bluuebunny/crossref_metadata_2025 huggingface dataset:
Cryopreservation as a Key Element in the Successful Delivery of Cell-Based Therapies—A Review
Authors: Meneghel Julie , Kilbride Peter , Morris G. John
Published: November 2020

Cryopreservation is a key enabling technology in regenerative medicine that provides stable and secure extended cell storage for primary tissue isolates and constructs and prepared cell preparations. The essential detail of the process as it can be applied to cell-based therapies is set out in this review, covering tissue and cell isolation, cryoprotection, cooling and freezing, frozen storage and transport, thawing, and recovery. The aim is to provide clinical scientists with an overview of the benefits and difficulties associated with cryopreservation to assist them with problem resolution in their routine work, or to enable them to consider future involvement in cryopreservative procedures. It is also intended to facilitate networking between clinicians and cryo-researchers to review difficulties and problems to advance protocol optimization and innovative design.
Salmonella and S. aureus Escape From the Clearance of Macrophages via Controlling TFEB
Authors: Rao Shanshan , Xu Tao , Xia Yu , Zhang Hongfeng
Published: November 2020

Phagosome- and xenophagosome-lysosome systems play a critical role in the defense of pathogenic bacteria, such as Salmonella and S. aureus, in macrophages. A great part of the bacteria escapes from the digestion and can survive through some mechanisms that are still poorly understood and which require further exploration. Here we identified that Salmonella inhibited the expression and activation of TFEB to blunt the functions of lysosomes and defense of clearance by activating caspase-1. The expression and activation of TFEB were enhanced early under the infection of S. aureus, which was followed by shrinkage to weaken lysosomal functions due to the delayed activation of ERK, mTOR, and STAT3. Thus, we have identified novel escape mechanisms for Salmonella and S. aureus to deepen and strengthen our strategies fighting with pathogens.
Identification of Novel Thermosensors in Gram-Positive Pathogens
Authors: Fernández Pilar , Díaz Alejandra Raquel , Ré María Florencia , Porrini Lucía , de Mendoza Diego , Albanesi Daniela , Mansilla María Cecilia
Published: November 2020

Temperature is a crucial variable that every living organism, from bacteria to humans, need to sense and respond to in order to adapt and survive. In particular, pathogenic bacteria exploit host-temperature sensing as a cue for triggering virulence gene expression. Here, we have identified and characterized two integral membrane thermosensor histidine kinases (HKs) from Gram-positive pathogens that exhibit high similarity to DesK, the extensively characterized cold sensor histidine kinase from Bacillus subtilis. Through in vivo experiments, we demonstrate that SA1313 from Staphylococcus aureus and BA5598 from Bacillus anthracis, which likely control the expression of putative ATP binding cassette (ABC) transporters, are regulated by environmental temperature. We show here that these HKs can phosphorylate the non-cognate response regulator DesR, partner of DesK, both in vitro and in vivo, inducing in B. subtilis the expression of the des gene upon a cold shock. In addition, we report the characterization of another DesK homolog from B. subtilis, YvfT, also closely associated to an ABC transporter. Although YvfT phosphorylates DesR in vitro, this sensor kinase can only induce des expression in B. subtilis when overexpressed together with its cognate response regulator YvfU. This finding evidences a physiological mechanism to avoid cross talk with DesK after a temperature downshift. Finally, we present data suggesting that the HKs studied in this work appear to monitor different ranges of membrane lipid properties variations to mount adaptive responses upon cooling. Overall, our findings point out that bacteria have evolved sophisticated mechanisms to assure specificity in the response to environmental stimuli. These findings pave the way to understand thermosensing mediated by membrane proteins that could have important roles upon host invasion by bacterial pathogens.
Subarachnoid Hemorrhage Increases Level of Heme Oxygenase-1 and Biliverdin Reductase in the Choroid Plexus
Authors: Solár Peter , Brázda Václav , Levin Shahaf , Zamani Alemeh , Jančálek Radim , Dubový Petr , Joukal Marek
Published: November 2020

Subarachnoid hemorrhage is a specific, life-threatening form of hemorrhagic stroke linked to high morbidity and mortality. It has been found that the choroid plexus of the brain ventricles forming the blood-cerebrospinal fluid barrier plays an important role in subarachnoid hemorrhage pathophysiology. Heme oxygenase-1 and biliverdin reductase are two of the key enzymes of the hemoglobin degradation cascade. Therefore, the aim of present study was to investigate changes in protein levels of heme oxygenase-1 and biliverdin reductase in the rat choroid plexus after experimental subarachnoid hemorrhage induced by injection of non-heparinized autologous blood to the cisterna magna. Artificial cerebrospinal fluid of the same volume as autologous blood was injected to mimic increased intracranial pressure in control rats. Immunohistochemical and Western blot analyses were used to monitor changes in the of heme oxygenase-1 and biliverdin reductase levels in the rat choroid plexus after induction of subarachnoid hemorrhage or artificial cerebrospinal fluid application for 1, 3, and 7 days. We found increased levels of heme oxygenase-1 and biliverdin reductase protein in the choroid plexus over the entire period following subarachnoid hemorrhage induction. The level of heme oxygenase-1 was the highest early (1 and 3 days) after subarachnoid hemorrhage indicating its importance in hemoglobin degradation. Increased levels of heme oxygenase-1 were also observed in the choroid plexus epithelial cells at all time points after application of artificial cerebrospinal fluid. Biliverdin reductase protein was detected mainly in the choroid plexus epithelial cells, with levels gradually increasing during subarachnoid hemorrhage. Our results suggest that heme oxygenase-1 and biliverdin reductase are involved not only in hemoglobin degradation but probably also in protecting choroid plexus epithelial cells and the blood-cerebrospinal fluid barrier from the negative effects of subarachnoid hemorrhage.
The Paradox of Astroglial Ca2 + Signals at the Interface of Excitation and Inhibition
Authors: Caudal Laura C. , Gobbo Davide , Scheller Anja , Kirchhoff Frank
Published: November 2020

