bluuebunny/crossref_metadata_2025 huggingface dataset:
Titrating Growth Hormone Dose to High-Normal IGF-1 Levels Has Beneficial Effects on Body Fat Distribution and Microcirculatory Function Despite Causing Insulin Resistance
Authors: van Bunderen Christa C. , Meijer Rick I. , Lips Paul , Kramer Mark H. , Serné Erik H. , Drent Madeleine L.
Published: February 2021

To clarify the mechanism underlying the described U-shaped relation of both low and high levels of IGF-1 with cardiovascular disease this study explores the effect of decreasing and increasing growth hormone dose in GH deficient adults on (micro)vascular function, body composition and insulin resistance. In this randomized clinical trial, thirty-two subjects receiving GH therapy with an IGF-1 concentration between −1 and 1 SD score (SDS) for at least one year were randomized to receive either a decrease (IGF-1 target level of −2 to −1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Microvascular endothelium (in)dependent vasodilatation and vasomotion, vascular stiffness by pulse wave analysis, and HOMA-IR were measured. At the end of the study 30 subjects (65.6% men, mean age 46.6 (SD 9.9) years) were analyzed. There was a favorable effect of increasing the IGF-1 level on waist circumference compared to decreasing the IGF-1 level (p=0.05), but a detrimental effect on insulin resistance (p=0.03). Decreasing IGF-1 level significantly lowered the endothelial domain of vasomotion (p=0.03), whereas increasing IGF-1 level increased the contribution of the neurogenic domain (p=0.05). This change was related to the favorable change in waist circumference. In conclusion, increasing IGF-1 levels was beneficial for body composition but detrimental with respect to insulin resistance. The contribution of the neurogenic vasomotion domain increased in parallel, and could be explained by the favorable change in waist circumference.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT01877512.
Tissue-Specific Approaches Reveal Diverse Metabolic Functions of Rho-Kinase 1
Authors: Landry Taylor , Shookster Daniel , Huang Hu
Published: February 2021

Rho-kinase 1 (ROCK1) has been implicated in diverse metabolic functions throughout the body, with promising evidence identifying ROCK1 as a therapeutic target in diabetes and obesity. Considering these metabolic roles, several pharmacological inhibitors have been developed to elucidate the mechanisms underlying ROCK1 function. Y27632 and fasudil are two common ROCK1 inhibitors; however, they have varying non-specific selectivity to inhibit other AGC kinase subfamily members and whole-body pharmacological approaches lack tissue-specific insight. As a result, interpretation of studies with these inhibitors is difficult, and alternative approaches are needed to elucidate ROCK1’s tissue specific metabolic functions. Fortunately, recent technological advances utilizing molecular carriers or genetic manipulation have facilitated discovery of ROCK1’s tissue-specific mechanisms of action. In this article, we review the tissue-specific roles of ROCK1 in the regulation of energy balance and substrate utilization. We highlight prominent metabolic roles in liver, adipose, and skeletal muscle, in which ROCK1 regulates energy expenditure, glucose uptake, and lipid metabolism via inhibition of AMPK2α and paradoxical modulation of insulin signaling. Compared to ROCK1’s roles in peripheral tissues, we also describe contradictory functions of ROCK1 in the hypothalamus to increase energy expenditure and decrease food intake via leptin signaling. Furthermore, dysregulated ROCK1 activity in either of these tissues results in metabolic disease phenotypes. Overall, tissue-specific approaches have made great strides in deciphering the many critical metabolic functions of ROCK1 and, ultimately, may facilitate the development of novel treatments for metabolic disorders.
To Prevent or Promote Grid Expansion? Analyzing the Future Role of Power Transmission in the European Energy System
Authors: Cao Karl-Kiên , Pregger Thomas , Haas Jannik , Lens Hendrik
Published: February 2021

Future energy supply systems must become more flexible than they are today to accommodate the significant contributions expected from intermittent renewable power sources. Although numerous studies on planning flexibility options have emerged over the last few years, the uncertainties related to model-based studies have left the literature lacking a proper understanding of the investment strategy needed to ensure robust power grid expansion. To address this issue, we focus herein on two important aspects of these uncertainties: the first is the relevance of various social preferences for the use of certain technologies, and the second is how the available approaches affect the flexibility options for power transmission in energy system models. To address these uncertainties, we analyze a host of scenarios. We use an energy system optimization model to plan the transition of Europe’s energy system. In addition to interacting with the heating and transport sectors, the model integrates power flows in three different ways: as a transport model, as a direct current power flow model, and as a linearized alternating current power flow model based on profiles of power transfer distribution factors. The results show that deploying transmission systems contribute significantly to system adequacy. If investments in new power transmission infrastructure are restricted—for example, because of social opposition—additional power generation and storage technologies are an alternative option to reach the necessary level of adequacy at 2% greater system costs. The share of power transmission in total system costs remains widely stable around 1.5%, even if cost assumptions or the approaches for modeling power flows are varied. Thus, the results indicate the importance of promoting investments in infrastructure projects that support pan-European power transmission. However, a wide range of possibilities exists to put this strategy into practice.
Development and Validation of Multiscale Coupled Thermal-Hydraulic Code Combining RELAP5 and Fluent Code
Authors: Sun Lin , Peng Minjun , Xia Genglei , Wang Xuesong , Wu Mingyu
Published: February 2021

