bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conformation and Dynamics of the Kinase Domain Drive Subcellular Location and Activation of LRRK2.
Authors: Schmidt Sven H. , Weng Jui-Hung , Aoto Phillip C. , Boassa Daniela , Silletti Steven , Mathea Sebastian , Hu Junru , Wallbott Maximilian , Komives Elizabeth A. , Knapp Stefan , Herberg Friedrich W. , Taylor Susan S. 
Published: August 2020

Abstract
Background: Leucine-Rich Repeat Kinase 2 (LRRK2) is a complex multi-domain protein where LRRK2-mutations are associated with Parkinson´s Disease (PD). To explore how pathogenic PD-mutations hijack the finely tuned activation process of LRRK2, we here used a multi-tiered approach. Methods: First, the spatial and temporal distribution of full-length LRRK2 was investigated by a real-time cell-based assay in the presence and absence of LRRK2-kinase inhibitors. In a 2nd layer we explored the consequences of PD mutations as well as removal of the N-terminal domains employing a construct containing the ROC, Cor, Kinase and WD40 domains (LRRK2RCKW). We focused on the biochemical characterization of LRRK2RCKW variants based on kinase assays using Rab8a or LRRKtide as substrates. Next, we used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to map the solvent accessible regions of LRRK2RCKW in the presence and absence of the LRRK2 inhibitor MLi-2. Finally, Molecular Dynamics simulations on the kinase domain were applied to elucidate differences in breathing dynamics between wild type and mutants of the DYGψ motif. Results: Our cellular approaches revealed that the kinase inhibitors MLi-2 and rebastinib both freeze the kinase domain in a stable conformation, however, only MLi-2 resembles an active conformation and induces filament formation. LRRK2RCKW showed, regardless of the mutation it was combined with, filament formation, indicating a shielding function of the N-terminal domains. This shielding function is impaired for pathogenic mutations in full length LRRK2. LRRK2RCKW retained kinase activity similar to full-length LRRK2. HDX-MS provided a comprehensive allosteric portrait of the kinase domain and revealed how MLi-2 binding is sensed by the entire protein. Molecular Dynamics simulations suggest that, while all domains contribute to regulating kinase activity and spatial distribution, it is the highly dynamic kinase domain, driven by the DYGψ motif, that coordinates the overall domain crosstalk and serves as a regulatory hub for the intrinsic regulation of LRRK2.Conclusion: These studies confirm our hypothesis that the N-terminal scaffolding domains shield the catalytic domains in an inactive state. PD mutations, MLi-2, or Rab GTPases can all unleash the catalytic domains while the active kinase conformation, but not kinase activity, is essential for docking onto microtubules.
Structural and biochemical mechanisms of NLRP1 inhibition by DPP9
Authors: Chai Jijie , Huang Menghang , Zhang Xiaoxiao , Ann Toh Gee , Gong Qin , Wang Jia , Han Zhifu , Wu Bin , Zhong Franklin 
Published: August 2020

Abstract
The nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires auto-cleavage within its FIIND domain1-7. In resting cells, the dipeptidyl peptidase DPP9 interacts with NLRP1-FIIND and together with a related enzyme DPP8, suppresses spontaneous NLRP1 activation8,9. The mechanisms of DPP8/9-mediated NLRP1 inhibition, however, remain elusive. Here we provide structural and biochemical evidence demonstrating that rat NLRP1 (rNLRP1) interacts with rDPP9 in a stepwise manner to form a 2:1 complex. An auto-inhibited rNLRP1 molecule first interacts with rDPP9 via its ZU5 domain. This 1:1 rNLRP1-rDPP9 complex then captures the UPA domain of a second rNLRP1 molecule via a UPA-interacting site on DPP9 and dimeric UPA-UPA interactions with the first rNLRP1. The 2:1 rNLRP1-rDPP9 complex prevents NLRP1 UPA-mediated higher order oligomerization and maintains NLRP1 in the auto-inhibited state. Structure-guided biochemical and functional assays show that both NLRP1-binding and its enzymatic activity are required for DPP9 to suppress NLRP1, supporting guard-type activation of the NLR. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on activation of the NLRP1 inflammasome.
Laser-stimulated fluorescence reveals unseen details in fossils from the Solnhofen Limestone (Upper Jurassic, Bavaria, Germany)
Authors: Barlow Luke , Pittman Michael , Martill David , Kaye Thomas , Butcher Anthony 
Published: August 2020

