bluuebunny/crossref_metadata_2025_split huggingface dataset:
Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells
Authors: Li Qian , Feng Yi , Xue Yingchao , Zhan Xiping , Fu Yi , Gui Gege , Zhou Weiqiang , Richard Jean-Philippe , Taga Arens , Li Pan , Mao Xiaobo , Maragakis Nicholas J. , Ying Mingyao 
Published: May 2021

AbstractBackgroundSpinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy.MethodsWe induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy.ResultsWe generate highly pure and functional mRNA-induced MNs (miMNs) from normal and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment.ConclusionsThis study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases.Graphic Abstract
An interplay between cellular growth and atypical fusion defines morphogenesis of a modular glial niche
Authors: Rujano Maria Alexandra , Briand David , Ðelić Bojana , Spéder Pauline 
Published: May 2021

AbstractNeural stem cells (NSCs) are embedded in a multi-layered, intricate cellular microenvironment supporting their activity, the niche. Whilst shape and function are inseparable, the morphogenetic aspects of niche development are poorly understood. Here, we use the formation of the glial network of a NSC niche to investigate acquisition of architectural complexity. Cortex glia (CG) in Drosophila regulate neurogenesis and build a reticular structure around NSCs. We first show that individual CG cells grow tremendously to ensheath several NSC lineages, eventually spanning the entire tissue while partitioning the NSC population. Elaborate proliferative mechanisms convert these cells into syncytia rich in cytoplasmic bridges. Unexpectedly, CG syncytia further undergo homotypic cell-cell fusion, relying on defined molecular players of cell fusion such as cell surface receptors and actin regulators. Exchange of cellular components is however dynamic in space and time, a previously unreported unique mechanism. This atypical cell fusion remodels cellular borders, restructuring the CG syncytia. Ultimately, the coordination of growth and fusion builds the multi-level architecture of the niche, and creates a modular, spatial partition of the NSC population. Our findings provide novel insights into how a niche forms and organises while developing intimate contacts with a stem cell population.
Morphometric relationships and their contribution to biomass and cannabinoid yield in hybrids of hemp (Cannabis sativa)
Authors: Carlson Craig H. , Stack George M. , Jiang Yu , Taşkıran Bircan , Cala Ali R. , Toth Jacob A. , Philippe Glenn , Rose Jocelyn K.C. , Smart Christine D. , Smart Lawrence B. 
Published: May 2021

AbstractThe breeding of hybrid cultivars of hemp (Cannabis sativaL.) is not well described, especially the segregation and inheritance of traits that are important for yield. A total of 23 families were produced from genetically diverse parents to investigate the inheritance of morphological traits and their association with biomass accumulation and cannabinoid yield. In addition, a novel classification method for canopy architecture was developed. The strong linear relationship between wet and dry biomass provided an accurate estimate of final dry stripped floral biomass. Of all field and aerial measurements, basal stem diameter was determined to be the single best selection criterion for final dry stripped floral biomass yield. Along with stem diameter, canopy architecture and stem growth predictors described the majority of the explainable variation of biomass yield. Within-family variance for morphological and cannabinoid measurements reflected the heterozygosity of the parents. While selfed populations suffered from inbreeding depression, hybrid development in hemp will require at least one inbred parent to achieve uniform growth and biomass yield. Nevertheless, floral phenology remains a confounding factor in selection because of its underlying influence on biomass production highlighting the need to understand the genetic basis for flowering time in the breeding of uniform cultivars.HighlightStem and canopy architecture traits are superior predictors of floral biomass yield and offer a good indication of hybrid uniformity in field plantings of genetically diverse cannabinoid hemp populations.
Synthetic Nanobody-Functionalized Nanoparticles for Accelerated Development of Rapid, Accessible Detection of Viral Antigens
Authors: Chen Xiahui , Kang Shoukai , Ikbal Ashif , Zhao Zhi , Pan Yuxin , Zuo Jiawei , Gu Liangcai , Wang Chao 
Published: May 2021

