bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet proteome analysis reveals an early hyperactive phenotype in SARS-CoV-2-infected humanized ACE2 mice
Authors: Subramaniam Saravanan , Hekman Ryan Matthew , Jayaraman Archana , O’Connell Aoife Kateri , Montanaro Paige , Blum Benjamin , Kenney Devin , Ericsson Maria , Ravid Katya , Crossland Nicholas A , Emili Andrew , Douam Florian , Bosmann Markus 
Published: August 2021

AbstractCoronavirus disease-2019 (COVID-19) provokes a hypercoagulable state with increased incidence of thromboembolism and mortality. Platelets are major effectors of thrombosis and hemostasis. Suitable animal models are needed to better understand COVID-19-associated coagulopathy (CAC) and underlying platelet phenotypes. Here, we assessed K18-hACE2 mice undergoing a standardized SARS-CoV-2 infection protocol to study dynamic platelet responses via mass spectrometry-based proteomics. In total, we found significant changes in >1,200 proteins. Strikingly, protein alterations occurred rapidly by 2 days post-infection (dpi) and preceded outward clinical signs of severe disease. Pathway enrichment analysis of 2dpi platelet proteomes revealed that SARS-CoV-2 infection upregulated complement-coagulation networks (F2, F12, CFH, CD55/CD59), platelet activation-adhesion-degranulation proteins (PF4, SELP, PECAM1, HRG, PLG, vWF), and chemokines (CCL8, CXCL5, CXCL12). When mice started to lose weight at 4dpi, pattern recognition receptor signaling (RIG-I/MDA5, CASP8, MAPK3), and interferon pathways (IFIT1/IFIT3, STAT1) were predominant. Interestingly, SARS-CoV-2 spike protein in the lungs was observed by immunohistochemistry, but in platelets was undetected by proteomics. Similar to patients, K18-hACE2 mice during SARS-CoV-2 infection developed progressive lymphohistiocytic interstitial pneumonia with platelet aggregates in the lungs and kidneys. In conclusion, this model recapitulates activation of coagulation, complement, and interferon responses in circulating platelets, providing valuable insight into platelet pathology during COVID-19.Key PointsSARS-CoV-2-infected humanized ACE2 mice recapitulate platelet reprogramming towards activation-degranulation-aggregation.Complement/coagulation pathways are dominant in platelets at 2 days post-infection (dpi), while interferon signaling is dominant at 4dpi.
Discovery of 42 Genome-Wide Significant Loci Associated with Dyslexia
Authors: Doust Catherine , Fontanillas Pierre , Eising Else , Gordon Scott D , Wang Zhengjun , Alagöz Gökberk , Molz Barbara ,   23andMe Research Team,   Quantitative Trait Working Group of the GenLang Consortium, Pourcain Beate St , Francks Clyde , Marioni Riccardo E , Zhao Jingjing , Paracchini Silvia , Talcott Joel B , Monaco Anthony P , Stein John F , Gruen Jeffrey R , Olson Richard K , Willcutt Erik G , DeFries John C , Pennington Bruce F , Smith Shelley D , Wright Margaret J , Martin Nicholas G , Auton Adam , Bates Timothy C , Fisher Simon E , Luciano Michelle 
Published: August 2021

ABSTRACTReading and writing are crucial for many aspects of modern life but up to 1 in 10 children are affected by dyslexia [1, 2], which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70% [3, 4], yet no convincing genetic markers have been found due to limited study power [5]. Here, we present a genome-wide association study representing a 20-fold increase in sample size from prior work, with 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls. We identified 42 independent genome-wide significant loci: 17 are in genes linked to or pleiotropic with cognitive ability/educational attainment; 25 are novel and may be more specifically associated with dyslexia. Twenty-three loci (12 novel) were validated in independent cohorts of Chinese and European ancestry. We confirmed a similar genetic aetiology of dyslexia between sexes, and found genetic covariance with many traits, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Causal analyses revealed a directional effect of dyslexia on attention deficit hyperactivity disorder and bidirectional effects on socio-educational traits but these relationships require further investigation. Dyslexia polygenic scores explained up to 6% of variance in reading traits in independent cohorts, and might in future enable earlier identification and remediation of dyslexia.
Virtual Delivery of Simulation Education to Undergraduate Medical Students During the COVID-19 Pandemic
Authors: Wu Kay , Chan Alex , Pandey Avinash , Panchal Puru , Khalid Maroof , Bala Sudarshan , Shah Samveg , Miller Matthew C. 
Published: August 2021