Abstract
Laser-Stimulated Fluorescence (LSF) has seen increased use in palaeontological investigations in recent years. The method uses the high flux of laser light to reveal details sometimes missed by ultraviolet (UV) and optical wavelengths. In this study, we compare the results of LSF with UV on a range of fossils from the Upper Jurassic Solnhofen Limestone Konservat-Lagerstätte of Bavaria, Germany. The methodology follows previous protocols with modifications made to enhance laser beam intensity. Our experiments show the value of LSF in revealing shallow subsurface detail of specimens, previously not widely applied to Solnhofen fossils. In particular, fossil decapods from the Solnhofen Limestone reveal full body outlines, even under the matrix, along with details of segmentation within the appendages such as limbs and antennae. The results indicate that LSF can be used on both vertebrate and invertebrate fossils and may surpass the information provided by traditional UV methods in some specimens.
Neuropathology and Virus in Brain of SARS-CoV-2 Infected Non-Human Primates
Authors: Fischer Tracy , Rutkai Ibolya , Mayer Meredith , Hellmers Linh , Ning Bo , Huang Zhen , Monjure Christopher , Coyne Carol , Silvestri Rachel , Golden Nadia , Hensley Krystle , Chandler Kristin , Lehmicke Gabrielle , Bix Geregory , Maness Nicholas , Russell-Lodrigue Kasi , Hu Tony , Roy Chad , Blair Robert , Bohm Rudolf , Doyle-Meyers Lara , Rappaport Jay 
Published: August 2020

Abstract
Neurological manifestations are a significant complication of coronavirus infection disease-19 (COVID-19). Understanding how COVID-19 contributes to neurological disease is needed for appropriate treatment of infected patients, as well as in initiating relevant follow-up care after recovery. Investigation of autopsied brain tissue has been key to advancing our understanding of the neuropathogenesis of a large number of infectious and non-infectious diseases affecting the central nervous system (CNS). Due to the highly infectious nature of the etiologic agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a paucity of tissues available for comprehensive investigation. Here, we show for the first time, microhemorrhages and neuropathology that is consistent with hypoxic injury in SARS-CoV-2 infected non-human primates (NHPs). Importantly, this was seen among infected animals that did not develop severe respiratory disease. This finding underscores the importance of vaccinating against SARS-CoV-2, even among populations that have a reduced risk for developing of severe disease, to prevent long-term or permanent neurological sequelae. Sparse virus was detected in brain endothelial cells but did not associate with the severity of CNS injury. We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.
Epidemiological profile of Plasmodium ovale spp. imported from Africa to Anhui Province, China, 2012 – 2019
Authors: Zhang Tao , Wang Shuqi , Wang Duoquan , Auburn Sarah , Lu Shenning , Xu Xian , Jiang Jingjing , Lyu Xiaofeng , Yu Chen , Tian Cuicui , Li Shizhu , Li Weidong 
Published: August 2020

Abstract
Background
Although autochthonous malaria cases are no longer reported in Anhui Province, China, imported malaria has become a major health concern. The proportion of reported malaria cases caused by Plasmodium ovale spp. increased to levels higher than expected during 2012 to 2019, and showed two peaks, 19.69% in 2015 and 19.35% in 2018.
Methods
We conducted a case-based retrospective study, using data collected from the China Information System for Disease Control and Prevention and Information System for Parasitic Disease Control and Prevention from 2012–2019, to describe the trends and differences between P. o. curtisi and P. o. wallikeri. Epidemiological characteristics were analyzed using descriptive statistics.
Results
P. ovale curtisi and P. ovale wallikeri were found simultaneously circulating in 14 African countries. Among 128 patients infected with P. ovale spp., the proportion of mixed infection cases was 10.16%. Six cases of co-infection by P. ovale and P. falciparum were observed, each presenting with two clinical attacks (the first attack was due to P. falciparum and the second was due to P. ovale spp.) at different intervals. Accurate identification of the infecting species was achieved in only 20.00% of cases with P. ovale infection. At the reporting units, 32.17% and 6.96% of P. ovale spp. cases were misdiagnosed as P. vivax and P. falciparum, respectively.
Conclusion
Our finding indicates that the ability of P. ovale spp. to co-infect with other malarial species has been previously underestimated and providing rational evidence for the existence of hypnozoites in P. ovale spp. P. o. curtisi and P. o. wallikeri circulate simultaneously in Africa, and the incidence of P. ovale spp. is probably also underestimated in these source countries where the disease is endemic. Given the low rate of species identification, more sensitive point-of-care detection methods need to be developed for P. ovale spp., and introduced in non-endemic areas.
Altered Circulating Free Oxysterols in Mild Cognitive Impairment: Relationship to Diet, Lipids and Genetics
Authors: An Yu , Yu Huiyan , Zhang Xiaona , Wang Yushan , Liu Wen , Wang Tao , Wang Lijing , Xiao Rong 
Published: August 2020

