bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beyond linear dynamic functional connectivity: a vine copula change point model
Authors: Xiong Xin , Cribben Ivor 
Published: April 2021

AbstractTo estimate dynamic functional connectivity for functional magnetic resonance imaging (fMRI) data, two approaches have dominated: sliding window and change point methods. While computationally feasible, the sliding window approach has several limitations. In addition, the existing change point methods assume a Gaussian distribution for and linear dependencies between the fMRI time series. In this work, we introduce a new methodology called Vine Copula Change Point (VCCP) to estimate change points in the functional connectivity network structure between brain regions. It uses vine copulas, various state-of-the-art segmentation methods to identify multiple change points, and a likelihood ratio test or the stationary bootstrap for inference. The vine copulas allow for various forms of dependence between brain regions including tail, symmetric and asymmetric dependence, which has not been explored before in the dynamic analysis of neuroimaging data. We apply VCCP to various simulation data sets and to two fMRI data sets: a reading task and an anxiety inducing experiment. In particular, for the former data set, we illustrate the complexity of textual changes during the reading of Chapter 9 inHarry Potter and the Sorcerer’s Stoneand find that change points across subjects are related to changes in more than one type of textual attributes. Further, the graphs created by the vine copulas indicate the importance of working beyond Gaussianity and linear dependence. Finally, the R packagevccpimplementing the methodology from the paper is available from CRAN.
Host cytoskeletal vimentin serves as a structural organizer and an RNA-binding protein regulator to facilitate Zika viral replication
Authors: Zhang Yue , Zhao Shuangshuang , Li Min , Li Yian , Feng Fengping , Cui Jie , Xue Yanhong , Jin Xia , Jiu Yaming 
Published: April 2021

ABSTRACTEmerging microbe infections such as Zika virus (ZIKV) pose an increasing threat to human health. Current investigations on ZIKV replication have revealed the construction of replication compartments (RCs) and the utilization of host cellular endomembranes, without careful examination of the cytoskeletal network. Here, we investigated the function of vimentin, one of the intermediate filaments (IFs) that play a central role in basic cellular functions and diseases, in the life cycle of ZIKV infection. Using advanced imaging techniques, we uncovered that vimentin filaments have drastic reorganization upon viral protein synthesis, to form a perinuclear cage-like structure that embraces and concentrates RCs. Genetically removal of vimentin markedly reduced viral genome replication, viral protein production and infectious virions release, without interrupting viral binding and entry. Furthermore, proteomics and transcriptome screens by mass spectrometry and RNA sequencing identified intense interaction and regulation between vimentin and hundreds of endoplasmic reticulum (ER)-resident RNA-binding proteins. Among them, the cytoplasmic-region of ribosome receptor binding protein 1 (RRBP1), an ER transmembrane protein directly binds viral RNA, can interact with vimentin, resulting in modulation of ZIKV replication. Together, our work discovered a dual role for vimentin as being not only a structural element for RCs but also an RNA-binding-regulating hub in the ZIKV infection model, unveiling another layer of the complexity between host and virus interaction.
LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
Authors: Emmenegger Marc , De Cecco Elena , Hruska-Plochan Marian , Eninger Timo , Schneider Matthias M. , Barth Melanie , Tantardini Elena , de Rossi Pierre , Bacioglu Mehtap , Langston Rebekah G. , Kaganovich Alice , Bengoa-Vergniory Nora , Gonzalez-Guerra Andrès , Avar Merve , Heinzer Daniel , Reimann Regina , Häsler Lisa M. , Herling Therese W. , Matharu Naunehal S. , Landeck Natalie , Luk Kelvin , Melki Ronald , Kahle Philipp J. , Hornemann Simone , Knowles Tuomas P. J. , Cookson Mark R. , Polymenidou Magdalini , Jucker Mathias , Aguzzi Adriano 
Published: April 2021

AbstractWhile the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analyzed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid.
NMR structures and functional roles of two related chitin-binding domains of a lytic polysaccharide monooxygenase fromCellvibrio japonicus
Authors: Madland Eva , Forsberg Zarah , Wang Yong , Lindorff-Larsen Kresten , Niebisch Axel , Modregger Jan , Eijsink Vincent G. H. , Aachmann Finn L. , Courtade Gaston 
Published: April 2021