Astroglial networks constitute a non-neuronal communication system in the brain and are acknowledged modulators of synaptic plasticity. A sophisticated set of transmitter receptors in combination with distinct secretion mechanisms enables astrocytes to sense and modulate synaptic transmission. This integrative function evolved around intracellular Ca2+ signals, by and large considered as the main indicator of astrocyte activity. Regular brain physiology meticulously relies on the constant reciprocity of excitation and inhibition (E/I). Astrocytes are metabolically, physically, and functionally associated to the E/I convergence. Metabolically, astrocytes provide glutamine, the precursor of both major neurotransmitters governing E/I in the central nervous system (CNS): glutamate and γ-aminobutyric acid (GABA). Perisynaptic astroglial processes are structurally and functionally associated with the respective circuits throughout the CNS. Astonishingly, in astrocytes, glutamatergic as well as GABAergic inputs elicit similar rises in intracellular Ca2+ that in turn can trigger the release of glutamate and GABA as well. Paradoxically, as gliotransmitters, these two molecules can thus strengthen, weaken or even reverse the input signal. Therefore, the net impact on neuronal network function is often convoluted and cannot be simply predicted by the nature of the stimulus itself. In this review, we highlight the ambiguity of astrocytes on discriminating and affecting synaptic activity in physiological and pathological state. Indeed, aberrant astroglial Ca2+ signaling is a key aspect of pathological conditions exhibiting compromised network excitability, such as epilepsy. Here, we gather recent evidence on the complexity of astroglial Ca2+ signals in health and disease, challenging the traditional, neuro-centric concept of segregating E/I, in favor of a non-binary, mutually dependent perspective on glutamatergic and GABAergic transmission.
SARA-GAN: Self-Attention and Relative Average Discriminator Based Generative Adversarial Networks for Fast Compressed Sensing MRI Reconstruction
Authors: Yuan Zhenmou , Jiang Mingfeng , Wang Yaming , Wei Bo , Li Yongming , Wang Pin , Menpes-Smith Wade , Niu Zhangming , Yang Guang
Published: November 2020

Research on undersampled magnetic resonance image (MRI) reconstruction can increase the speed of MRI imaging and reduce patient suffering. In this paper, an undersampled MRI reconstruction method based on Generative Adversarial Networks with the Self-Attention mechanism and the Relative Average discriminator (SARA-GAN) is proposed. In our SARA-GAN, the relative average discriminator theory is applied to make full use of the prior knowledge, in which half of the input data of the discriminator is true and half is fake. At the same time, a self-attention mechanism is incorporated into the high-layer of the generator to build long-range dependence of the image, which can overcome the problem of limited convolution kernel size. Besides, spectral normalization is employed to stabilize the training process. Compared with three widely used GAN-based MRI reconstruction methods, i.e., DAGAN, DAWGAN, and DAWGAN-GP, the proposed method can obtain a higher peak signal-to-noise ratio (PSNR) and structural similarity index measure(SSIM), and the details of the reconstructed image are more abundant and more realistic for further clinical scrutinization and diagnostic tasks.
A New Dichoptic Training Strategy Leads to Better Cooperation Between the Two Eyes in Amblyopia
Authors: Liu Zitian , Chen Zidong , Gao Le , Liu Manli , Huang Yiru , Feng Lei , Yuan Junpeng , Deng Daming , Huang Chang-Bing , Yu Minbin
Published: November 2020

Recent clinical trials failed to endorse dichoptic training for amblyopia treatment. Here, we proposed an alternative training strategy that focused on reducing signal threshold contrast in the amblyopic eye under a constant and high noise contrast in the fellow eye (HNC), and compared it to a typical dichoptic strategy that aimed at increasing the tolerable noise contrast in the fellow eye (i.e., TNC strategy). We recruited 16 patients with amblyopia and divided them into two groups. Eight patients in Group 1 received the HNC training, while the other eight patients in Group 2 performed the TNC training first (Phase 1) and then crossed over to the HNC training (Phase 2). We measured contrast sensitivity functions (CSFs) separately in the amblyopic and fellow eyes when the untested eye viewed mean luminance (monocularly unmasked) or noise stimuli (dichoptically masked) before and after training at a particular frequency. The area under the log contrast sensitivity function (AULCSF) of masked and unmasked conditions, and dichoptic gain (the ratio of AULCSF of masked to unmasked condition) were calculated for each eye. We found that both dichoptic training paradigms substantially improved masked CSF, dichoptic gain, and visual acuity in the amblyopic eye. As opposed to the TNC paradigm, the HNC training produced stronger effects on masked CSFs, stereoacuity, dichoptic gain, and visual acuity in the amblyopic eye. Interestingly, the second-phase HNC training in Group 2 also induced further improvement in the masked contrast sensitivity and AULCSF in the amblyopic eye. We concluded that the HNC training strategy was more effective than the TNC training paradigm. Future design for dichoptic training should not only focus on increasing the tolerable noise contrast in the fellow eye but should also “nurture” the amblyopic eye under normal binocular viewing conditions and sustained interocular suppression.
A Functional Comparison of Homopentameric Nicotinic Acetylcholine Receptors (ACR-16) Receptors From Necator americanus and Ancylostoma ceylanicum
Authors: Kaji Mark D. , Geary Timothy G. , Beech Robin N.
Published: November 2020