Abstract
BackgroundOxysterols, products of cholesterol oxidation, seem dysregulated in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, little is known about serum free oxysterol (biologically active form) profiles for MCI.MethodsSerum free oxysterol profiles were measured by ultra-performance liquid chromatography-mass spectrometry in discovery (n = 145) and validation batch (n = 356), both of which were constituted with cognitively normal individuals and MCI patients. We assessed associations of oxysterols with demographics, cognition, diet, lipids and genetics.Results27-Hydroxycholesterol and 7α-hydroxy-3-oxo-4-cholestenoic acid could distinguish MCI from control with good performance in both discovery batch (AUC = 0.80) and validation batch (AUC = 0.71). MCI status could affect correlation patterns among oxysterols, cognition and lipids. Genetic variants in APOE, CYP27A1, CYP46A1 showed inverse associations with cognition and lipids/oxysterol levels while CYP7A1 showed consistent associations.ConclusionsWe identify for the first time an altered free oxysterol profile and report associations with genetic variants in MCI using two-step case-control studies.Trial registration: EMCOA, ChiCTR-OOC-17011882, Registered 5th, July 2017-Retrospectively registered, http://www.medresman.org/uc/project/projectedit.aspx?proj=2610
Measuring the International Structural Competitiveness and the Hierarchy of National Economies: The Case of the European Union
Authors: Markaki Maria Socrates , Economakis George 
Published: August 2020

Abstract
The determination of the level of competitiveness of national economies and the resulting hierarchy in the world economy is a central economic issue. Research on the subject has been mostly dominated by empirical, rather atheoretical, studies. In this paper, the determination of the international competitiveness level is achieved by using three criteria, which jointly define the level of international structural competitiveness: –the ratio of technologically advanced products in exports, the degree of economic diversification, and the level of the interconnectedness of the economy. The Technologically Advanced Domestic Valued Added in Exports condenses the above three criteria and it is proposed as a measure of international structural competitiveness. In addition, another measure of international structural competitiveness is being examined and tested: the Economic Complexity Index. The implementation of both measures in the European Union reveals similar results regarding the hierarchical position of the economies of the European Union member states, in terms of their international competitiveness.JEL classification: R15, C67, F15
O-vanillin Attenuated Toll-like Receptor 2 Induces Senescence in Intervertebral Disc Cells of Patients With Back Pain
Authors: Mannarino Matthew , Cherif Hosni , Li Li , Sheng Kai , Rabau Oded , Jarzem Peter , Weber Michael H. , Ouellet Jean A. , Haglund Lisbet 
Published: August 2020