AbstractAmong the extensive repertoire of carbohydrate-active enzymes, lytic polysaccharide monooxygenases (LPMOs) have a key role in recalcitrant biomass degradation. LPMOs are copper-dependent enzymes that catalyze oxidative cleavage of glycosidic bonds in polysaccharides such as cellulose and chitin. Several LPMOs contain carbohydrate-binding modules (CBMs) that are known to promote LPMO efficiency. Still, structural and functional properties of some of these CBMs remain unknown and it is not clear why some LPMOs, likeCjLPMO10A fromCellvibriojaponicus, have two CBMs (CjCBM5 andCjCBM73). Here, we studied substrate binding by these two CBMs to shine light on the functional variation, and determined the solution structures of both by NMR, which includes the first structure of a member of the CBM73 family. Chitin-binding experiments and molecular dynamics simulations showed that, while both CBMs bind crystalline chitin withKdvalues in the µM range,CjCBM73 has higher affinity thanCjCBM5. Furthermore, NMR titration experiments showed thatCjCBM5 binds soluble chitohexaose, whereas no binding to soluble chitin was detected forCjCBM73. These functional differences correlated with distinctly different architectures of the substrate-binding surfaces of the two CBMs. Taken together, these results provide insight into natural variation among related chitin-binding CBMs and the possible functional implications of such variation.
The cortical hubs related to recovery of consciousness
Authors: Wu Hang , Qi Zengxin , Zhang Jun , Wu Changwei , Wu Xuehai , Huang Zirui , Zang Di , Fogel Stuart , Tanabe Sean , Hudetz Anthony G. , Northoff Georg , Mao Ying , Qin Pengmin 
Published: April 2021

AbstractBackground and ObjectivesThe neural mechanism that enables the recovery of consciousness in patients with unresponsive wakefulness syndrome (UWS) remains unclear. The aim of the current study is to characterize the cortical hub regions related to the recovery of consciousness in patients with UWS.MethodsVoxel-wise degree centrality analysis was adopted to identify the cortical hubs related to the recovery of consciousness, for which a total of 27 UWS patients were used, including 13 patients who emerged from UWS (UWS-E), and 14 patients who remained in UWS (UWS-R) at least three months after the experiment performance. Furthermore, other recoverable unconscious states including three independent deep sleep datasets (n = 12, 9, 9 respectively) and three independent anesthesia datasets (n = 27, 14, 6 respectively) were adopted as validation groups. Spatial similarity of the hub characteristic with the validation groups between the UWS-E and UWS-R was compared using the dice coefficient. Finally, with the cortical regions persistently shown as hubs across UWS-E and validation states, functional connectivity analysis was further performed to explore the connectivity patterns underlying the recovery of consciousness.ResultsFour cortical hubs were identified with significantly higher degree centrality for UWS-E than UWS-R, including the anterior precuneus, left inferior parietal lobule, left inferior frontal gyrus, and left middle frontal gyrus, of which the degree centrality value also positively correlated with the patients’ Glasgow Outcome Scale (GOS) score. Furthermore, the anterior precuneus was found to show significantly higher similarity of hub characteristics as well as functional connectivity pattern between UWS-E and validation groups, compared with UWS-R.DiscussionThe results suggest that the recovery of consciousness may be relevant to the integrity of cortical hubs, especially the anterior precuneus. The identified cortical hub regions could serve as potential targets for noninvasive stimulation aimed at promoting the patients’ consciousness recovery.
The nematode wormC. eleganschooses between bacterial foods as if maximizing economic utility
Authors: Katzen Abraham , Chung Hui-Kuan , Harbaugh William T. , Iacono Christina Della , Jackson Nicholas , Glater Elizabeth E. , Taylor Charles J. , Yu Stephanie K. , Flavell Steven W. , Glimcher Paul W. , Andreoni James , Lockery Shawn R. 
Published: April 2021

AbstractIn value-based decision making, options are selected according to subjective values assigned by the individual to available goods and actions. Despite the importance of this faculty of the mind, the neural mechanisms of value assignments, and how choices are directed by them, remain obscure. To investigate this problem, we used a classic measure of utility maximization, the Generalized Axiom of Revealed Preference, to quantify internal consistency of food preferences inCaenorhabditis elegans, a nematode worm with a nervous system of only 302 neurons. Using a novel combination of microfluidics and electrophysiology, we found thatC. elegansfood choices fulfill the necessary and sufficient conditions for utility maximization, indicating that nematodes behave as if they maintain, and attempt to maximize, an underlying representation of subjective value. Food choices are well-fit by a utility function widely used to model human consumers. Moreover, as in many other animals, subjective values inC. elegansare learned, a process we find requires intact dopamine signaling. Differential responses of identified chemosensory neurons to foods with distinct growth potentials are amplified by prior consumption of these foods, suggesting that these neurons may be part of a value-assignment system. The demonstration of utility maximization in an organism with a very small nervous system sets a new lower bound on the computational requirements for utility maximization and offers the prospect of an essentially complete explanation of value-based decision making at single neuron resolution in this organism.
Disruption ofmiR-18aalters proliferation, photoreceptor replacement kinetics, inflammatory signaling and microglia/macrophage numbers during retinal regeneration in zebrafish
Authors: Magner Evin , Sandoval-Sanchez Pamela , Kramer Ashley C. , Thummel Ryan , Hitchcock Peter F. , Taylor Scott M. 
Published: April 2021