Effective control of hookworm infections in humans and animals relies on using a small group of anthelmintics. Many of these drugs target cholinergic ligand-gated ion channels, yet the direct activity of anthelmintics has only been studied in a subset of these receptors, primarily in the non-parasitic nematode,Caenorhabditis elegans. Here we report the characterization of a homopentameric ionotropic acetylcholine receptor (AChR), ACR-16, fromNecator americanusandAncylostoma ceylanicum, the first known characterization of human hookworm ion channels. We used two-electrode voltage clamp electrophysiology inXenopus laevisoocytes to determine the pharmacodynamics of cholinergics and anthelmintics on ACR-16 from both species of hookworm. TheA. ceylanicumreceptor (Ace-ACR-16) was more sensitive to acetylcholine (EC50= 20.64 ± 0.32 μM) and nicotine (EC50= 24.37 ± 2.89 μM) than theN. americanusreceptor (Nam-ACR-16) (acetylcholine EC50= 170.1 ± 19.23 μM; nicotine EC50= 597.9 ± 59.12 μM), at which nicotine was a weak partial agonist (% maximal acetylcholine response = 30.4 ± 7.4%). Both receptors were inhibited by 500 μM levamisole (Ace-ACR-16 = 65.1 ± 14.3% inhibition, Nam-ACR-16 = 79.5 ± 7.7% inhibition), and responded to pyrantel, but only Ace-ACR-16 responded to oxantel. We usedin silicohomology modeling to investigate potential structural differences that account for the differences in agonist binding and identified a loop E isoleucine 130 of Nam-ACR-16 as possibly playing a role in oxantel insensitivity. These data indicate that key functional differences exist among ACR-16 receptors from closely related species and suggest mechanisms for differential drug sensitivity.
Hopf Bifurcation in Mean Field Explains Critical Avalanches in Excitation-Inhibition Balanced Neuronal Networks: A Mechanism for Multiscale Variability
Authors: Liang Junhao , Zhou Tianshou , Zhou Changsong
Published: November 2020

Cortical neural circuits display highly irregular spiking in individual neurons but variably sized collective firing, oscillations and critical avalanches at the population level, all of which have functional importance for information processing. Theoretically, the balance of excitation and inhibition inputs is thought to account for spiking irregularity and critical avalanches may originate from an underlying phase transition. However, the theoretical reconciliation of these multilevel dynamic aspects in neural circuits remains an open question. Herein, we study excitation-inhibition (E-I) balanced neuronal network with biologically realistic synaptic kinetics. It can maintain irregular spiking dynamics with different levels of synchrony and critical avalanches emerge near the synchronous transition point. We propose a novel semi-analytical mean-field theory to derive the field equations governing the network macroscopic dynamics. It reveals that the E-I balanced state of the network manifesting irregular individual spiking is characterized by a macroscopic stable state, which can be either a fixed point or a periodic motion and the transition is predicted by a Hopf bifurcation in the macroscopic field. Furthermore, by analyzing public data, we find the coexistence of irregular spiking and critical avalanches in the spontaneous spiking activities of mouse cortical slice in vitro, indicating the universality of the observed phenomena. Our theory unveils the mechanism that permits complex neural activities in different spatiotemporal scales to coexist and elucidates a possible origin of the criticality of neural systems. It also provides a novel tool for analyzing the macroscopic dynamics of E-I balanced networks and its relationship to the microscopic counterparts, which can be useful for large-scale modeling and computation of cortical dynamics.
Enhancing the Nutritional Quality of Major Food Crops Through Conventional and Genomics-Assisted Breeding
Authors: Gaikwad Kiran B. , Rani Sushma , Kumar Manjeet , Gupta Vikas , Babu Prashanth H. , Bainsla Naresh Kumar , Yadav Rajbir
Published: November 2020

Nutritional stress is making over two billion world population malnourished. Either our commercially cultivated varieties of cereals, pulses, and oilseed crops are deficient in essential nutrients or the soils in which these crops grow are becoming devoid of minerals. Unfortunately, our major food crops are poor sources of micronutrients required for normal human growth. To overcome the problem of nutritional deficiency, greater emphasis should be laid on the identification of genes/quantitative trait loci (QTLs) pertaining to essential nutrients and their successful deployment in elite breeding lines through marker-assisted breeding. The manuscript deals with information on identified QTLs for protein content, vitamins, macronutrients, micro-nutrients, minerals, oil content, and essential amino acids in major food crops. These QTLs can be utilized in the development of nutrient-rich crop varieties. Genome editing technologies that can rapidly modify genomes in a precise way and will directly enrich the nutritional status of elite varieties could hold a bright future to address the challenge of malnutrition.
Species Quantification in Complex Herbal Formulas—Vector Control Quantitative Analysis as a New Method
Authors: Zhao Bo , Xiong Chao , Li Jingjian , Zhang Deng , Shi Yancai , Sun Wei , Duan Xiaoqun
Published: November 2020