In nuclear reactor system research, the multiscale coupled thermal-hydraulic (T-H) system code and CFD code is one of the most prevalent research areas, and it could help improve simulation fidelity and optimize nuclear reactor design. Additionally, a new idea known as the function fitting method (FFM) for coupling parameter distribution has been newly proposed for exchanging data on the coupling interface, which uses math equations to present the velocity distribution characteristics at the coupling interface. This method could improve the simulation error and numerical instability. To verify and validate the abovementioned FFM, a comparison between the velocity function shape by FFM and real velocity distribution was completed. Besides, the Edwards pipe blowdown test results were used to verify the coupled code. The results showed good agreement with experiment results, and a better simulation accuracy compared to previous work. The current work will establish the ability to explore multiscale coupled thermal-hydraulic operation characteristics which permit precise local parameter distribution.
A Novel Methodology for Electric-Thermal Mixed Power Flow Simulation and Transmission Loss Analysis in Multi-Energy Micro-Grids
Authors: Lei Yi , Chen Xiaoyuan , Jiang Keteng , Li Haibo , Zou Zhice
Published: February 2021

For urban electrical and thermal energy supply and consumption terminals, the multi-energy system is a way to realize the energy conversion and consumption efficiently, cleanly and economically. To further study the power flow character of multi-energy systems, additional factors such as electric-thermal coupling equipment, thermal flow rules should be taken into consideration. The traditional Newton-Raphson iteration method which has been commonly used for electrical power flow calculation must be expanded to electric-thermal mixed power flow. This paper realized a new expression of hot water temperature drop with the thermal supply pipe network. This expression modified the Sukhov cooling operator and intuitively revealed the impact factor of transmission loss in hot water pipes. As a result, mathematical descriptions of electricity, heat and hydraulic flow in a multi-energy system were established. With the modified Sukhov cooling operator, the mathematical model of the expanded Newton-Raphson fast iterative solution algorithm, together with its Jacobian matrix elements affected by the electro-thermal coupling relationship was derived. A regional electric-heat supply system was selected as an example to verify the effectiveness of the method. Results showed that the transmission loss in electrical grid is related with the power load while in thermal pipes it was mainly related with the ambient temperature.
Catalytic Conversion of Carbon Dioxide to Methanol: Current Status and Future Perspective
Authors: Zhang Xinbao , Zhang Guanghui , Song Chunshan , Guo Xinwen
Published: February 2021

With the increasing environmental problems caused by carbon dioxide (CO2) emission and the ultimate carbon resources needed for the development of human society, CO2 hydrogenation to methanol with H2 produced with renewable energy represents a promising path forward. Comprehensive analysis shows that the production of methanol by thermal catalytic CO2 hydrogenation is the most promising technology for large-scale industrialization. This review highlights current developments and future perspectives in the production of methanol from CO2, as well as the main existing problems based on a thorough techno-economic analysis. Moreover, the utilization status and future role of methanol as a platform molecule in the energy system is analyzed. Finally, in this review attention is paid to the development of new catalysts, new routes and new technologies for CO2 conversion aiming to clarify the future direction.
The Use of Barriers to Limit the Spread of Aquatic Invasive Animal Species: A Global Review
Authors: Jones Peter E. , Tummers Jeroen S. , Galib Shams M. , Woodford Darragh J. , Hume John B. , Silva Luiz G. M. , Braga Raul R. , Garcia de Leaniz Carlos , Vitule Jean R. S. , Herder Jelger E. , Lucas Martyn C.
Published: February 2021

Aquatic invasive species (AIS) are one of the principal threats to freshwater biodiversity. Exclusion barriers are increasingly being used as a management strategy to control the spread of AIS. However, exclusion barriers can also impact native organisms and their effectiveness is likely to be context dependent. We conducted a quantitative literature review to evaluate the use of barriers to control animal AIS in freshwater ecosystems worldwide. The quantitative aspect of the review was supplemented by case studies that describe some of the challenges, successes, and opportunities for the use of the use of AIS exclusion barriers globally. Barriers have been used since the 1950s to control the spread of AIS, but effort has been increasing since 2005 (80% of studies) and an increasingly diverse range of AIS taxa are now targeted in a wide range of habitat types. The global use of AIS barriers has been concentrated in North America (74% of studies), Australasia (11%), and Europe (10%). Physical barriers (e.g., weirs, exclusion screens, and velocity barriers) have been most widely used (47%), followed by electric (27%) and chemical barriers (12%). Fish were the most targeted taxa (86%), followed by crustaceans (10%), molluscs (3%) and amphibians (1%). Most studies have been moderately successful in limiting the passage of AIS, with 86% of the barriers tested deterring >70% of individuals. However, only 25% of studies evaluated barrier impacts on native species, and development of selective passage is still in its infancy. Most studies have been too short (47% < 1 year, 87% < 5 years) to detect ecological impacts or have failed to use robust before-after-control-impact (BACI) study designs (only 5%). Hence, more effective monitoring is required to assess the long-term effectiveness of exclusion barriers as an AIS management tool. Our global case studies highlight the pressing need for AIS control in many ecoregions, and exclusion barriers have the potential to become an effective tool in some situations. However, the design and operation of exclusion barriers must be refined to deliver selective passage of native fauna, and exclusion barriers should only be used sparingly as part of a wider integrated management strategy.
Transcriptome Analysis Reveals a Potential Role of Benzoxazinoid in Regulating Stem Elongation in the Wheat Mutant qd
Authors: Xu Daxing , Xie Yongdun , Guo Huijun , Zeng Weiwei , Xiong Hongchun , Zhao Linshu , Gu Jiayu , Zhao Shirong , Ding Yuping , Liu Luxiang
Published: February 2021

