Martin , Wächter Bettina , Keil Julian
Published: May 2021

The combination of signals from different sensory modalities can enhance perception and facilitate behavioral responses. While previous research described crossmodal influences in a wide range of tasks, it remains unclear how such influences drive performance enhancements. In particular, the neural mechanisms underlying performance-relevant crossmodal influences, as well as the latency and spatial profile of such influences are not well understood. Here, we examined data from high-density electroencephalography (N = 30) and electrocorticography (N = 4) recordings to characterize the oscillatory signatures of crossmodal facilitation of response speed, as manifested in the speeding of visual responses by concurrent task-irrelevant auditory information. Using a data-driven analysis approach, we found that individual gains in response speed correlated with reduced beta power (13-25 Hz) in the audiovisual compared with the visual condition, starting within 80 ms after stimulus onset in multisensory association and secondary visual areas. In addition, the electrocorticography data revealed a beta power suppression in audiovisual compared with visual trials in the superior temporal gyrus (STG). Our data suggest that the crossmodal facilitation of response speed is associated with early beta power in multisensory association and secondary visual areas, presumably reflecting the enhancement of early sensory processing through selective attention. This finding furthers our understanding of the neural correlates underlying crossmodal response speed facilitation and highlights the critical role of beta oscillations in mediating behaviorally relevant audiovisual processing.

Significance Statement

The use of complementary information across multiple senses can enhance perception. Previous research established a central role of neuronal oscillations in multisensory perception, but it remains poorly understood how they relate to multisensory performance enhancement. To address this question, we recorded electrophysiological signals from scalp and intracranial electrodes (implanted for presurgical monitoring) in response to simple visual and audiovisual stimuli. We then associated the difference in oscillatory power between the two conditions with the speeding of responses in the audiovisual trials. We demonstrate, that the crossmodal facilitation of response speed is associated with beta power in multisensory association areas during early stages of sensory processing. This finding highlights the importance of beta oscillations in mediating behaviorally relevant audiovisual processing.
Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability
Authors: Jang Grace N , MacIver M Bruce
Published: May 2021

Background

Ketamine 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.

Methods

Extracellular 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.

Results

Ketamine 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.

Conclusions

This 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 Abstracts

Society for Neuroscience Annual Meeting 2019

Association of University Anesthesiologists Annual Meeting 2020

International Anesthesia Research Society Annual Meeting 2020

The Science of Consciousness Conference 2020

International Society for Anaesthetic Pharmacology Annual Meeting 2020

Western Anesthesia Residents Conference 2021

Association of University Anesthesiologists Annual Meeting 2021

International 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

Topographic 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

Problem-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

The 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

Bacteriophage 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.

Importance

Research 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

In 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

Recently, 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

The 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

Currently 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

Objective

The 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 Results

First 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.

Conclusions

Arterial 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

Clustered 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

The 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

Intrinsic 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

Spatial 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.
New fossils ofAustralopithecus sedibareveal a nearly complete lower back
Authors: Williams Scott A. , Prang Thomas C. , Meyer Marc R. , Nalley Thierra K. , Van Der Merwe Renier , Yelverton Christopher , García-Martínez Daniel , Russo Gabrielle A. , Ostrofsky Kelly R. , Eyre Jennifer , Grabowski Mark , Nalla Shahed , Bastir Markus , Schmid Peter , Churchill Steven E. , Berger Lee R.
Published: May 2021

Adaptations of the lower back to bipedalism are frequently discussed but infrequently demonstrated in early fossil hominins. Newly discovered lumbar vertebrae contribute to a near-complete lower back of Malapa Hominin 2 (MH2), offering additional insights into posture and locomotion inAustralopithecus sediba. We show that MH2 demonstrates a lower back consistent with human-like lumbar lordosis and other adaptations to bipedalism, including an increase in the width of intervertebral articular facets from the upper to lower lumbar column (“pyramidal configuration”). This contrasts with recent work on lordosis in fossil hominins, where MH2 was argued to demonstrate no appreciable lordosis (“hypolordosis”) similar to Neandertals. Our three-dimensional geometric morphometric (3D GM) analyses show that MH2’s nearly complete middle lumbar vertebra is human-like in shape but bears large, cranially-directed transverse processes, implying powerful trunk musculature. We interpret this combination of features to indicate thatA. sedibaused its lower back in both human-like bipedalism and ape-like arboreal positional behaviors, as previously suggested based on multiple lines of evidence from other parts of the skeleton and reconstructed paleobiology ofA. sediba.
Physically active lifestyle is associated with attenuation of hippocampal dysfunction in healthy older adults
Authors: Eisenstein Tamir , Giladi Nir , Hendler Talma , Havakuk Ofer , Lerner Yulia
Published: May 2021