Product mislabeling and/or species fraud in Traditional Chinese Medicine (TCM) not only decrease TCM quality, but also pose a potential health issue to the end user. Up to now, methods to control TCM quality have been developed to detect specific metabolites or identify the original species. However, species quantification in complex herbal formulas is rarely concerned. Here, we reported a simple Vector Control Quantitative Analysis (VCQA) method for flexible and accurate multiplex species quantification in traditional Chinese herbal formulas. We developed PCR-based strategy to quickly generate the integrated DNA fragments from multiple targeted species, which can be assembled into the quantitative vector in one round of cloning by Golden Gate ligation and Gateway recombination technique. With this method, we recruited the nuclear ribosomal DNA Internal Transcribed Spacer (ITS) region for the quantification of Ligusticum sinense “Chuanxiong,” Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Notopterygium incisum K. C. Ting ex H. T. Chang, Asarum sieboldii Miq., Saposhnikovia divaricata (Turcz.) Schischk., Nepeta cataria L., Mentha canadensis L., and Glycyrrhiza uralensis Fisch. ex DC. in ChuanXiong ChaTiao Wan, a classic Chinese herbal formula with very long historical background. We found that, firstly, VCQA method could eliminate the factors affecting such as the variations in DNA extracts when in combination with the use of universal and species-specific primers. Secondly, this method detected the limit of quantification of A. sieboldii Miq. in formula products down to 1%. Thirdly, the stability of quality of ChuanXiong ChaTiao Wan formula varies significantly among different manufacturers. In conclusion, VCQA method has the potential power and can be used as an alternative method for species quantification of complex TCM formulas.
PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC
Authors: Wang Xiao , Liang Chao , Yao Xin , Yang Ruo-Han , Zhang Zhan-Sheng , Liu Fan-Ye , Li Wen-Qi , Pei Shu-Hua , Ma Jing , Xie Song-Qiang , Fang Dong
Published: November 2020

High expression of programmed death-ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) cells usually inhibits the proliferation and functions of T cells, leading to immune suppression in tumor microenvironment. However, very little has been described regarding the mechanism of PD-L1 overexpression in HCC cells. In the present study, we found epidermal growth factor (EGF) stimulation promoted the expression of PD-L1 mRNA and protein in HCC cells. Inhibition of epidermal growth factor receptor (EGFR) could reverse EGF-induced the expression of PD-L1 mRNA and protein. Subsequently, we also observed that the phosphorylation level of Pyruvate kinase isoform M2 (PKM2) at Ser37 site was also increased in response to EGF stimulation. Expression of a phosphorylation-mimic PKM2 S37D mutant stimulated PD-L1 expression as well as H3-Thr11 phosphorylation in HCC cells, while inhibition of PKM2 significantly blocked EGF-induced PD-L1 expression and H3-Thr11 phosphorylation. Furthermore, mutation of Thr11 of histone H3 into alanine abrogated EGF-induced mRNA and protein expression of PD-L1, Chromatin immunoprecipitation (ChIP) assay also suggested that EGF treatment resulted in enhanced H3-Thr11 phosphorylation at the PD-L1 promoter. In a diethylnitrosamine (DEN)-induced rat model of HCC, we found that the expression of phosphorylated EGFR, PKM2 nuclear expression, H3-Thr11 phosphorylation as well as PD-L1 mRNA and protein was higher in the livers than that in normal rat livers. Taken together, our study suggested that PKM2-dependent histone H3-Thr11 phosphorylation was crucial for EGF-induced PD-L1 expression at transcriptional level in HCC. These findings may provide an alternative target for the treatment of hepatocellular carcinoma.
Association Between Vitamin D and Novel SARS-CoV-2 Respiratory Dysfunction – A Scoping Review of Current Evidence and Its Implication for COVID-19 Pandemic
Authors: Santaolalla Aida , Beckmann Kerri , Kibaru Joyce , Josephs Debra , Van Hemelrijck Mieke , Irshad Sheeba
Published: November 2020

Objectives

To assess the association between vitamin D deficiency and increased morbidity/mortality with COVID-19 respiratory dysfunction.

Design

Scoping review.

Data Sources

Ovid MEDLINE (1946 to 24 of April 2020) and PubMed (2020 to 17 of September 2020).

Eligibility Criteria for Selecting Studies

A search using the search terms: [(cholecalciferol or ergocalciferol or vitamin D2 or vitamin D3 or vitamin D or 25OHD) and (SARS-CoV-2 or coronavirus or COVID or betacoronavirus or MERS-CoV or SARS-CoV or respiratory infection or acute respiratory distress syndrome or ARDS)]m.p. was conducted on the 24/04/2020 (Search A) and 17/09/2020 (Search B).

Results

91 studies were identified as being concerned with Acute Respiratory Infection (ARI)/Acute Respiratory Distress Syndrome (ARDS) and vitamin D, and 25 publications specifically explored the role of vitamin D deficiency in the development and progression of SARS-CoV-2/COVID-19 related ARDS. Search “A” identified three main themes of indirect evidence supporting such an association. Consistent epidemiological evidence exists linking low vitamin D levels to increased risk and severity of respiratory tract infections. We also report on plausible biological processes supporting such an association; and present weaker evidence supporting the benefit of vitamin D supplementation in reducing the risk and severity of ARIs. Uncertainty remains about what constitutes an appropriate dosing regimen in relation to reducing risk/severity of ARI/ARDS. More recent evidence (Search B) provided new insights into some direct links between vitamin D and COVID-19; with a number of cohort and ecological studies supporting an association with PCR-positivity for SARS-CoV-2 and vitamin D deficiency. The exact efficacy of the vitamin D supplementation for prevention of, or as an adjunct treatment for COVID-19 remains to be determined; but a number of randomized control trials (RCTs) currently underway are actively investigating these potential benefits.