ABSTRACTSuccessful control of emerging infectious diseases requires accelerated development of fast, affordable, and accessible assays to be widely implemented at a high frequency. Here we present a generalizable assay platform, nanobody-functionalized nanoparticles for rapid, electronic detection (Nano2RED), demonstrated in the detection of Ebola and COVID-19 antigens. To efficiently generate high-quality affinity reagents, synthetic nanobody co-binders and mono-binders with high affinity, specificity, and stability were selected by phage display screening of a vastly diverse, rationally randomized combinatorial library, bacterially expressed and site-specifically conjugated to gold nanoparticles (AuNPs) as multivalent in-solution sensors. Without requiring fluorescent labelling, washing, or enzymatic amplification, these AuNPs reliably transduce antigen binding signals upon mixing into physical AuNP aggregation and sedimentation processes, displaying antigen-dependent optical extinction readily detectable by spectrometry or simple electronic circuitry. With nanobodies against an Ebola virus secreted glycoprotein (sGP) and a SARS-CoV-2 spike protein receptor binding domain (RBD) as targets, Nano2RED showed a high sensitivity (limit of detection of ∼10 pg/mL for sGP and ∼40 pg/mL for RBD in diluted human serum), a high specificity, and a large dynamic range (∼7 logs). Unlike conventional assays where slow mass transport for surface binding limits the assay time, Nano2RED features fast antigen diffusion at micrometer scale, and can be accelerated to deliver results within a few minutes. The rapid detection, low material cost (estimated < $0.01 per test), inexpensive and portable readout system (< $5 and < 100 cm3), and digital data output, make Nano2RED particularly suitable for screening of patient samples with simplified operation and accelerated data transmission. Our method is widely applicable for prototyping diagnostic assays for other antigens from new emerging viruses.
Making the invisible visible: New perspectives on the intersection of human-environment interactions of clinical teams in intensive care
Authors: Visram Sheena , Potts Laura , Sebire Neil J , Rogers Yvonne , Broughton Emma , Chigaru Linda , Nambyiah Pratheeban 
Published: May 2021

AbstractUnderstanding human behaviour is essential to the adoption practices for new technologies that promote safer care. This requires capturing the detail of clinical workflows to inform the design of new interactions including those with touchless technologies that decipher human-speech, gesture and motion and allow for interactions that are free of contact. Many environments in hospitals are sub-optimally designed, with a poor layout of work surfaces, cumber-some equipment that requires space and effort to manoeuvre, designs that require healthcare staff to reach awkwardly and medical devices that require extensive touch. This suggests there is a need to better understand how they can be designed. Here, we employ a new approach by installing a single 360° camera into a clinical environment to analyse touch patterns and human-environment interactions across a clinical team to recommend design considerations for new technologies with potential to reduce avoidable touch.
The impact of COVID-19 pandemic on the provision of ambulatory care for patients with chronic neurological diseases in Japan: evaluation of an administrative claims database
Authors: Sato Kenichiro , Mano Tatsuo , Niimi Yoshiki , Iwata Atsushi , Toda Tatsushi , Iwatsubo Takeshi 
Published: May 2021

AbstractBackgroundThe COVID-19 pandemic has affected not only the emergency medical system, but also patients’ regular ambulatory care. The number of patients visiting outpatient internal medicine clinics decreased during March–April 2020 compared to 2019. Moreover, the ban on telephone re-examination for outpatient clinics in lieu of ambulatory care for chronic diseases has been lifted since March 2020. In this context, we investigate the impact of the COVID-19 pandemic on ambulatory care at Japanese outpatient clinics for patients with chronic neurological diseases during the first half of 2020.MethodsWe collected data from the administrative claims database by DeSC Healthcare. Serial changes in the frequency of subsequent outpatient visits to clinics or hospitals (excluding large hospitals with beds >200) for chronic ambulatory care of epilepsy, migraine, Parkinson’s disease (PD), and Alzheimer’s disease were measured. We also evaluated the utilization rate of telephone re-examination at outpatient clinics.ResultsSince April 2020, the monthly count of outpatient clinic visits for epilepsy or PD decreased slightly but significantly. The use of telephone re-examination was facility-dependent, and it was used in less than 5% of all outpatient clinic visits for the examined neurological diseases in May 2020. The utilization rate of telephone re-examination was not associated with age or the neurological diseases of interest.ConclusionThe impact of the COVID-19 pandemic on ambulatory care for several chronic neurological diseases may have been relatively limited, in terms of the frequency or type of outpatient visit, during the first half of 2020 in Japan.
Outlier detection in multimodal MRI identifies rare individual phenotypes among 20,000 brains
Authors: Ma Zhiwei , Reich Daniel S. , Dembling Sarah , Duyn Jeff H. , Koretsky Alan P. 
Published: May 2021