The stems of cereal crops provide both mechanical support for lodging resistance and a nutrient supply for reproductive organs. Elongation, which is considered a critical phase for yield determination in winter wheat (Triticum aestivum L.), begins from the first node detectable to anthesis. Previously, we characterized a heavy ion beam triggered wheat mutant qd, which exhibited an altered stem elongation pattern without affecting mature plant height. In this study, we further analyzed mutant stem developmental characteristics by using transcriptome data. More than 40.87 Mb of clean reads including at least 36.61 Mb of unique mapped reads were obtained for each biological sample in this project. We utilized our transcriptome data to identify 124,971 genes. Among these genes, 4,340 differentially expressed genes (DEG) were identified between the qd and wild-type (WT) plants. Compared to their WT counterparts, qd plants expressed 2,462 DEGs with downregulated expression levels and 1878 DEGs with upregulated expression levels. Using DEXSeq, we identified 2,391 counting bins corresponding to 1,148 genes, and 289 of them were also found in the DEG analysis, demonstrating differences between qd and WT. The 5,199 differentially expressed genes between qd and WT were employed for GO and KEGG analyses. Biological processes, including protein-DNA complex subunit organization, protein-DNA complex assembly, nucleosome organization, nucleosome assembly, and chromatin assembly, were significantly enriched by GO analysis. However, only benzoxazinoid biosynthesis pathway-associated genes were enriched by KEGG analysis. Genes encoding the benzoxazinoid biosynthesis enzymes Bx1, Bx3, Bx4, Bx5, and Bx8_9 were confirmed to be differentially expressed between qd and WT. Our results suggest that benzoxazinoids could play critical roles in regulating the stem elongation phenotype of qd.
Psychological Distress Among Women Healthcare Workers: A Health System's Experience Developing Emotional Support Services During the COVID-19 Pandemic
Authors: Sanford Jesse , Agrawal Alpna , Miotto Karen
Published: February 2021

Ensuring the mental health and well-being of the healthcare workforce globally, especially women healthcare workers (HCWs), is an ongoing challenge that has been accentuated by the novel coronavirus (COVID-19) pandemic. Already at high risk of experiencing symptoms of stress, burnout, and depression, women HCWs are now also facing the psychosocial impacts of the COVID-19 pandemic. Although different types of mental health interventions have been introduced to support HCW well-being, the current needs of women HCWs have not been emphasized and replicable processes for developing and implementing specific emotional support services for women HCWs have not yet been well-described in the literature. Therefore, in this perspective, we discuss the approach our institution (University of California, Los Angeles) took for developing emotional support services for women HCWs that incorporate aspects of disaster behavioral health models and address various barriers to support and treatment. In addition, we describe and illustrate the process that we utilized to develop individual-level and institutional-level emotional support services. Finally, based on our institution's experience, we share recommendations for developing emotional support services for women HCWs during the COVID-19 pandemic and other future crises.
T Cell Repertoire During Ontogeny and Characteristics in Inflammatory Disorders in Adults and Childhood
Authors: Foth Svenja , Völkel Sara , Bauersachs Daniel , Zemlin Michael , Skevaki Chrysanthi
Published: February 2021

Since the first day of life, a newborn has to deal with various pathogens from the environment. While passive immune protection is provided by diaplacental maternal antibodies, the development of cellular immunity is ongoing. A mature immune system should be able not only to defend against pathogens, but should also be able to differentiate between self- and non-self-antigens. Dysregulation in the development of cellular immunity can lead to severe disorders like immunodeficiency, autoimmunity and chronic inflammation. In this review, we explain the role of T cell immunity in antigen detection and summarize the characteristics of a mature TCR repertoire as well as the current state of knowledge about the development of the TCR repertoire in ontogenesis. In addition, methods of assessments are outlined, with a focus on the advantages and disadvantages of advanced methods such as next generation sequencing. Subsequently, we provide an overview of various disorders occuring in early childhood like immunodeficiencies, autoimmunity, allergic diseases and chronic infections and outline known changes in the TCR repertoire. Finally, we summarize the latest findings and discuss current research gaps as well as potential future developments.
Full Activation of Kinase Protein Kinase B by Phosphoinositide-Dependent Protein Kinase-1 and Mammalian Target of Rapamycin Complex 2 Is Required for Early Natural Killer Cell Development and Survival
Authors: He Junming , Zhao Jun , Quan Yuhe , Hou Xinlei , Yang Meixiang , Dong Zhongjun
Published: February 2021