Conclusion

Our rapid review of literature supports the need for observational studies with COVID-19 infected populations to measure and assess vitamin D levels in relation to risk/severity and outcomes; alongside RCTs designed to evaluate the efficacy of supplementation both in preventive and therapeutic contexts. The overlap in the vitamin D associated biological pathways with the dysregulation reported to drive COVID-19 outcomes warrants further investigation.
Protocol for a Case-Control Study to Investigate the Association of Pellagra With Isoniazid Exposure During Tuberculosis Preventive Treatment Scale-Up in Malawi
Authors: Nabity Scott A. , Mponda Kelvin , Gutreuter Steve , Surie Diya , Williams Anne , Sharma Andrea J. , Schnaubelt Elizabeth R. , Marshall Rebekah E. , Kirking Hannah L. , Zimba Suzgo B. , Sunguti Joram L. , Chisuwo Laphiod , Chiwaula Mabvuto J. , Gregory Jesse F. , da Silva Robin , Odo Michael , Jahn Andreas , Kalua Thokozani , Nyirenda Rose , Girma Belaineh , Mpunga James , Buono Nicole , Maida Alice , Kim Evelyn J. , Gunde Laurence J. , Mekonnen Tigest F. , Auld Andrew F. , Muula Adamson S. , Oeltmann John E.
Published: November 2020

Background:Pellagra is caused by niacin (vitamin B3) deficiency and manifested by a distinctive dermatitis. Isoniazid is critical for treating tuberculosis globally and is a component of most regimens to prevent tuberculosis. Isoniazid may contribute to pellagra by disrupting intracellular niacin synthesis. In 2017, Malawian clinicians recognized a high incidence of pellagra-like rashes after scale-up of isoniazid preventive treatment (IPT) to people living with HIV (PLHIV). This increase in pellagra incidence among PLHIV coincided with a seasonal period of sustained food insecurity in the region, which obscured epidemiological interpretations. Although isoniazid has been implicated as a secondary cause of pellagra for decades, no hypothesis-driven epidemiological study has assessed this relationship in a population exposed to isoniazid. We developed this case-control protocol to assess the association between large-scale isoniazid distribution and pellagra in Malawi.

Methods:We measure the relative odds of having pellagra among isoniazid-exposed people compared to those without exposure while controlling for other pellagra risk factors. Secondary aims include measuring time from isoniazid initiation to onset of dermatitis, comparing niacin metabolites 1-methylnicotinamide (1-MN), and l-methyl-2-pyridone-5-carboxamide (2-PYR) in urine as a proxy for total body niacin status among subpopulations, and describing clinical outcomes after 30-days multi-B vitamin (containing 300 mg nicotinamide daily) therapy and isoniazid cessation (if exposed). We aim to enroll 197 participants with pellagra and 788 age- and sex-matched controls (1:4 ratio) presenting at three dermatology clinics. Four randomly selected community clinics within 3–25 km of designated dermatology clinics will refer persons with pellagra-like symptoms to one of the study enrollment sites for diagnosis. Trained study dermatologists will conduct a detailed exposure questionnaire and perform anthropometric measurements. A subset of enrollees will provide a casual urine specimen for niacin metabolites quantification and/or point-of-care isoniazid detection to confirm whether participants recently ingested isoniazid. We will use conditional logistic regression, matching age and sex, to estimate odds ratios for the primary study aim.

Discussion:The results of this study will inform the programmatic scale-up of isoniazid-containing regimens to prevent tuberculosis.
The Economic Burden of Clostridioides difficile in Denmark: A Retrospective Cohort Study
Authors: Braae Uffe Christian , Møller Frederik Trier , Ibsen Rikke , Ethelberg Steen , Kjellberg Jakob , Mølbak Kåre
Published: November 2020

Objectives: The aim of this study was to make a comprehensive economic assessment of the costs of hospital-acquired C. difficile infections (CDI).

Methods: We carried out a retrospective matched cohort study utilizing Danish registry data with national coverage to identify CDI cases and matched reference patients without CDI (controls) for economic burden assessment in Denmark covering 2011–2014. Health care costs and public transfer costs were obtained from national registries, and calculated for 1 year prior to, and 2 years after index admission using descriptive statistics and regression analysis.

Results: The study included 12,768 CDI patients and 23,272 matched controls. The total health care cost was significantly larger for CDI cases than controls throughout all periods. During the index admission period, cost was €12,867 per CDI case compared to €4,522 (p < 0.001) for controls, which increased to an average of €31,388 and €19,512 (p < 0.001) in Year 1 for the two groups, respectively. Excess costs were found both among infections with onset in hospitals and in the community. Diagnosis compatible with complications increased costs to on average >€91,000 per case. The regression analysis showed that CDI adds a substantial economic burden, but only explains about 1/3 of the crude difference observed in the matched analysis.