Abstract
Backgroud: There are an increased level of senescent cells and Toll Like Receptor-1 -2 -4 and -6 (TLR) expression in degenerating IVDs from back pain patients. However, it is currently not known if the higher expression is related to the senescent cells or if it is a more general increase on all cells. It is also not known if TLR activation in IVD cells will induce cell senescence.Methods: Cells from non-degenerate human IVD were obtained from spine donors and cells from degenerate IVDs came from patients undergoing surgery for low back pain. Gene expression of TLR-1,2,4,6, senescence and senescence-associated secretory phenotype (SASP) markers was evaluated by RT-qPCR in isolated cells. Matrix synthesis was verified with safranin-O staining and Dimethyl-Methylene Blue Assay (DMMB) confirmed proteoglycan content. Protein expression of p16INK4a, SASP factors and TLR-2 was evaluated by immunocytochemistry (ICC) and/or by enzyme-linked immunosorbent assay (ELISA). Results: An increase in senescent cells was found following 48h induction with a TLR-2/6 agonist in cells from both non-degenerate and degenerating human IVDs. Higher levels of SASP factors, TLR-2 gene expression and protein expression was found following 48h induction with TLR-2/6 agonist. Treatment with o-Vanillin reduced the number of senescent cells, and increased matrix synthesis in IVD cells from back pain patients. Treatment with o-Vanillin after induction with TLR-2/6 agonist reduced gene and protein expression of SASP factors and TLR-2. Co-localized staining of p16INK4a and TLR-2 demonstrated that senescent cells have a high TLR-2 expression.Conclusions: Taken together our data demonstrate that activation of TLR-2/6 induce senescence and increase TLR-2 and SASP expression in cells from non-degenerate IVDs of organ donors without degeneration and backpain and in cells from degenerating human IVD of patients with disc degeneration and backpain. The senescent cells showed high TLR-2 expression suggesting a link between TLR activation and cell senescence in human IVD cells. The reduction in senescence, SASP and TLR-2 expression suggest o-Vanillin as a potential disease modifying drug for patients with disc degeneration and backpain.
Research on PDMA communication system based on Complete Complementary Sequence
Authors: Li Shufeng , Su Baoxin , Jin Libiao 
Published: August 2020

Abstract
Pattern division multiple access (PDMA) is a new non-orthogonal multiple access (NOMA) technology. It is proposed to meet the challenge of 5G large-scale connectivity and high-frequency spectral efficiency. Compared with traditional orthogonal multiple access (OMA), PDMA can support more users through the allocation of non-orthogonal resources. Due to perfect aperiodic correlation, complete complementary sequences (CCS) still has research value in 5G. In order to apply the advantages of CCS to NOMA communication system, this paper proposes a system model of CCS spread spectrum coding based on PDMA. CCS is used as spread spectrum code to improve the performance of PDMA communication system. At the same time, on the basis of spread spectrum technology, this paper analyzes the average power allocation algorithm and water-filling power allocation algorithm, and a dynamic power allocation algorithm based on the transmission rate and practical application is proposed. The simulation results show that the system model can effectively improve the performance of the system.
Mechanism of Eucalyptus Volatile Oil Application for Preventing and Treating Pseudomonas Aeruginosa Infection in Vitro
Authors: Yang Lei , Huang Qing , Huang Xiaodong , Lin Zhimin , Gao Xingxin , Chen Songlin , Zhao Lili , Lin Yinghui , Hua Guangzong , Li Sheng 
Published: August 2020

Abstract
Background The mechanism of eucalyptus volatile oil application on the prevention and treatment of burn infections caused by Pseudomonas aeruginosa (PA) was need to examined.Methods The effect of eucalyptus volatile oil on bacterial biofilm was investigated using a PA biofilm model. The expression of LasI mRNA in PA was detected by RT-PCR. Results The minimum inhibitory concentration test showed that the volatile oil of Eucalyptus urophylla in 20% concentration or more could exert an antibacterial effect. However, neither high nor low concentration of the eucalyptus volatile oil had a zone of inhibition. In scanning electron microscopy, the volatile oil group exhibited a significant delay compared with the control group. The volatile oil group also had a significantly lower LasI mRNA expression than the control group. Conclusion As a Chinese medicine, the volatile oil of E. urophylla can affect PA proliferation and biofilm formation by interfering with the expression of LasI, thereby successfully preventing and treating burn infection caused by PA.
Outcome measures for assessing change over time in studies of symptomatic children with hypermobility: a systematic review
Authors: Maarj Muhammad , Coda Andrea , Tofts Louise , Williams Cylie , Santos Derek , Pacey Verity 
Published: August 2020