The role of PI3K-mTOR pathway in regulating NK cell development has been widely reported. However, it remains unclear whether NK cell development depends on the protein kinase B (PKB), which links PI3K and mTOR, perhaps due to the potential redundancy of PKB. PKB has two phosphorylation sites, threonine 308 (T308) and serine 473 (S473), which can be phosphorylated by phosphoinositide-dependent protein kinase-1 (PDK1) and mTORC2, respectively. In this study, we established a mouse model in which PKB was inactivated through the deletion of PDK1 and Rictor, a key component of mTORC2, respectively. We found that the single deletion of PDK1 or Rictor could lead to a significant defect in NK cell development, while combined deletion of PDK1 and Rictor severely hindered NK cell development at the early stage. Notably, ectopic expression of myristoylated PKB significantly rescued this defect. In terms of mechanism, in PDK1/Rictor-deficient NK cells, E4BP4, a transcription factor for NK cell development, was less expressed, and the exogenous supply of E4BP4 could alleviate the developmental defect of NK cell in these mice. Besides, overexpression of Bcl-2 also helped the survival of PDK1/Rictor-deficient NK cells, suggesting an anti-apoptotic role of PKB in NK cells. In summary, complete phosphorylation of PKB at T308 and S473 by PDK1 and mTORC2 is necessary for optimal NK cell development, and PKB regulates NK cell development by promoting E4BP4 expression and preventing cell apoptosis.
Study on Immune Response of Organs of Epinephelus coioides and Carassius auratus After Immersion Vaccination With Inactivated Vibrio harveyi Vaccine
Authors: Gong Hua , Wang Qing , Lai Yingtiao , Zhao Changchen , Sun Chenwen , Chen Zonghui , Tao Jiafa , Huang Zhibin
Published: February 2021

Immersion vaccination relies on the response of fish mucosa-associated lymphoid tissues, the Crucian carp (Carassius auratus) and Grouper (Epinephelus coioides) were researched in this paper to examine local mucosal immune responses and associated humoral system responses following immersion vaccination. We administered 1.5 × 107CFU/ml formalin-inactivatedVibrio harveyicells and measured mucus and serum antibody titers as well as IgM, MHC II mRNA levels in immune organs. The mucosal antibody response preceded the serum response indicating a role for local mucosal immunity in immersion vaccination. IgM and MHC II mRNA levels were relatively greater for the spleen and head kidney indicating the importance and central position of systemic immunity. Expression levels were also high for the gills while skin levels were the lowest. IgM and MHC II mRNA levels were altered over time following vaccination and the hindgut, liver and spleen were similar indicating a close relationship, so the absolute value ofris used to analyze the correlation among different organs immunized. It can be inferred the existence of an internal immune molecular mechanism for Immune synergy hindgut-liver-spleen, from the peak time (14thday), the relative ratio of genes expression in the same tissues between the immunized grouper and the control group (26 times), and Pearson correlation coefficient (0.8<|r|<1). Injection challenges with liveV. harveyiindicated that the relative protection rates for the crucian carp and Grouper was basically the same at 44.4% and 47.4%, respectively. It is believe that crucian carp may be used as a substitute for the valuable grouper in immunity experiment, just from aspect of the relative percent survival (RPS) and how it changes with time. But they were not consistent about the IgM mRNA expression between that of crucian carp and grouper after immersion theVibriovaccine.
Controversies and Opportunities in the Use of Inflammatory Markers for Diagnosis or Risk Prediction in Fatty Liver Disease
Authors: Lambrecht Joeri , Tacke Frank
Published: February 2021

In the Western society, non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat in the liver, represents the most common cause of chronic liver disease. If left untreated, approximately 15%–20% of patients with NAFLD will progress to non-alcoholic steatohepatitis (NASH), in which lobular inflammation, hepatocyte ballooning and fibrogenesis further contribute to a distorted liver architecture and function. NASH initiation has significant effects on liver-related mortality, as even the presence of early stage fibrosis increases the chances of adverse patient outcome. Therefore, adequate diagnostic tools for NASH are needed, to ensure that relevant therapeutic actions can be taken as soon as necessary. To date, the diagnostic gold standard remains the invasive liver biopsy, which is associated with several drawbacks such as high financial costs, procedural risks, and inter/intra-observer variability in histology analysis. As liver inflammation is a major hallmark of disease progression, inflammation-related circulating markers may represent an interesting source of non-invasive biomarkers for NAFLD/NASH. Examples for such markers include cytokines, chemokines or shed receptors from immune cells, circulating exosomes related to inflammation, and changing proportions of peripheral blood mononuclear cell (PBMC) subtypes. This review aims at documenting and critically discussing the utility of such novel inflammatory markers for NAFLD/NASH-diagnosis, patient stratification and risk prediction.
Mass Mortality of Foundation Species on Rocky Shores: Testing a Methodology for a Continental Monitoring Program
Authors: Mendez María M. , Livore Juan P. , Márquez Federico , Bigatti Gregorio
Published: February 2021