Discussion: The major economic impact of hospital-acquired CDI with complications underlines the importance of preventing complications in these patients. Our study provides an informed estimate of the potential economic gain per patient by successful intervention, which is likely to be relatively comparable across countries.
Management and Prevention Strategies for Non-communicable Diseases (NCDs) and Their Risk Factors
Authors: Budreviciute Aida , Damiati Samar , Sabir Dana Khdr , Onder Kamil , Schuller-Goetzburg Peter , Plakys Gediminas , Katileviciute Agne , Khoja Samir , Kodzius Rimantas
Published: November 2020

Non-communicable diseases (NCDs) are of increasing concern for society and national governments, as well as globally due to their high mortality rate. The main risk factors of NCDs can be classified into the categories of self-management, genetic factors, environmental factors, factors of medical conditions, and socio-demographic factors. The main focus is on the elements of self-management and to reach a consensus about the influence of food on risk management and actions toward the prevention of NCDs at all stages of life. Nutrition interventions are essential in managing the risk of NCDs. As they are of the utmost importance, this review highlights NCDs and their risk factors and outlines several common prevention strategies. We foresee that the best prevention management strategy will include individual (lifestyle management), societal (awareness management), national (health policy decisions), and global (health strategy) elements, with target actions, such as multi-sectoral partnership, knowledge and information management, and innovations. The most effective preventative strategy is the one that leads to changes in lifestyle with respect to diet, physical activities, cessation of smoking, and the control of metabolic disorders.
Spatial Correlations Don't Predict Changes in Agricultural Ecosystem Services: A Canada-Wide Case Study
Authors: Mitchell Matthew G. E. , Chan Kai M. A. , Newlands Nathaniel K. , Ramankutty Navin
Published: November 2020

Improving the management of multiple ecosystem services (e.g., food provision, water and air quality regulation, carbon storage, and erosion control) in agricultural landscapes is a critical challenge to improve food system sustainability. However, we currently lack spatially-resolved national-level assessments of the relationships among services in agricultural landscapes over time. This limits our ability to make decisions and predict how environmental changes or agricultural management actions will impact multiple services. How do multiple ecosystem services vary across both space and time, at regional-to-national scales? To address this question, we quantified eight indicators of four ecosystem services across 290 Canadian agricultural landscapes in 1996, 2001, and 2006. We observed consistent correlations between pairs of services across the 290 ecodistricts in each of the 3 years of our study. In particular, ecodistricts with high livestock production had low provision of most regulating services, while ecodistricts with high air quality (ammonia retention) also had high soil and water quality regulation services. However, these ‘snapshot’ correlations poorly predicted how pairs of services changed through time. Ecosystem service change from 1996–2001 to 2001–2006 (as measured by pairwise correlations) showed markedly different patterns than snapshot correlations. In particular, where livestock production increased between years, so did most regulating services. Ecosystem service bundles also showed similar divergent patterns. The distribution of ecosystem service “snapshot” bundles—sets of ecodistricts with similar levels of provision across multiple ecosystem services in a single year—was generally stable between 1996 and 2006; only 15% of ecodistricts changed bundle types in this time period. However, ecosystem service “change” bundles—sets of ecodistricts with similar changes in ecosystem service provision through time—were much more dynamic. Nearly 60% of ecodistricts exhibited a different set of ecosystem service changes from 2001 to 2006 compared to 1996 to 2001. Our results add to the growing evidence that relationships between services across space do not necessarily predict service change through time. Improved understanding of the spatial patterns and temporal dynamics of ecosystem services, and better understanding of underlying processes, is crucial to improve agricultural landscape management for multifunctionality and sustainability.
Developing a Hernia Mesh Tissue Integration Index Using a Porcine Model—A Pilot Study
Authors: Patiniott Paul , Stagg Brendan , Karatassas Alex , Maddern Guy
Published: November 2020

Introduction: With so many prosthetics available, it can be difficult for surgeons to choose the most appropriate hernia mesh. Successful hernia repair mandates an understanding of how the patient's inflammatory response influences surgical outcomes. Failure to appreciate the importance of the biological aspect of hernia repair can be very costly as emerging evidence supports that biofilm formation and reduction in effective mesh porosity gives rise to long-term mesh complications including fibrosis, chronic mesh infection, and pain. In this pilot study, we utilized a large animal (porcine) model to develop a numerical Mesh Tissue Integration (MTI) Index focused on visible tissue ingrowth, fibrosis, adhesion formation and resorption of mesh. The aim is to help surgeons adopt an evidence-based approach in selecting the most appropriate mesh according to its tissue ingrowth characteristics, matched to the patient to achieve improved surgical outcomes and optimal patient-centered care.

Methods: Two forty kg female Landrace pigs were recruited for this pilot study. A total of eight commonly used hernia mesh products and two controls measuring 5 × 5cm were surgically implanted in subrectus and intraperitoneal planes. The pigs were euthanised at 2 and 4 weeks, respectively. The abdominal wall was explanted, and the mesh specimens underwent macroscopic, histologic and biomechanical analysis, with engineering and pathology teams blinded to the mesh.

Results: Significant differences between the degrees of MTI were observed at 2 weeks and the distinctions were even more apparent at 4 weeks. One of the interesting incidental findings we observed is that mesh products placed in the subrectus plane displayed greater degrees of adhesion strength and integration than those placed intraperitoneally.