AbstractBackgroundThe COVID-19 pandemic has restricted in-person clinical training for medical students. Simulation-based teaching is a promising tool to introduce learners to the clinical environment. MacSim is a student-led simulation workshop for learners to develop clinical competencies. The objective of this study was to assess the impacts of MacSim and participants’ perspectives regarding simulation-based teaching.MethodsA comprehensive simulation, representative of a virtual care scenario, was delivered to 42 pre-clerkship medical students via video conferencing. In pairs, participants obtained histories and carried out management plans for simulated patients. Participants were surveyed and interviewed. Survey data were analyzed using the Wilcoxon signed-ranks test. Interview transcript data were thematically analyzed.ResultsPost-simulation, participants (n=24) felt more prepared to make clinical decisions, collaborate, and communicate in a virtual setting. 92% of respondents agreed MacSim was a valuable learning experience and 96% agreed more simulation-based learning should be integrated into curricula. Emergent themes from interviews (n=12) included: 1) value of simulation fidelity, 2) value of physician feedback, and 3) effectiveness of MacSim in improving virtual clinical skills.ConclusionSimulation-based teaching is of importance and educational value to medical students. It may play an increasingly prevalent role in education as virtual care is likely to become more prevalent.
SafeSwab, a sample collection and dispensing device for near-patient testing
Authors: Grys Thomas E. , McAulay Kathrine , Ingram Darrell , Duffy Craig , Williams Ashley , Arumugam Siddarth , Ma Jiawei , Macar Uzay , Han Guangxing , Reynolds Andy , Chang Shih-Fu , Sia Samuel K. , Mayer Ken 
Published: August 2021

AbstractBackgroundThe COVID-19 pandemic has accelerated the pace of innovation around virtual care visits and testing technology. Here we present the SafeSwab (Safe Health Systems, Los Angeles, CA), an integrated, universal sample collection and dispensing device that is designed to minimize user error and enable rapid testing in a point of care or self-testing format.MethodsThe SafeSwab was used with the Safe Health Systems HealthCheck digital health application to enable self-testing by patients using lateral flow tests for SARS-CoV-2 antigen or for antibodies against SARS-CoV-2.ResultsPatients (n=74) using the SafeSwab produced a valid rapid test result in 96% of attempts, and 96% of patients felt confident that they had collected a good sample. The Safe HealthCheck app has an integrated image analysis algorithm, AutoAdapt LFA, that interprets a picture of a rapid test result, and the algorithm interpreted the result correctly 100% of the time.ConclusionThe SafeSwab was found to be versatile and easy to use for both self-collected nasal sampling as well as fingerstick blood sampling. The use of Safe Health Systems HealthCheck app allows an integrated solution for patient instruction and test interpretation
Homologous recombination induced by a replication fork barrier requires cooperation between strand invasion and strand annealing activities
Authors: Marie Léa , Symington Lorraine S. 
Published: August 2021

ABSTRACTReplication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. Elucidating the mechanism of recombination between repeated sequences in the context of replication stress is essential to understanding how genome rearrangements occur. To gain insight into this process, we used a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome. Remarkably, we show that the replication fork block stimulates a unique recombination pathway dependent on Rad51 strand invasion and Rad52-Rad59 strand annealing activities, as well as Mph1/Rad5 fork remodelers, Mre11/Exo1 short and long-range resection machineries, Rad1-Rad10 nuclease and DNA polymerase δ. Furthermore, we show recombination at stalled replication forks is limited by the Srs2 helicase and Mus81-Mms4/Yen1 structure-selective nucleases. Physical analysis of replication-associated recombinants revealed that half are associated with an inversion of sequence between the repeats. Based on our extensive genetic characterization, we propose a model for recombination of closely linked repeats at stalled replication forks that can actively contribute to genomic rearrangements.
Novel roles of small extracellular vesicles in regulating the quiescence and proliferation of neural stem cells
Authors: Zhang Jingtian , Uchiyama Junki , Imami Koshi , Ishihama Yasushi , Kageyama Ryoichiro , Kobayashi Taeko 
Published: August 2021