AbstractOutliers in neuroimaging represent spurious data or the data of unusual phenotypes that deserve special attention such as clinical follow-up. Outliers have usually been detected in a supervised or semi-supervised manner for labeled neuroimaging cohorts. There has been much less work using unsupervised outlier detection on large unlabeled cohorts like the UK Biobank brain imaging dataset. Given its large sample size, rare imaging phenotypes within this unique cohort are of interest, as they are often clinically relevant and could be informative for discovering new processes. Here we developed a two-level outlier detection and screening methodology to characterize individual outliers of multiple different brain imaging phenotypes from 20,000 UK Biobank subjects. In primary screening, every subject was parameterized with an outlier score per imaging phenotype to quantitate the degree of outlierness. This approach enabled the assessment of test-retest reliability via outlier scores, which ranged from excellent reliability for ventricular volume, white matter lesion volume, and fractional anisotropy, to good reliability for mean diffusivity and cortical thickness. Resting-state functional connectivity was eliminated for individual-level outlier screening due to its low test-retest reliability of outlier scores. In secondary screening, the extreme outliers (1110 subjects) were examined individually, and those arising from data collection/processing errors were eliminated. A subgroup (108 subjects) of the remaining non-artifactual outliers were radiologically reviewed, and radiological findings were identified in 98%. This study establishes an unsupervised framework for investigating rare individual imaging phenotypes within a large neuroimaging cohort.
High-resolution mapping of the period landscape reveals polymorphism in cell cycle frequency tuning
Authors: Li Zhengda , Wang Shiyuan , Sun Meng , Jin Minjun , Khain Daniel , Yang Qiong 
Published: May 2021

AbstractMany biological oscillators exhibit widely tunable frequency in adapting to environmental changes. Although theoretical studies have proposed positive feedback as a mechanism underlying an oscillator’s large tunability, there have been no experiments to test it. Here, applying droplet microfluidics, we created a population of synthetic cells, each containing a cell-cycle oscillator and varying concentrations of cyclin B mRNAs for speed-tuning and positive-feedback inhibitors for modulating network interactions, allowing a continuous mapping of the cell-cycle period landscape in response to network perturbation. We found that although the cell cycle’s high tunability to cyclin B can reduce with Wee1 inhibition, the reduction is not as great as theoretically predicted, and another positive-feedback regulator, PP2A, may provide additional machinery to ensure the robustness of cell cycle period tunability. Remarkably, we discovered polymorphic responses of cell cycles to the PP2A inhibition. Droplet cells display a monomodal distribution of oscillations peaking at either low or high PP2A activity or a bimodal distribution with both low and high PP2A peaks. We explain such polymorphism by a model of two interlinked bistable switches of Cdk1 and PP2A where cell cycles exhibit two different oscillatory modes in the absence or presence of PP2A bistability.
C. elegans PEZO-1 is a Mechanosensitive Ion Channel Involved in Food Sensation
Authors: Millet Jonathan RM , Romero Luis O , Lee Jungsoo , Bell Briar , Vásquez Valeria 
Published: May 2021

ABSTRACTPIEZO channels are force sensors essential for physiological processes, including baroreception and proprioception. The Caenorhabditis elegans genome encodes an ortholog gene of the Piezo family, pezo-1, which is expressed in several tissues, including the pharynx. This myogenic pump is an essential component of the C. elegans alimentary canal, whose contraction and relaxation are modulated by mechanical stimulation elicited by food content. Whether pezo-1 encodes a mechanosensitive ion channel and contributes to pharyngeal function remain unknown. Here, we leverage genome editing, genetics, microfluidics, and electropharyngeogram recording to establish that pezo-1 is expressed in the pharynx, including in a proprioceptive-like neuron, and regulates pharyngeal function. Knockout (KO) and gain-of-function (GOF) mutants reveal that pezo-1 is involved in fine-tuning pharyngeal pumping frequency, sensing osmolarity, and food mechanical properties. Using pressure-clamp experiments in primary C. elegans embryo cultures, we determine that pezo-1 KO cells do not display mechanosensitive currents, whereas cells expressing wild-type or GOF PEZO-1 exhibit mechanosensitivity. Moreover, infecting the Spodoptera frugiperda cell line with a baculovirus containing the G-isoform of pezo-1 (among the longest isoforms) demonstrates that pezo-1 encodes a mechanosensitive channel. Our findings reveal that pezo-1 is a mechanosensitive ion channel that regulates food sensation in worms.
The RNA helicases DDX5 and DDX17 facilitate neural differentiation of human pluripotent stem cells NTERA2
Authors: Suthapot Praewa , Xiao Tiaojiang , Felsenfeld Gary , Hongeng Suradej , Wongtrakoongate Patompon 
Published: May 2021