ABSTRACTIn mammals, photoreceptor loss causes permanent blindness, but in zebrafish (Danio rerio), photoreceptor loss reprograms Müller glia to function as stem cells, producing progenitors that regenerate photoreceptors. MicroRNAs (miRNAs) regulate CNS neurogenesis, but the roles of miRNAs in injury-induced neuronal regeneration are largely unknown. In the embryonic zebrafish retina,miR-18aregulates photoreceptor differentiation. The purpose of the current study was to determine, in zebrafish, the function ofmiR-18aduring injury-induced photoreceptor regeneration. RT-qPCR, in-situ hybridization and immunohistochemistry showed thatmiR-18aexpression increases throughout the retina between 1 and 5 days post-injury (dpi). To testmiR-18afunction during photoreceptor regeneration, we used homozygousmiR-18amutants (miR-18ami5012), and knocked downmiR-18awith morpholino oligonucleotides. During photoreceptor regeneration,miR-18ami5012retinas have fewer mature photoreceptors than WT at 7 and 10 dpi, but there is no difference at 14 dpi, indicating that photoreceptor regeneration is delayed. Labeling dividing cells with 5-bromo-2′-deoxyuridine (BrdU) showed that at 7 and 10 dpi, there are excess dividing progenitors in both mutants and morphants, indicating thatmiR-18anegatively regulates injury-induced proliferation. Tracing 5-ethynyl-2′-deoxyuridine (EdU) and BrdU-labeled cells showed that inmiR-18ami5012retinas excess progenitors migrate to other retinal layers in addition to the photoreceptor layer. Inflammation is critical for photoreceptor regeneration, and RT-qPCR showed that inmiR-18ami5012retinas, inflammatory gene expression and microglia activation are prolonged. Suppressing inflammation with dexamethasone rescues themiR-18ami5012phenotype. Together, these data show that in the injured zebrafish retina, disruption ofmiR-18aalters proliferation, inflammation, the microglia/macrophage response, and the timing of photoreceptor regeneration.
A SARS CoV-2 nucleocapsid vaccine protects against distal viral dissemination
Authors: Class Jacob , Dangi Tanushree , Richner Justin M. , Penaloza-MacMaster Pablo 
Published: April 2021

AbstractThe SARS CoV-2 pandemic has killed millions of people. This viral infection can also result in substantial morbidity, including respiratory insufficiency and neurological manifestations, such as loss of smell and psychiatric diseases. Most SARS CoV-2 vaccines are based on the spike antigen, and although they have shown extraordinary efficacy at preventing severe lung disease and death, they do not always confer sterilizing immune protection. We performed studies in K18-hACE2 mice to evaluate whether the efficacy of SARS CoV-2 vaccines could be augmented by incorporating nucleocapsid as a vaccine antigen. We vaccinated mice with adenovirus-based vaccines encoding spike antigen alone, nucleocapsid antigen alone, or combined spike and nucleocapsid antigens. Mice were then challenged intranasally with SARS CoV-2, and acute viral loads were quantified at a proximal site of infection (lung) and a distal site of infection (brain). Interestingly, the spike-based vaccine conferred acute protection in the lung, but not in the brain. The spike-based vaccine conferred acute protection in the brain only if combined with the nucleocapsid-based vaccine. These findings suggest that nucleocapsid-specific immunity is important for the distal control of SARS CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines.
Oral health changes among Indigenous and non‐Indigenous Australians: findings from two national oral health surveys
Authors: Jamieson L , Do L , Kapellas K , Chrisopoulos S , Luzzi L , Brennan D , Ju X 
Published: April 2021