Abstract
Background This study aimed to synthesise outcome measure type and use in interventional or prospective longitudinal studies of children with generalised joint hypermobility (GJH) and associated symptoms. Method Electronic searches of Medline, CINAHL and Embase databases from inception to 16th March 2020 were performed for studies of children with GJH and symptoms between 5-18 years reporting repeated outcome measures collected at least 4 weeks apart. Methodological quality of eligible studies were described using the Downs and Black checklist.Results Six studies comprising of five interventional, and one prospective observational study (total of 388 children) met the inclusion criteria. Interventional study durations were between 2 to 3 months, with up to 10 months post-intervention follow-up, while the observational study spanned 3 years. Three main constructs of pain, function and quality of life were reported as primary outcome measures using 20 different instruments. All but one measure was validated in paediatric populations, but not specifically for children with GJH and symptoms. One study assessed fatigue, reporting disabling fatigue to be associated with higher pain intensity. Conclusions There were no agreed sets of outcome measures for children with GJH and symptoms found. The standardisation of assessment tools across paediatric clinical trials is needed. Four constructs of pain, function, quality of life and fatigue are recommended to be included with agreed upon, validated, objective tools
Isometric Strength Database for Muscle Maximal Voluntary Endurance Field Tests: Normative Data.
Authors: Janik Frédérick , Toulotte Claire , Seichepine Anne Laure , Masquelier Bernadette , Barbier Fabienne , Fabre Claudine 
Published: August 2020

Abstract
Background: Different field tests are used to evaluate muscular capacity, in particular maximal voluntary endurance. However, although there are some normative values for a few muscle endurance tests, these do not consider the mass, size or age of individuals, which are well-known factors that influence muscle performance.Hypothesis/Purpose: The purpose of this study was to investigate the test-retest reliability of 8 field tests and establish muscle endurance norms, in an healthy population, based on their anthropometric characteristics which could permit to evaluate at best the entire muscle function in a quick manner.Design:Case series. Methods:This study was conducted in two phases. The first phase was to check the reproducibility inter- and intra-assessor for 8 isometric muscle fields tests on twenty volunteered subjects age of 40.9 ± 11.6 years old. The second part was to establish muscle maximal voluntary endurance norms according of these tests on a total of 400 healthy participants segmented by age (50 males and females by age bracket: 20-29; 30-39; 40-49; 50-59 years old, for a total of 200 males and 200 females).Results:The intra and inter-assessor reproducibility tests was very high for all muscle measurements (the ICC varied between 0.915 and 0.996). Good sensitivity is observed for all isometric tests highlights with simple linear regression test demonstrating a significant impact for the variable age for all tests (p<0.001). Each muscle belt presents same ratio regardless of the age and gender group. The simultaneous multiple regression analyses highlight that the anthropometric characteristics of subjects influence significantly the performance of isometric tests. Conclusion:This study has permitted to established prediction equations in an healthy population according to their anthropometric characteristics as well as agonist/antagonist ratios for eight muscle isometric field tests after to be demonstrated an excellent reproducibility of all tests.
A Novel “Three-port” Trocar Placement Technique for Laparoscopic Radical Prostatectomy
Authors: Xu Ben , Song Hai-feng , Luo Cheng , Zhang Qian 
Published: August 2020

Abstract
Background: To introduce a novel “three-port” trocar placement technique for laparoscopic radical prostatectomy (LRP) in prostate cancer (PCa) patients.Methods: We retrospectively reviewed 300 patients with PCa who received surgical treatment between November 2010 and June 2015 at our institution. They were divided into group A: three-port LRP, group B: conventional four-five port LRP, group C: open RP (ORP) and group D: robotic-assisted RP (RARP). A learning curve was analyzed by dividing patients of group A into the early and late stages.Results: All groups were comparable with regard to the preoperative characteristics except for the relatively smaller prostate volume in group A. The three-port LRP operations were performed successfully with only 8 cases conversion to the conventional LRP. None of any severe complications or conversion to ORP occurred. In group A, the mean operative time (OT) duration was 113.8 min, the mean estimated blood loss (EBL) was 94.2 ml, the mean drainage days was 4.0d, the mean hospitalization was 5.1 d, and 27.8% of the prostate specimen margins (PSM) were positive. The differences of OT, EBL, drainage days, hospitalization and transfusion in group A were statistically significant among the majority of the other groups (p<0.05). After undergoing the early stages of a learning curve analysis in three-port LRP, the EBL was obviously decreased.Conclusions: Three-port LRP is a novel technique that exhibits superior intraoperative advantages to the conventional LRP. Due to its less OT, EBL, drainage days, hospitalization and transfusion with a shorter learning curve, it should be recommended and popularized in the clinical practice!