AbstractNeural stem cells (NSCs) quiescence plays pivotal roles in securing sustainable neurogenesis and avoiding stemness exhaustion in the adult brain. The maintenance of quiescence and transition between proliferation and quiescence are complex processes associated with multiple niche signals, and environmental stimuli. Though the mechanisms of the transitions between NSC states have been extensively investigated, they remain to be fully elucidated. Exosomes are small extracellular vesicles (sEVs) containing functional units such as proteins, microRNAs, and mRNAs. It has already been demonstrated that sEVs actively participate in cancer cell proliferation and metastasis. However, the role of sEVs in NSC quiescence has not been investigated. Here, we applied proteomics to analyze the protein cargos of sEVs derived from proliferating, quiescent, and reactivating NSCs. Our findings revealed expression level fluctuations of NSCs sEV protein cargo at different proliferative conditions. We also identified functional clusters of gene ontology annotations from differentially expressed proteins in three sources of exosomes. Moreover, the use of exosome inhibitors revealed the contribution of exosomes to NSC quiescence at the entrance into quiescence, as well as in quiescence maintenance. Exosome inhibition delayed the entrance into quiescence by proliferating NSCs and allowed quiescent NSCs to exit from the G0 phase of the cell cycle. Protein translation was significantly upregulated in both quiescent NSCs and quiescent-induced NSCs via the exosome inhibition. Our results demonstrated that NSC exosomes are involved in regulating the quiescence of NSCs and provide a functional prediction of NSCs exosome protein cargos in terms of cell-cycle regulation and protein synthesis.
Computational metabolomics illuminates the lineage-specific diversification of resin glycoside acylsugars in the morning glory (Convolvulaceae) family
Authors: Kruse Lars H. , Bennett Alexandra A. , Mahood Elizabeth H. , Lazarus Elena , Park Se Jin , Schroeder Frank , Moghe Gaurav D. 
Published: August 2021

AbstractAcylsugars are a class of plant defense compounds produced across many distantly related families. Members of the horticulturally important morning glory (Convolvulaceae) family produce a diverse sub-class of acylsugars called resin glycosides (RGs), which comprise oligosaccharide cores, hydroxyacyl chain(s), and decorating aliphatic and aromatic acyl chains. While many RG structures are characterized, the extent of structural diversity of this class in different genera and species is not known. In this study, we asked whether there has been lineage-specific diversification of RG structures in different Convolvulaceae species that may suggest diversification of the underlying biosynthetic pathways. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed from root and leaf extracts of 26 species sampled in a phylogeny-guided manner. LC-MS/MS revealed thousands of peaks with signature RG fragmentation patterns with one species producing over 300 signals, mirroring the diversity in Solanaceae-type acylsugars. A novel RG from Dichondra argentea was characterized using Nuclear Magnetic Resonance spectroscopy, supporting previous observations of RGs with open hydroxyacyl chains instead of closed macrolactone ring structures. Substantial lineage-specific differentiation in utilization of sugars, hydroxyacyl chains, and decorating acyl chains was discovered, especially among Ipomoea and Convolvulus – the two largest genera in Convolvulaceae. Adopting a computational, knowledge-based strategy, we further developed a high-recall workflow that successfully explained ~72% of the MS/MS fragments, predicted the structural components of 11/13 previously characterized RGs, and partially annotated ~45% of the RGs. Overall, this study improves our understanding of phytochemical diversity and lays a foundation for characterizing the evolutionary mechanisms underlying RG diversification.
Cross-scale Analysis of Temperature Compensation in the Cyanobacterial Circadian Clock System
Authors: Furuike Yoshihiko , Ouyang Dongyan , Tominaga Taiki , Matsuo Tatsuhito , Mukaiyama Atsushi , Kawakita Yukinobu , Fujiwara Satoru , Akiyama Shuji 
Published: August 2021