Global concern around substantial losses of biodiversity has led to the development of a number of monitoring programs. Networks were established to obtain appropriate data on the spatial and temporal variation of marine species on rocky shores. Recently, the Marine Biodiversity Observation Network Pole to Pole of the Americas (MBON P2P) program was established and is coordinating biodiversity surveys along coastal areas throughout the continent. The goal of this paper was to test the usefulness and adequacy of a methodology proposed for the MBON P2P program. Changes in benthic assemblage cover were studied on monitored sites in northern Patagonia before and after the 2019 austral summer. Long-term dynamics of mussel bed is described based on existing data. Results showed that assemblages before the 2019 austral summer were different from assemblages after it. Thus, a mussel mass mortality event could be detected with this methodology. It took less than a year for mussel cover to drop from 90 to almost 0%; even where substantial changes in mussel bed cover were not registered in the previous ~20 years at the study area. This simple methodology is an adequate tool for monitoring rocky intertidal habitats. Yearly monitoring is needed, as a minimum, to perceive this kind of process timely. Real-time detection offers the opportunity of properly understanding the causes that lead to the loss of key community components, such as these foundation species. Furthermore, it would provide early warning to decision-makers enhancing the chances of conservation of natural environments and their ecosystem services.
Diagenetic Processes in Aquaculture Ponds Showing Metal Accumulation on Shrimp Gills
Authors: Lemonnier Hugues , Royer Florence , Caradec Florian , Lopez Etienne , Hubert Clarisse , Rabiller Émilie , Desclaux Térence , Fernandez Jean-Michel , Andrieux-Loyer Françoise
Published: February 2021

The gill is the organ by which many toxic metals are taken up by crustaceans. Iron is known to precipitate at its surface, a phenomenon recently observed in some tropical aquaculture ponds. The present study uses a field approach to understand better the environmental conditions and ecological processes involved in this deposit. Because shrimp are exposed to reduced products originating from organic waste accumulated in the sediment, spatial variation in pH, redox potential and concentrations of dissolved metals in pore water were investigated in these ponds. Total organic carbon, acid volatile sulfide and pyrite were also analyzed in the solid phase. Fe2+in pore waters showed high spatial variability between ponds and within the same pond with concentrations up to 1,193 μmol l–1. Behaviors of Fe2+, Mn2+and Co2+in pore water were similar. Four geochemical environments were identified, based on their physico-chemical characteristics. Highest concentrations for Fe2+, Mn2+and Co2+in sediment pore water occurred in slightly acidic and suboxic conditions. When the sediment became anoxic, the H2S produced reacted with Fe2+and/or Co2+to form acid volatile sulfide and pyrite. When pH increased, the concentration of free H2S rose up to 736 μmol l–1. With neutral and suboxic conditions, dissolved metal concentrations could be controlled by their precipitation as oxides and hydroxides. The production of pyrite suggested the existence of a possible process of sediment acidification between two crop periods through the production of sulfuric acid. This acidification could increase with pond age and be the cause of the accumulation of reduced metal after 30 years of aquaculture activity.
Species Diversity of the Pleurostomatid Ciliate Genus Amphileptus (Ciliophora, Haptoria), With Notes on the Taxonomy and Molecular Phylogeny of Three Species
Authors: Wu Lei , Li Jiqiu , Warren Alan , Lin Xiaofeng
Published: February 2021

Amphileptusis one of the largest genera of pleurostomatid ciliates and its species diversity has been reported in various habitats all over the world. In the present work, we review its biodiversity based on data with reliable morphological records. Our work confirms that there are 50 validAmphileptusspecies, some of which have a wide range of salinity adaptability and diverse lifestyles. This genus has a high diversity in China but this might be because of the relatively intensive sampling. Phylogenetic analyses based on SSU rDNA sequence data verify the non-monophyly of the genusAmphileptus. Furthermore, two new and one poorly knownAmphileptusspecies, namelyA. shenzhenensissp. n.,A. cocoussp. n., andA.multinucleatusWang, 1934, from coastal habitats of southern China were investigated using morphological and molecular phylogenetic methods. These three species are highly similar based on their contractile vacuoles and macronuclear nodules. However, they can be discriminated by details of their living morphology and somatic kineties. We also propose two new combinations,Amphileptus polymicronuclei(Li, 1990) comb. n. (original combinationHemiophrys polymicronucleiLi, 1990) andAmphileptus salimicus(Burkovsky, 1970b) comb. n. (original combinationHemiophrys salimicaBurkovsky, 1970b).
Recombinant Spider Silk Protein Matrices Facilitate Differentiation of Neural Stem Cells Into Mature and Functional Neurons
Authors: Lewicka Michalina , Rebellato Paola , Lewicki Jakub , Uhlén Per , Rising Anna , Hermanson Ola
Published: February 2021

Neural stem cells (NSCs) show great promise in drug discovery and clinical application. Yet few efforts have been made to optimize biocompatible materials for such cells to be expanded and used in clinical conditions. We have previously demonstrated that NSCs are readily cultured on substrates of certain recombinant spider silk protein without addition of animal- or human-derived components. The question remains however whether this material allows differentiation into functional neurons, and whether such differentiation can take place also when the NSCs are cultured not only upon but also within the biodegradable material. Here we demonstrate that “foam”-like structures generated from recombinant spider silk protein (4RepCT) provided excellent matrices for the generation and multicellular analysis of functional excitatory neurons from NSCs without addition of animal- or human-derived components. NSCs isolated from the cerebral cortices of rat embryos were cultured at either 4RepCT matrices shaped as foam-like structures without coating, or on conventional polystyrene plates coated with poly-L-ornithine and fibronectin. Upon treatment with recombinant proteins including the extracellular signaling factor BMP4 or a combination of BMP4 and the signaling factor Wnt3a, the cortical NSCs cultured in 4RepCT foam-like structures differentiated efficiently into neurons that responded to glutamate receptor agonists, such as AMPA, to the same extent as control cultures. Matrices derived from recombinant spider silk proteins thus provide a functional microenvironment for neural stem cells with little or no animal- or human-derived components and can be employed in the development of new strategies in stem cell research and tissue engineering.
A General Modeling Approach for Shock Absorbers: 2 DoF MR Damper Case Study
Authors: Lozoya-Santos Jorge de-J. , Tudon-Martinez Juan C. , Morales-Menendez Ruben , Sename Olivier , Spaggiari Andrea , Ramírez-Mendoza Ricardo
Published: February 2021