AbstractBackgroundHistorically, Indigenous Australians experienced poorer oral health than non‐Indigenous Australians. We aimed to ascertain if Indigenous Australian oral health improved relative to non‐Indigenous oral health between the 2004‐06 and 2017‐18 National Surveys of Adult Oral Health (NSAOH).MethodsBoth NSAOHs were population‐based cross‐sectional surveys of Australian adults aged 15 years or more. In both surveys, representative samples of adults were drawn through a three‐stage, stratified sample design within metropolitan and regional areas in each state/territory. Frequencies of Indigenous and non‐Indigenous self‐reported and clinical oral health variables were ascertained, and differences were calculated between the 2004‐06 and 2017‐18 NSAOHs. Ninety‐five per cent confidence intervals were calculated and weights were used to account for the complex sampling methodology of both surveys.ResultsIn 2004‐06, 229 Indigenous and 13 882 non‐Indigenous Australians provided self‐report data, and 87 and 5418 of these had dental examinations, respectively. In 2017‐18, 334 Indigenous and 15 392 non‐Indigenous Australians provided self‐report data, and 84 and 4937 of them had dental examinations respectively. Between the surveys, relative to their non‐Indigenous counterparts, Indigenous Australians experienced greater levels of: inadequate dentition (4.2%), experience of toothache (4.8%), problem‐based dental attendance (4.5%) and 1+ teeth decayed, missing or filled (4.4%).ConclusionsThe gap between poor self‐reported and clinical oral health between Indigenous and non‐Indigenous Australians was greater in the more recent survey.
Ceramic technology and paintings of archaic architectural slabs, louteria and antefixes from the Palatine Hill in Rome (Italy)
Authors: Fugazzotto Maura , Stroscio Antonio , Mazzoleni Paolo , Panella Clementina , Russo Alfonsina , Raneri Simona , Barone Germana 
Published: April 2021

AbstractArchaic Roman painted antefixes, architectural slabs and louteria from the Palatine Hill in Rome, Italy, were studied by non‐destructive and micro‐destructive methods: Portable X‐ray fluorescence (XRF), micro‐Raman spectroscopy, optical microscopy, scanning electron microscopy with energy‐dispersive spectroscopy (SEM‐EDS) and X‐ray diffraction (XRD). The investigation enabled the characterization of raw materials and ceramic technology, providing insights on provenance. In fact, similarities were recognized with terracottas from the neighbouring Etruscan Veii. The analysis of pictorial layers revealed the use of Fe‐ and Mn‐based pigments, as well as the identification of more precious pigments on worthy pieces. The research intended to support the archaeological discussion about the frame of the nascent city of Rome, also in relation to the coeval Etruscan culture.
Pharmacogenetic testing to guide therapeutic decision‐making and improve outcomes for children undergoing anthracycline‐based chemotherapy
Authors: Loucks Catrina M. , Yan Kevin , Tanoshima Reo , Ross Colin J. D. , Rassekh Shahrad R. , Carleton Bruce C. 
Published: April 2021

AbstractAnthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline‐induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision‐making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline‐induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision‐making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions.
Lymphocyte modulation by tofacitinib in patients with rheumatoid arthritis
Authors: Isailovic Natasa , Ceribelli Angela , Cincinelli Gilberto , Vecellio Matteo , Guidelli Giacomo , Caprioli Marta , Luciano Nicoletta , Motta Francesca , Selmi Carlo , De Santis Maria 
Published: April 2021

SummaryTofacitinib is an oral small molecule targeting the intracellular Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B and T cell collagen epitopes in their native and post-translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261-273, B359-369, carT261-273, citB359-369) or with phorbol myristate acetate (PMA)/ionomycin/CD40L in the presence or absence of 100 nM tofacitinib for 20 h and analyzed by fluorescence activated cell sorter (FACS). Cultures without brefeldin A were used for cytokine supernatant enzyme-linked immunosorbent assay (ELISA) analysis. Tofacitinib down-regulated inflammatory cytokines by stimulated B [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] and T [interferon (IFN)-γ, IL-17 or TNF-α] cells in the short term, while a significant reduction of IL-17 and IL-6 levels in peripheral blood mononuclear cell (PBMC) supernatant was also observed. IL-10 was significantly reduced in collagen-stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self-epitopes in RA. Tofacitinib partially prevented the IL-10 down-modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes.
Effect of forging process on high cycle and very high cycle fatigue properties of TC4 titanium alloy under three‐point bending
Authors: Wang Bohan , Cheng Li , Cui Wenbin , Chen Xuan , Wang Changkai , Li Dongchun 
Published: April 2021

AbstractThe ultrasonic fatigue tests under two three‐point bending loading modes were carried out on TC4 specimens with the equiaxed, bimodal, and lamellar microstructure in the range of 105 to 109 cycles. The S‐N curves with different shapes were obtained, and it was found that the crack initiation in very high cycle regime changed from surface to subsurface. The crack initiation mechanism with different microstructures was revealed by fracture analysis. The axial tension influence mechanism is that it changes the axial stress distribution on the specimen cross section and makes the crack origin migrate to the interior.