AbstractUnderstanding human neurogenesis is critical toward regenerative medicine for neurodegeneration. However, little is known how neural differentiation is regulated by RNA helicases, which comprise a diverse class of RNA remodeling enzymes. We show here that expression of the DEAD boxcontaining RNA helicases DDX5 and DDX17 is abundant throughout retinoic acid-induced neural differentiation of the human pluripotent stem cell (hPSC) line NTERA2, and is mostly localized within the nucleus. Using ChIP-seq, we identify that the two RNA helicases occupy chromatin genome-wide at regions associated with neurogenesis- and differentiation-related genes in both hPSCs and their neural derivatives. Further, RNA-seq analyses indicate both DDX5 and DDX17 are mutually required for controlling transcriptional expression of these genes. We show that the two RNA helicases are not important for maintenance of stem cell state of hPSCs. In contrast, they facilitate early neural differentiation of hPSCs, generation of neurospheres from the stem cells, and expression of key neurogenic transcription factors during neural differentiation. Importantly, DDX5 and DDX17 are important for differentiation of hPSCs toward NESTIN- and TUBB3-positive cells, which represent neural progenitors and mature neurons. Collectively, our findings suggest the role of DDX5 and DDX17 in transcriptional regulation of genes involved in neurogenesis, and hence in neural differentiation of hPSCs.
How much pollen do solitary bee larvae consume? : Or establishing realistic exposure estimates of solitary bee larvae via pollen for the use in risk assessment
Authors: Pamminger Tobias , Schneider Christof , Maas Raffael , Bergtold Matthias 
Published: May 2021

AbstractBees foraging in agricultural habitats can be exposed to plant protection products. In order to limit the risk of adverse events to occur a robust risk assessment is needed, which requires reliable estimates for the expected exposure. Especially the exposure pathways to developing solitary bees are not well described and in the currently proposed form rely on limited information. To address this topic, we used a published data set on the volume of pollen solitary bees provide for their larvae to build two scaling models predicting the amount of protein and pollen developing solitary bees need based on adult body weight. We test our models using both literature and experimental data, which both support the validity of the presented models. Using scaling models in the bee risk assessment could complement existing risk assessment approaches, facilitate the further development of accurate risk characterization for solitary bees and ultimately will help to protect them during their foraging activity in agricultural settings.
The genetic architecture of phenotypic diversity in the betta fish (Betta splendens)
Authors: Zhang Wanchang , Wang Hongru , Brandt Débora Y. C. , Hu Beijuan , Sheng Junqing , Wang Mengnan , Luo Haijiang , Guo Shujie , Sheng Bin , Zeng Qi , Peng Kou , Zhao Daxian , Jian Shaoqing , Wu Di , Wang Junhua , van Esch Joep H. M. , Shi Wentian , Ren Jun , Nielsen Rasmus , Hong Yijiang 
Published: May 2021

SummaryThe Betta fish displays a remarkable variety of phenotypes selected during domestication. However, the genetic basis underlying these traits remain largely unexplored. Here, we report a high-quality genome assembly and re-sequencing of 727 individuals representing diverse morphologies of the betta fish. We show that current breeds have a complex domestication history with extensive introgression with wild species. Using GWAS, we identify the genetic basis of multiple traits, including several coloration phenotypes, sex-determination which we map toDMRT1, and the long-fin phenotype which maps toKCNJ15. We identify a polygenic signal related to aggression with many similarities to human psychiatric traits, involving genes such asCACNB2andDISC1. Our study provides a resource for developing the Betta fish as a genetic model for morphology and behavior in vertebrates.
Cell Surface Glycan Engineering Reveals that Matriglycan Alone can Recapitulate Dystroglycan Binding and Function
Authors: Osman Sheikh M. , Capicciotti Chantelle J. , Liu Lin , Praissman Jeremy , Mead Daniel G. , Brindley Melinda A. , Willer Tobias , Campbell Kevin P. , Moremen Kelley W. , Wells Lance , Boons Geert-Jan 
Published: May 2021

Abstractα-Dystroglycan (α-DG) is uniquely modified on O-mannose sites by a repeating disaccharide (-Xylα1,3-GlcAβ1,3-)n termed matriglycan, which is a receptor for laminin-G domain-containing proteins and employed by old-world arenaviruses for infection. Using chemoenzymatically synthesized matriglycans printed as a microarray, we demonstrated length-dependent binding to Laminin, Lassa virus GP1, and the clinically-important antibody IIH6. Utilizing an enzymatic engineering approach, an N-linked glycoprotein was converted into a IIH6-positive Laminin-binding glycoprotein. Engineering of the surface of cells deficient for either α-DG or O-mannosylation with matriglycans of sufficient length recovered infection with a Lassa-pseudovirus. Finally free matriglycan in a dose and length dependent manner inhibited viral infection of wildtype cells. These results indicate that matriglycan alone is necessary and sufficient for IIH6 staining, Laminin and LASV GP1 binding, and Lassa-pseudovirus infection and support a model in which it is a tunable receptor for which increasing chain length enhances ligand-binding capacity.
Graphical Abstract