A methodology is proposed for designing a mathematical model for shock absorbers; the proposal is guided by characteristic diagrams of the shock absorbers. These characteristic diagrams (Force-Displacement, Velocity-Acceleration) are easily constructed from experimental data generated by standard tests. By analyzing the diagrams at different frequencies of interest, they can be classified into one of seven patterns, to guide the design of a model. Finally, the identification of the mathematical model can be obtained using conventional algorithms. This methodology has generated highly non-linear models for 2 degrees of freedom magneto-rheological dampers with high precision (2–10% errors).
Effect of Coconut Fiber Dosage on Flexural Performances of Magnesium Phosphate Cement
Authors: Jiang Zuqian , Zhang Liwen , Zhang Junping , Sun Zhuo , Li Jing
Published: February 2021

Magnesium phosphate cement (MPC), as a new type of inorganic cementitious material, has the advantages of fast curing speed and high early strength. However, MPC still exhibits poor toughness similar to other cementitious materials. Coconut fiber (CF), a renewable plant fiber, was found to have the potential to improve the toughness of MPC in our previous research. As a result, further research should be completed to investigate the mechanical behaviors of MPC mixed with CF. This paper focused on the effect of CF volume dosage on MPC’s flexural performances. Flexural strength, load-deflection (L-D) relationship, fractural patterns, and flexural toughness were obtained by carrying out a three-point bending test. The results showed that flexural strength first increased and then decreased with increasing CF dosage, and the optimal CF dosage for flexural strength was 3%. Besides, it could be observed from the L-D relationship that the toughness increased continuously with increasing CF dosage. Additionally, the technique of scanning electron microscopy (SEM) was employed to analyze the microstructure of MPC mixed with different CF dosages.
Methylphenidate for Mild Cognitive Impairment: An Exploratory 3-Day, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Press Yan , Punchik Boris , Kagan Ella , Berzak Alexander , Freud Tamar , Dwolatzky Tzvi
Published: February 2021

Background: To evaluate the efficacy, safety and tolerability of methylphenidate (MPH) for cognitive function in older patients with mild cognitive impairment (MCI).

Methods: Male and female subjects aged 65 years and older with a clinical diagnosis MCI were included in an exploratory randomized, double-blind, placebo-controlled trial. Eligible subjects were assigned to either treatment with immediate-release MPH or placebo. The active compound was administered in an increasing-dose stepwise fashion, namely 10 mg MPH on day 1, 20 mg on day 2, and 30 mg on day 3. Subjects remained under observation for 4 h following drug administration and were monitored for changes in blood pressure and for adverse events. Cognitive outcome measures included the Montreal Cognitive Assessment (MoCA) and the Neurotrax Mindstreams computerized cognitive assessment battery.

Results: Of 17 subjects enrolled, 15 subjects completed the study, 7 in the active MPH group and 8 in the placebo group. The average age of the participants was 76.1 ± 6.6 years and 10 (66.7%) were men. Following the final dose a significant benefit on memory (predominantly non-verbal memory) was found in the MPH group. While 12 adverse events were reported, they were all rated as mild to moderate.

Conclusions: Our finding of modest beneficial effects of MPH on memory tests in older subjects with MCI in this exploratory study is of interest and should be investigated in further studies.
Transcriptional and Proteomic Characterization of Telomere-Induced Senescence in a Human Alveolar Epithelial Cell Line
Authors: Sullivan Daniel I. , Jiang Mao , Hinchie Angela M. , Roth Mark G. , Bahudhanapati Harinath , Nouraie Mehdi , Liu Jie , McDyer John F. , Mallampalli Rama K. , Zhang Yingze , Kass Daniel J. , Finkel Toren , Alder Jonathan K.
Published: February 2021