AbstractClock proteins maintain constant enzymatic activity regardless of temperature, even though thermal fluctuation is accelerated as temperature increases. We investigated temperature influences on the dynamics of KaiC, a temperature-compensated ATPase in the cyanobacterial circadian clock system, using quasielastic neutron scattering. The frequency of picosecond to sub-nanosecond incoherent local motions in KaiC was accelerated very slightly in a temperature-dependent manner. Our mutation studies revealed that internal motions of KaiC include several contributions of opposing temperature sensitivities. To take advantage of this balancing effect, the motional frequency of local dynamics in KaiC needs to exceed ∼0.3 ps-1. Some of the mutation sites may be in a pathway through which the motional frequency in the C-terminal domain of KaiC is fed back to the active site of ATPase in its N-terminal domain. The temperature-compensating ability at the dynamics level is likely crucial for circadian clock systems, into which the clock proteins are incorporated, to achieve reaction- or even system-level temperature compensation of the oscillation frequency.
Free for all, or free-for-all? A content analysis of Australian university open access policies
Authors: Wakeling Simon , Kingsley Danny , Jamali Hamid R. , Kennan Mary Anne , Jamali Hamid , Sarrafzadeh Maryam 
Published: August 2021

AbstractRecent research demonstrates that Australia lags in providing open access to research outputs. In Australia, while the two major research funding bodies require open access of outputs from projects they fund, these bodies only fund a small proportion of research conducted. The major source of research and experimental development funding in Australian higher education is general university, or institutional, funding, and such funds are not subject to national funder open access policies. Thus, institutional policies and other institutional supports for open access are important in understanding Australia’s OA position. The purpose of this paper is, therefore, to understand the characteristics of Australian institutional open access policies and to explore the extent they represent a coherent and unified approach to delivering and promoting open access in Australia. Open access policies were located using a systematic web search approach and then their contents were analysed. Only half of Australian universities were found to have an open access policy. There was a wide variation in language used, expressed intent of the policy and expectations of researchers. Few policies mention monitoring or compliance and only three mention consequences for non-compliance. While it is understandable that institutions develop their own policies, when language is used which does not reflect national and international understandings, when requirements are not clear and with consequences, policies are unlikely to contribute to understanding of open access, to uptake of the policy, or to ease of transferring understanding and practices between institutions. A more unified approach to open access is recommended.
Mg2+-dependent conformational equilibria in CorA: an integrated view on transport regulation
Authors: Johansen Nicolai Tidemand , Bonaccorsi Marta , Bengtsen Tone , Larsen Andreas Haahr , Tidemand Frederik Grønbæk , Pedersen Martin Cramer , Huda Pie , Berndtsson Jens , Darwish Tamim , Yepuri Nageshwar Rao , Martel Anne , Pomorski Thomas Günther , Bertarello Andrea , Sansom Mark , Rapp Mikaela , Crehuet Ramon , Schubeis Tobias , Lindorff-Larsen Kresten , Pintacuda Guido , Arleth Lise 
Published: August 2021

AbstractThe CorA family of proteins regulates the homeostasis of divalent metal ions in many bacteria, archaea, and eukaryotic mitochondria, making it an important target in the investigation of the mechanisms of transport and its functional regulation. Although numerous structures of open and closed channels are now available for the CorA family, the mechanism of the transport regulation remains elusive. Here, we investigated the conformational distribution and associated dynamic behaviour of the pentameric Mg2+ channel CorA at room temperature using small-angle neutron scattering (SANS) in combination with molecular dynamics (MD) simulations and solid-state nuclear magnetic resonance spectroscopy (NMR). We find that neither the Mg2+-bound closed structure nor the Mg2+-free open forms are sufficient to explain the average conformation of CorA. Our data support the presence of conformational equilibria between multiple states, and we further find a variation in the behaviour of the backbone dynamics with and without Mg2+. We propose that CorA must be in a dynamic equilibrium between different non-conducting states, both symmetric and asymmetric, regardless of bound Mg2+ but that conducting states become more populated in Mg2+-free conditions. These properties are regulated by backbone dynamics and are key to understanding the functional regulation of CorA.
Voltage imaging identifies spinal circuits that modulate locomotor adaptation in zebrafish
Authors: Böhm Urs L. , Kimura Yukiko , Kawashima Takashi , Ahrens Misha B. , Higashijima Shin-ichi , Engert Florian , Cohen Adam E. 
Published: August 2021