Alterations in hippocampal function have been shown in older adults, expressed as changes in hippocampal activity and connectivity. While hippocampal activation during memory demands have been demonstrated to decrease with age, some older individuals present increased activity, or hyperactivity, of the hippocampus which is associated with increased neuropathology and poorer memory function. In addition, lower functional coherence between the hippocampus and core hubs of the default mode network (DMN), namely the posteromedial and medial prefrontal cortices, as well as increased local intrahippocampal connectivity, were also demonstrated in cognitively intact older adults. Aerobic exercise has been shown to elicit neuroprotective effects on hippocampal structure and vasculature in aging, and improvements in maximal aerobic capacity (MAC) have been suggested to mediate these exercise-related effects. However, how these lifestyle factors relate to hippocampal function is not clear. Fifty-two cognitively intact older adults (age 65-80) have been recruited and divided into physically active (n=29) or non-active (n=23) groups based on their aerobic activity lifestyle habits. Participants underwent resting-state as well as task-based fMRI experiments which included an associative memory encoding paradigm followed by a post-scan memory recognition test. In addition, forty-four participants also performed cardiopulmonary exercise tests to evaluate MAC. While both groups demonstrated increased anterior hippocampal activation during memory encoding, physically active lifestyle was associated with significantly lower activity level and higher memory performance in the recognition task. In addition, the physically active group also demonstrated higher functional connectivity of the anterior and posterior hippocampi with the core hubs of the DMN, and lower local intra-hippocampal connectivity within and between hemispheres. MAC was negatively associated with hippocampal activation level and demonstrated positive correlation with hippocampal-DMN connectivity. According to these findings, aerobically active lifestyle may be associated with attenuation of hippocampal dysfunction in cognitively healthy older adults.
Cell type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons
Authors: Forget Benoit , Garcia Elena Martin , Godino Arthur , Rodriguez Laura Domingo , Kappes Vincent , Poirier Pierre , Andrianarivelo Andry , Marchan Eric Senabre , Allichon Marie-Charlotte , Marias Mélanie , Vanhoutte Peter , Girault Jean-Antoine , Maldonado Rafael , Caboche Jocelyne
Published: May 2021

The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express respectively the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially up-regulated in the NAc. We then focused on miR-1 considering the important role of some of its predicted mRNA targets, such as fosb and npas4, in the effects of cocaine. We validated these targets in vitro and in vivo and further showed that overexpression of miR-1 in D1-SPNs of the DS reduced cocaine-induced CPP reinstatement, whereas it increased cue-induced reinstatement of cocaine-SA, without affecting other cocaine-mediated adaptive behavior. In addition, miR-1 overexpression in D2-SPNs of the DS reduced the motivation to self-administer cocaine but did not modify other measured behaviors. Together, our results highlight a precise cell-type- and region-specific control of relapse to cocaine-seeking behaviors by miR-1, and illustrate the importance of cell-specific investigations.
The “dark matter” of protein variants carries a distinct DNA signature and predicts damaging variant effects
Authors: Ng Joseph Chi-Fung , Fraternali Franca
Published: May 2021

Abstract

Signatures of DNA motifs associated with distinct mutagenic exposures have been defined for somatic variants, but little is known about the consequences different mutational processes pose to the cell, especially how mutagens exert damage on specific proteins and their three-dimensional structures. Here we identify a DNA mutational signature which corresponds to damaging protein variants. We show that this mutational signature is under-sampled in sequencing data from tumour cohorts, constituting the “dark matter” of the mutational landscape which could only be accessed using deep mutational scanning (DMS) data. By training a set of gradient boosting classifiers, we illustrate that DMS data from only a handful (≈ 10) of experiments can accurately predict variant impact, and that DNA mutational signatures embed information about the protein-level impact of variants. We bridge the gap between DNA sequence variations and protein-level consequences, discuss the significance of this signature in informing protein design and molecular principles of protein stability, and clarify the relationship between disease association and the true impact mutations bring to protein function.
The Skeletal Muscle Circadian Clock Regulates Titin Splicing Through RBM20
Authors: Riley Lance A. , Zhang Xiping , Douglas Collin M. , Mijares Joseph M. , Hammers David W. , Wolff Christopher A. , Wood Neil B. , Olafson Hailey R. , Du Ping , Labeit Siegfried , Previs Michael J. , Wang Eric T. , Esser Karyn A.
Published: May 2021

Circadian rhythms are maintained by a cell autonomous, transcriptional-translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sarcomere filaments. Utilizing inducible, skeletal muscle specific, Bmal1 knockout (iMSBmal1-/-) mice, we showed that knocking out skeletal muscle clock function alters titin isoform expression using RNAseq, LC-MS, and SDS-VAGE. This alteration in titin’s spring length resulted in sarcomere length heterogeneity. We demonstrate the direct link between altered titin splicing and sarcomere length in vitro using U7 snRNPs that truncate the region of titin altered in iMSBmal1-/- muscle. We identified a mechanism whereby the skeletal muscle clock regulates titin isoform expression through transcriptional regulation of Rbm20, a potent splicing regulator of titin. Lastly, we used an environmental model of circadian rhythm disruption and identified significant down-regulation of Rbm20 expression. Our findings demonstrate the importance of the skeletal muscle circadian clock in maintaining titin isoform through regulation of RBM20 expression. Because circadian rhythm disruption is a feature of many chronic diseases, our results highlight a novel pathway that could be targeted to maintain skeletal muscle structure and function in a range of pathologies.
ZHX2 Promotes HIF1α Oncogenic Signaling in Triple-Negative Breast Cancer
Authors: Fang Wentong , Liao Chengheng , Shi Rachel , Simon Jeremy M. , Ptacek Travis S. , Zurlo Giada , Ye Youqiong , Han Leng , Fan Cheng , Ortiz Christopher Llynard , Lin Hong-Rui , Manocha Ujjawal , Luo Weibo , Kim William Y. , Yang Lee-Wei , Zhang Qing
Published: May 2021

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers And Homeoboxes 2 (ZHX2) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia inducible factor (HIF) family members and positively regulated HIF1α activity in TNBC. Integrated ChIP-Seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1α on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Furthermore, multiple residues (R491, R581 and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling HIF1α activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.