Cellular senescence due to telomere dysfunction has been hypothesized to play a role in age-associated diseases including idiopathic pulmonary fibrosis (IPF). It has been postulated that paracrine mediators originating from senescent alveolar epithelia signal to surrounding mesenchymal cells and contribute to disease pathogenesis. However, murine models of telomere-induced alveolar epithelial senescence fail to display the canonical senescence-associated secretory phenotype (SASP) that is observed in senescent human cells. In an effort to understand human-specific responses to telomere dysfunction, we modeled telomere dysfunction-induced senescence in a human alveolar epithelial cell line. We hypothesized that this system would enable us to probe for differences in transcriptional and proteomic senescence pathways in vitro and to identify novel secreted protein (secretome) changes that potentially contribute to the pathogenesis of IPF. Following induction of telomere dysfunction, a robust senescence phenotype was observed. RNA-seq analysis of the senescent cells revealed the SASP and comparisons to previous murine data highlighted differences in response to telomere dysfunction. We conducted a proteomic analysis of the senescent cells using a novel biotin ligase capable of labeling secreted proteins. Candidate biomarkers selected from our transcriptional and secretome data were then evaluated in IPF and control patient plasma. Four novel proteins were found to be differentially expressed between the patient groups: stanniocalcin-1, contactin-1, tenascin C, and total inhibin. Our data show that human telomere-induced, alveolar epithelial senescence results in a transcriptional SASP that is distinct from that seen in analogous murine cells. Our findings suggest that studies in animal models should be carefully validated given the possibility of species-specific responses to telomere dysfunction. We also describe a pragmatic approach for the study of the consequences of telomere-induced alveolar epithelial cell senescence in humans.
A Comparative Study of the Microbiological Efficacy of Polymyxin B on Different Carbapenem-Resistant Gram-Negative Bacteria Infections
Authors: Lu Qiong , Zhu Hai-Hong , Li Guo-Hua , Qi Ting-Ting , Ye Liang-Jun , Teng Xin-Qi , Qu Qiang , He Ge-Fei , Qu Jian
Published: February 2021

Objective: The emergence of carbapenem-resistant gram-negative bacteria (CR-GNB) has brought great challenges to clinical anti-infection treatment around the world. Polymyxins are often considered as the last line of defense in the treatment of CR-GNB infections. In this study, we explored the microbiological efficacy of Polymyxin B (PMB) on different CR-GNB infections as well as the factors influencing microbiological efficacy.

Methods: CR-GNB infected patients with PMB-based regimens were enrolled. Clinical and microbiological data were collected from the medical electronic record system of the Second Xiangya hospital. The efficacy of PMB on different CR-GNB was evaluated by the clearance rate at 7-days and within the course of treatment, as well as the 30-day mortality rate.

Results: A total of 294 CR-GNB infected patients were enrolled: 154 CR-Acinetobacter baumannii (CRAB), 55 CR-Klebsiella pneumoniae (CRKP), and 85 CR-Pseudomonas aeruginosa (CRPA). The CRAB group had the highest 7-day bacterial clearance rate [(CRAB: 39.0%) vs. (CRKP: 29.4%) vs. (CRPA: 14.5%), P = 0.003] and total bacterial clearance rate [(CRAB: 49.0%) vs. (CRKP: 39.8%) vs. (CRPA: 18.2%), P < 0.001] among the three groups, while the bacterial clearance rate of the CRPA group was the lowest. Multivariate logistic regression showed that the differences among the three groups were multiple CR-GNB infections (P = 0.004), respiratory infections (P = 0.001), PMB resistance (P < 0.001), and the combination of tigecycline (P < 0.001). Binary logistic regression showed that multiple CR-GNB infection [(7-day bacterial clearance: P = 0.004) & (total bacterial clearance: P = 0.011)] and bacterial species [(7-day bacterial clearance: P < 0.001) & (total bacterial clearance: P < 0.001)] were independent risk factors for microbiological efficacy.

Conclusion: PMB exhibited differential microbiological efficacy on different types of CR-GNB infections; it had the best effect on CRAB, followed by CRKP and CRPA. Multiple CR-GNB infections and bacterial species were independent risk factors for microbiological efficacy.
Endophytic Diaporthe Associated With Citrus grandis cv. Tomentosa in China
Authors: Dong Zhangyong , Manawasinghe Ishara S. , Huang Yinghua , Shu Yongxin , Phillips Alan J. L. , Dissanayake Asha J. , Hyde Kevin D. , Xiang Meimei , Luo Mei
Published: February 2021

Diaporthe species are associated with Citrus as endophytes, pathogens, and saprobes worldwide. However, little is known about Diaporthe as endophytes in Citrus grandis in China. In this study, 24 endophytic Diaporthe isolates were obtained from cultivated C. grandis cv. “Tomentosa” in Huazhou, Guangdong Province in 2019. The nuclear ribosomal internal transcribed spacer (ITS), partial sequences of translation elongation factor 1-α (tef1), β-tubulin (tub2), and partial calmodulin (cal) gene regions were sequenced and employed to construct phylogenetic trees. Based on morphology and combined multigene phylogeny, eleven Diaporthe species were identified including two new species, Diaporthe endocitricola and D. guangdongensis. These are the first report of D. apiculata, D. aquatica, D. arecae, D. biconispora, D. limonicola, D. masirevicii, D. passifloricola, D. perseae, and D. sennae on C. grandis. This study provides the first intensive study of endophytic Diaporthe species on C. grandis cv. tomentosa in China. These results will improve the current knowledge of Diaporthe species associated with C. grandis. The results obtained in this study will also help to understand the potential pathogens and biocontrol agents and to develop a platform in disease management.
A Hyper-Attenuated Variant of Rift Valley Fever Virus Generated by a Mutagenic Drug (Favipiravir) Unveils Potential Virulence Markers
Authors: Borrego Belén , Brun Alejandro
Published: February 2021