AbstractMotor systems must continuously adapt their output to maintain a desired trajectory. While the spinal circuits underlying rhythmic locomotion are well described, little is known about how the network modulates its output strength. A major challenge has been the difficulty of recording from spinal neurons during behavior. Here, we use voltage imaging to map the membrane potential of glutamatergic neurons throughout the spinal cord of the larval zebrafish during fictive swimming in a virtual environment. We mapped the spiking, subthreshold dynamics, relative timing, and sub-cellular electrical propagation across large populations of simultaneously recorded cells. We validated the approach by confirming properties of known sub-types, and we characterized a yet undescribed sub-population of tonic-spiking ventral V3 neurons whose spike rate correlated with swimming strength and bout length. Optogenetic activation of V3 neurons led to stronger swimming and longer bouts but did not affect tail-beat frequency. Genetic ablation of V3 neurons led to reduced locomotor adaptation. The power of voltage imaging allowed us to identify V3 neurons as a critical driver of locomotor adaptation in zebrafish.
Time evolution of PEG-shedding and serum protein coronation determines the cell uptake kinetics and delivery of lipid nanoparticle formulated mRNA
Authors: Gallud A. , Munson M. J. , Liu K. , Idström A. , Barriga H. M. G. , Tabaei S. R. , Aliakbarinodehi N. , Ojansivu M. , Lubart Q. , Doutch J. J. , Holme M. N. , Evenäs L. , Lindfors L. , Stevens M. M. , Collén A. , Sabirsh A. , Höök F. , Esbjörner E. K. 
Published: August 2021

AbstractDevelopment of efficient lipid nanoparticle (LNP) vectors remains a major challenge towards broad clinical translation of RNA therapeutics. New lipids will be required, but also better understanding LNP interactions with the biological environment. Herein, we model protein corona formation on PEG-ylated DLin-MC3-DMA LNPs and identify time-dependent maturation steps that critically unlock their cellular uptake and mRNA delivery. Uptake requires active serum proteins and precedes after a significant (∼2 hours) lag-time, which we show can be eliminated by pre-incubating LNPs for 3-4 hours in serum-containing media. This indicates an important role of protein corona maturation for the pharmacokinetic effects of these LNPs. We show, using single-nanoparticle imaging, NMR diffusometry, SANS, and proteomics, that the LNPs, upon serum exposure, undergo rapid PEG-shedding (∼30 minutes), followed by a slower rearrangement of the adsorbed protein layer. The PEG-shedding coincides in time with high surface abundance of Apolipoprotein A-II, whereas the LNPs preferentially bind Apolipoprotein E when their maximum uptake-competent state is reached. Finally, we show that pre-incubation of the LNPs enables rapid uptake and allows pulse-chase video-microscopy colocalization experiments with sufficiently short pulse durations to gain improved mechanistic understanding of how intracellular trafficking events determine delivery efficacy, emphasizing early endosomes as important delivery-mediating compartments.
Avifauna recovers faster in areas less accessible to trapping in regenerating tropical forests
Authors: Sagar H S Sathya Chandra , Gilroy James J. , Swinfield Tom , Yong Ding Li , Gemita Elva , Burivalova Zuzana , Novriyanti Novriyanti , Lee David C. , Janra Muhammad Nazri , Balmford Andrew , Hua Fangyuan 
Published: August 2021

ABSTRACTTropical forest restoration stands to deliver important conservation gains, particularly in lowland Southeast Asia, which has suffered some of the world’s highest rates of forest loss and degradation. This promise, however, depends on the extent to which biodiversity at forest restoration sites continues to be exposed to threats. A key knowledge gap concerns the extent to which biodiversity recovery in naturally regenerating tropical forests is impacted by trapping for the multi-million-dollar wildlife trade. Here, we use a repeated survey dataset to quantify rates of avian community recovery under forest regeneration, at a flagship restoration site in the lowland rainforests of Sumatra, Indonesia. We show that over a decade, forest regeneration was associated with significant abundance increases for 43.8% of bird species.However, the apparent negative impacts of trade-driven trapping on avian populations also intensified: the proportion of species that show increased abundance only in very remote forests increased from 5.4% to 16.2%, while the overall accessibility of the forest increased. We found that 14% of species did not recover as fast as predicted based on the observed improvement in forest conditions over the study period. Our results highlight the potential for rapid avifaunal recovery in regenerating tropical forests, but also emphasize the urgency of tackling the serious threat of wildlife trade to Southeast Asia’s biodiversity.