Conclusion: This pilot study is one of the first to propose a functional, biological standardized model for comparing hernia mesh products. The results are encouraging and demonstrate that this is a robust and transferrable model for assessing MTI in hernia mesh. The intention for this model is that it will be utilized synergistically with long term mesh/patient outcome registries and databases to inform improved matching of mesh to patient, particularly in the setting of the complex hernia repair and abdominal wall reconstruction.
Macrophage Activation in the Synovium of Healthy and Osteoarthritic Equine Joints
Authors: Menarim Bruno C. , Gillis Kiersten H. , Oliver Andrea , Ngo Ying , Werre Stephen R. , Barrett Sarah H. , Rodgerson Dwayne H. , Dahlgren Linda A.
Published: November 2020

Synovitis is a major component of osteoarthritis and is driven primarily by macrophages. Synovial macrophages are crucial for joint homeostasis (M2-like phenotype), but induce inflammation (M1-like) when regulatory functions become overwhelmed. Macrophage phenotypes in synovium from osteoarthritic and healthy joints are poorly characterized; however, comparative knowledge of their phenotypes during health and disease is paramount for developing targeted treatments. This study compared patterns of macrophage activation in healthy and osteoarthritic equine synovium and correlated histology with cytokine/chemokine profiles in synovial fluid. Synovial histology and immunohistochemistry for M1-like (CD86), M2-like (CD206, IL-10), and pan macrophage (CD14) markers were performed on biopsies from 29 healthy and 26 osteoarthritic equine joints. Synovial fluid cytokines (MCP-1, IL-10, PGE2, IL-1β, IL-6, TNF-α, IL-1ra) and growth factors (GM-CSF, SDF-1α+β, IGF-1, and FGF-2) were quantified. Macrophage phenotypes were not as clearly definedin vivoas they arein vitro. All macrophage markers were expressed with minimal differences between OA and normal joints. Expression for all markers increased proportionate to synovial inflammation, especially CD86. Synovial fluid MCP-1 was higher in osteoarthritic joints while SDF-1 and IL-10 were lower, and PGE2concentrations did not differ between groups. Increased CD14/CD86/CD206/IL-10 expression was associated with synovial hyperplasia, consistent with macrophage recruitment and activation in response to injury. Lower synovial fluid IL-10 could suggest that homeostatic mechanisms from synovial macrophages became overwhelmed preventing inflammation resolution, resulting in chronic inflammation and OA. Further investigations into mechanisms of arthritis resolution are warranted. Developing pro-resolving therapies may provide superior results in the treatment of OA.
Fault Tolerant Control of Vehicle Lateral Dynamic Using a New Pneumatic Forces Multiple Model
Authors: Abzi Imane , Kabbaj Mohammed Nabil , Benbrahim Mohammed
Published: November 2020

This paper presents a new accurate multiple model of nonlinear pneumatic lateral forces. The bicycle representation is used in order to build up an easy implemented vehicle dynamic model. Moreover, the Takagi–Sugeno fuzzy approach is applied in order to handle the vehicle model nonlinearities. This structure allows for taking into account the small variation of the vehicle longitudinal velocity. Subsequently, a Fault Tolerant Control strategy that is based on a bank of fuzzy Luenberger observers is proposed. The robustness of the control scheme against external noises is guaranteed by applying H∞ performance. Sufficient stability conditions that are based on Lyapunov method are formulated as Linear Matrix Inequality. Thus, allowing the computation of the observers’ and the controllers’ gains by using MATLAB. Finally, the simulation examples are performed to show the effectiveness of our proposal.
Effects of Thinner Compliant Electrodes on Self-Clearability of Dielectric Elastomer Actuators
Authors: Lau Gih-Keong , Shiau Li-Lynn , Chua Soo-Lim
Published: November 2020

A metalized plastic capacitor stands a higher chance to clear faults when embodied with thinner electrodes. However, it is not clear whether the same thickness effect applies to carbon-based compliant electrodes in clearing the defects in dielectric elastomer actuators (DEA). This experimental study showed that charcoal-powder compliant electrodes act like fuses and current limiters to successfully clear the defects of an acrylic dielectric elastomer actuator, provided a very thin electrode coating. For example, DEAs with 3 μm thick (average) charcoal-powder electrodes fast cleared faults and sustained high breakdown strength (300 to 400 MV/m), but the ones with thicker charcoal-powder electrodes (30 μm thick on average) succumbed to persisting breakdowns in a weaker electric field (200 to 300 MV/m). Thermo-gravitational analysis and differential scanning calorimetry showed that dielectric elastomer (3M VHB F9473PC) started to ignite at 350 ∘C, and charcoal powders (Mungyo charcoal pastel MP-12CP) started burning above 450 ∘C. This confirmed that flash ignition and its damping of charcoal powder is possible only with a very thin electrode coating relative to acrylic elastomer substrate thickness. Too thick of a charcoal-powder coating could lead to the spread of burning beyond the initial flash point, and incomplete burning that punctures the dielectric layer but shorts across opposite electrodes. With this insight, one can design self-clearable electrodes to improve the dielectric strength of dielectric elastomer actuators.
Antimicrobial Secretions of Toads (Anura, Bufonidae): Bioactive Extracts and Isolated Compounds against Human Pathogens
Authors: Rodriguez Candelario , Ibáñez Roberto , Rollins-Smith Louise A. , Gutiérrez Marcelino , Durant-Archibold Armando A.
Published: November 2020

Species of the family Bufonidae, better known as true toads, are widespread and produce bioactive substances in the secretions obtained from specialized skin macroglands. Some true toads have been employed as a folk remedy to treat infectious diseases caused by microbial pathogens. Recent publications based on in silico analysis highlighted the Bufonidae as promising sources of antimicrobial peptides. A review of the literature reveals that Bufonidae skin secretion extracts show inhibitory activity in vitro against clinical isolates of bacteria, resistant and standard strains of bacterial, and fungal and parasitic human pathogens. Secondary metabolites belonging to the classes of alkaloids, bufadienolides, and peptides with antimicrobial activity have been isolated from species of the genera Bufo, Bufotes, Duttaphrynus, and Rhinella. Additionally, some antimicrobial extracts and purified compounds display low cytotoxicity against mammal cells.
Phaseolus vulgaris L. var. Venanzio Grown in Tuscany: Chemical Composition and In Vitro Investigation of Potential Effects on Colorectal Cancer
Authors: Finetti Federica , Biagi Marco , Ercoli Jasmine , Macrì Giulia , Miraldi Elisabetta , Trabalzini Lorenza
Published: November 2020