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes Rift Valley fever (RVF), a zoonotic disease of wild and domestic ruminants, causing serious economic losses and a threat to human health that could be controlled by vaccination. Though RVF vaccines are available for livestock, no RVF vaccines have been licensed for veterinary use in non-endemic countries nor for human populations in RVF risk areas. In a recent work, we showed that favipiravir, a promising drug with antiviral activity against a number of RNA viruses, led to the extinction of RVFV from infected cell cultures. Nevertheless, certain drug concentrations allowed the recovery of a virus variant showing increased resistance to favipiravir. In this work, we characterized this novel resistant variant both at genomic and phenotypic level in vitro and in vivo. Interestingly, the resistant virus displayed reduced growth rates in C6/36 insect cells but not in mammalian cell lines, and was highly attenuated but still immunogenic in vivo. Some amino acid substitutions were identified in the viral RNA-dependent RNA-polymerase (RdRp) gene and in the virus encoded type I-interferon (IFN-I) antagonist NSs gene, in catalytic core motifs and nuclear localization associated positions, respectively. These data may help to characterize novel potential virulence markers, offering additional strategies for further safety improvements of RVF live attenuated vaccine candidates.
Distribution of Bacterial Endophytes in the Non-lesion Tissues of Potato and Their Response to Potato Common Scab
Authors: Shi Wencong , Su Gaoya , Li Mingcong , Wang Bing , Lin Rongshan , Yang Yutian , Wei Tao , Zhou Bo , Gao Zheng
Published: February 2021

The response of plant endophytes to disease within infected tissues has been well demonstrated, but the corresponding response of endophytes in non-lesion tissues remains unclear. Here, we studied the composition and distribution of bacterial endophytes in potato roots (RE), stems (SE), and tubers (TE), and explored the response of endophytes in non-lesion tissues to potato common scab (PCS), which is a soil-borne disease caused by pathogenic Streptomyces and results in serious losses to the global economy every year. Via high-throughput sequencing, it was seen that the composition of endophytes in roots, stems, and tubers had significant differences (P < 0.05) and the distribution of the bacterial communities illustrated a gradient from soil to root to tuber/stem. PCS significantly reduced bacterial endophytes α-diversity indexes, including ACE and the number of observed operational taxonomic units (OTUs), of RE without significantly reducing the indexes of SE and TE. No significant effect on the composition of endophytes were caused by PCS in roots, tubers, or stems between high PCS severity (H) and low PCS severity (L) infections at the community level, but PCS did have a substantial impact on the relative abundance of several specific endophytes. Rhizobium and Sphingopyxis were significantly enriched in root endophytes with low PCS severity (REL); Delftia and Ochrobactrum were significantly enriched in stem endophytes with low PCS severity (SEL); Pedobacter, Delftia, and Asticcacaulis were significantly enriched in tuber endophytes with high PCS severity (TEH). OTU62, a potential PCS pathogen in this study, was capable of colonizing potato tubers, roots, and stems with few or no symptoms present. Co-occurrence networks showed that the number of correlations to OTU62 was higher than average in these three tissue types, suggesting the importance of OTU62 in endophytic communities. This study clarified the distribution and composition of potato endophytes in tubers, roots, and stems, and demonstrated the response of endophytes in non-lesion tissues to PCS.
High Prevalence and Mechanism Associated With Extended Spectrum Beta-Lactamase-Positive Phenotype in Laribacter hongkongensis
Authors: Teng Jade L. L. , Luo Ruibang , Tang Bone S. F. , Fong Jordan Y. H. , Wang Li , Jia Lilong , Wong Chloe K. S. , Chan Elaine , Leung Amy W. S. , Siu Gilman K. H. , Chiu Tsz-Ho , Fung Ami M. Y. , Wu Alan K. L. , Yeung Man-Lung , Lau Susanna K. P. , Woo Patrick C. Y.
Published: February 2021

In this study, we reported the prevalence and mechanism associated with the extended-spectrum beta-lactamase (ESBL)-positive phenotype in Laribacter hongkongensis isolated from patients and fish. Using the inhibition zone enhancement test, 20 (95.2%) of the 21 patient strains and 8 (57.1%) of the 14 fish strains were tested ESBL-positive. However, ESBL genes, including SHV, TEM, CTX-M, GES, and PER, were not detected in all of these 28 L. hongkongensis isolates. No ESBL gene could be detected in either the complete genome of L. hongkongensis HLHK9 or the draft genome of PW3643. PCR and DNA sequencing revealed that all the 35 L. hongkongensis isolates (showing both ESBL-positive and ESBL-negative phenotypes) were positive for the ampC gene. When the AmpC deletion mutant, HLHK9ΔampC, was subject to the zone enhancement test, the difference of zone size between ceftazidime/clavulanate and ceftazidime was less than 5 mm. When boronic acid was added to the antibiotic disks, none of the 28 “ESBL-positive” isolates showed a ≥ 5 mm enhancement of inhibition zone size diameter between ceftazidime/clavulanate and ceftazidime and between cefotaxime/clavulanate and cefotaxime. A high prevalence (80%) of ESBL-positive phenotype is present in L. hongkongensis. Overall, our results suggested that the ESBL-positive phenotype in L. hongkongensis results from the expression of the intrinsic AmpC beta-lactamase. Confirmatory tests should be performed before issuing laboratory reports for L. hongkongensis isolates that are tested ESBL-positive by disk diffusion clavulanate inhibition test.