Phaseolus vulgaris L. (common bean) is a leguminous species that is an important dietary component due to its high content of proteins, unsaturated fatty acids, minerals, dietary fibers and vitamins. Due to the high content of polyphenols, several biological activities have been described for bean extracts, making it possible to include P. vulgaris among food with beneficial effects for human health. Moreover, more than 40,000 varieties of beans have been recognised with different nutraceutical properties, pointing out the importance of food biodiversity. In this work, we describe for the first time the chemical composition and biological activity of a newly recognized Italian variety of P. vulgaris grown in a restricted area of the Tuscany region and named “Fagiola di Venanzio”. Fagiola di Venanzio water extract is rich in proteins, sugars and polyphenols and displays antioxidant, anti-inflammatory and antiproliferative activities in in vitro assays on colon cancer cellular models. Our data indicate that this variety of P. vulgaris appears to be a promising source of bioactive compounds and encourage more in-depth studies to better elucidate the implications of its consumption for public health.
Screening of Antibacterial Activity, Antioxidant Activity, and Anticancer Activity of Euphorbia hirta Linn. Extracts
Authors: Tran Ngan , Nguyen Minh , Le Khanh PB , Nguyen Nhi , Tran Quan , Le Ly
Published: November 2020

This study aimed to screen the anticancer and antioxidant potential and antimicrobial activity of methanol, petroleum ether, chloroform, ethyl acetate, butanol of Euphorbia hirta Linn. extracts (EH-Me, EH-PE, EH-Ch, EH-EA and EH-Bu, respectively). The results of 2,2-diphenyl-1-pycrylhydrazyl (DPPH) radical scavenging assay and lipid peroxidation inhibition assay showed that EH-EA was the strongest antioxidant (IC50 = 10.33 ± 0.01 µg/mL; IC50 = 1.48 ± 0.12 µg/mL, respectively) compared to all other extracts. In the antimicrobial activity of the extracts against eight strains of Gram-positive and Gram-negative bacteria using the agar disc diffusion method, we found the EH-EA to be the best antimicrobial agent. Anticancer activities of those extracts were examined by sulforhodamine B (SRB) in vitro cytotoxicity assay on two cancer cell lines, including lung cancer cells NCI-H460 and liver cancer cells Hep G2. EH-EA at concentration of 100 μg/mL has significant inhibitory activity the growth of lung cancer cells NCI-H460 and liver cancer cells Hep G2 compared to all other extracts. Our results suggest that E. hirta Linn. extracts possess significant biological activities, including antimicrobial, antioxidant, and moderate anticancer properties. Our results show that this plant could be a good source for natural antioxidants and a possible pharmaceutical supplement. Among five analyzed extracts, EH-EA extract has the strongest activities, and should be used to determine phytochemicals and mechanisms of these activities.
System Studies on the Fusion-Fission Hybrid Systems and Its Fuel Cycle
Authors: Shlenskii Mikhail , Kuteev Boris
Published: November 2020

This paper is devoted to applications of fusion-fission hybrid systems (FFHS) as a powerful neutron source implementing transmutation of minor actinides (MA: Np, Am, Cm) extracted from the spent nuclear fuel (SNF) of nuclear reactors. Calculations which simulated nuclide kinetics for the metallic fuel containing MA and neutron transport were performed for particular facilities. Three FFHS with fusion power equal to 40 MW are considered in this study: demo, pilot-industrial and industrial reactors. In addition, needs for a fleet of such reactors are assessed as well as future FFHSs’ impact on Russian Nuclear Power System. A system analysis of nuclear energy development in Russia was also performed with the participation of the FFHSs, with the help of the model created at AO “Proryv”. The quantity of MA that would be produced and transmuted in this scenario is estimated. This research shows that by the means of only one hybrid facility it is possible to reduce by 2130 the mass of MA in the Russian power system by about 28%. In the case of the absence of partitioning and transmutation of MA from SNF, 287 t of MA will accumulate in the Russian power system by 2130.
Evolutionary Design Optimization of an Alkaline Water Electrolysis Cell for Hydrogen Production
Authors: Le Bideau Damien , Chocron Olivier , Mandin Philippe , Kiener Patrice , Benbouzid Mohamed , Sellier Mathieu , Kim Myeongsub , Ganci Fabrizio , Inguanta Rosalinda
Published: November 2020

Hydrogen is an excellent energy source for long-term storage and free of greenhouse gases. However, its high production cost remains an obstacle to its advancement. The two main parameters contributing to the high cost include the cost of electricity and the cost of initial financial investment. It is possible to reduce the latter by the optimization of system design and operation conditions, allowing the reduction of the cell voltage. Because the CAPEX (initial cost divided by total hydrogen production of the electrolyzer) decreases according to current density but the OPEX (operating cost depending on the cell voltage) increases depending on the current density, there exists an optimal current density. In this paper, a genetic algorithm has been developed to find the optimal evolution parameters and to determine an optimum electrolyzer design. The optimal current density has been increased by 10% and the hydrogen cost has been decreased by 1%.