bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological Insights Into Safety and Efficacy Determinants for the Development of Adenosine Receptor Biased Agonists in the Treatment of Heart Failure
Authors: Rueda Patricia , Merlin Jon , Chimenti Stefano , Feletou Michel , Paysant Jerome , White Paul J. , Christopoulos Arthur , Sexton Patrick M. , Summers Roger J. , Charman William N. , May Lauren T. , Langmead Christopher J.
Published: March 2021

Adenosine A1 receptors (A1R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been hampered by on-target side effects such as bradycardia and altered renal hemodynamics. Biased agonism has emerged as an attractive mechanism for A1R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A1R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterized, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A1R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca2+ influx relative to NECA and the cAMP pathway at the A1R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A1R. In contrast to VCP746, which displays more ‘adenosine-like’ signaling at the A2BR, neladenoson was a highly selective A1R agonist, with biased, weak agonism at the A2BR. Together these results show that unwanted hemodynamic effects of A1R agonists can be avoided by compounds biased away from Ca2+ influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A1R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients.
Targeting Macrophage Migration Inhibitory Factor in Acute Pancreatitis and Pancreatic Cancer
Authors: Wen Yongjian , Cai Wenhao , Yang Jingyu , Fu Xianghui , Putha Lohitha , Xia Qing , Windsor John A. , Phillips Anthony R. , Tyndall Joel D. A. , Du Dan , Liu Tingting , Huang Wei
Published: March 2021

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine response. Intracellular MIF is involved in Toll-like receptor and inflammasome-mediated inflammatory response. Pharmacological inhibition of MIF has been shown to hold great promise in treating inflammatory diseases and cancer, including small molecule MIF inhibitors targeting the tautomerase active site of MIF and antibodies that neutralize MIF. In the current review, we discuss the role of MIF signaling pathways in inflammation and cancer and summarize the recent advances of the role of MIF in experimental and clinical exocrine pancreatic diseases. We expect to provide insights into clinical translation of MIF antagonism as a strategy for treating acute pancreatitis and pancreatic cancer.
Fluid Meniscus Algorithms for Dynamic Pore-Network Modeling of Immiscible Two-Phase Flow in Porous Media
Authors: Sinha Santanu , Gjennestad Magnus Aa. , Vassvik Morten , Hansen Alex
Published: March 2021

We present in detail a set of algorithms for a dynamic pore-network model of immiscible two-phase flow in porous media to carry out fluid displacements in pores. The algorithms are universal for regular and irregular pore networks in two or three dimensions and can be applied to simulate both drainage displacements and steady-state flow. They execute the mixing of incoming fluids at the network nodes, then distribute them to the outgoing links and perform the coalescence of bubbles. Implementing these algorithms in a dynamic pore-network model, we reproduce some of the fundamental results of transient and steady-state two-phase flow in porous media. For drainage displacements, we show that the model can reproduce the flow patterns corresponding to viscous fingering, capillary fingering and stable displacement by varying the capillary number and viscosity ratio. For steady-state flow, we verify non-linear rheological properties and transition to linear Darcy behavior while increasing the flow rate. Finally we verify the relations between seepage velocities of two-phase flow in porous media considering both disordered regular networks and irregular networks reconstructed from real samples.
Disturbed Blood Flow Acutely Increases Endothelial Microparticles and Decreases Flow Mediated Dilation in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Silva Thiago O. C. , Sales Allan R. K. , Araujo Gustavo S. M. , Fonseca Guilherme W. P. , Braga Pedro G. S. , Faria Diego , Rocha Helena N. M. , Rocha Natalia G. , Lima Marta F. , Mady Charles , Negrão Carlos E. , Alves Maria Janieire N. N.
Published: March 2021

Introduction

Disturbed blood flow, characterized by high retrograde and oscillatory shear rate (SR), is associated with a proatherogenic phenotype. The impact of disturbed blood flow in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown. We tested the hypothesis that acute elevation to retrograde and oscillatory SR provoked by local circulatory occlusion would increase endothelial microparticles (EMPs) and decrease brachial artery flow-mediated dilation (FMD) in patients with HFrEF.

Methods

Eighteen patients with HFrEF aged 55 ± 2 years, with left ventricular ejection fraction (LVEF) 26 ± 1%, and 14 control subjects aged 49 ± 2 years with LVEF 65 ± 1 randomly underwent experimental and control sessions. Brachial artery FMD (Doppler) was evaluated before and after 30 min of disturbed forearm blood flow provoked by pneumatic cuff (Hokanson) inflation to 75 mm Hg. Venous blood samples were collected at rest, after 15 and 30 min of disturbed blood flow to assess circulating EMP levels (CD42b−/CD31+; flow cytometry).

Results

At rest, FMD was lower in patients with HFrEF compared with control subjects (P < 0.001), but blood flow patterns and EMPs had no differences (P > 0.05). The cuff inflation provoked a greater retrograde SR both groups (P < 0.0001). EMPs responses to disturbed blood flow significantly increased in patients with HFrEF (P = 0.03). No changes in EMPs were found in control subjects (P > 0.05). Disturbed blood flow decreased FMD both groups. No changes occurred in control condition.

Conclusion

Collectively, our findings suggest that disturbed blood flow acutely decreases FMD and increases EMP levels in patients with HFrEF, which may indicate that this set of patients are vulnerable to blood flow disturbances.
Differential Morphophysiological and Biochemical Responses of Cotton Genotypes Under Various Salinity Stress Levels During Early Growth Stage
Authors: Munawar Wajeeha , Hameed Amjad , Khan Muhammad Khashif Riaz
Published: March 2021

Cotton is a primary agriculture product important for fiber use in textiles and the second major oil seed crop. Cotton is considered as moderately tolerant to salt stress with salinity threshold of 7.7 dS/m at seedling stage. Salinity causes reduction in the growth of seedlings and cotton production that limits fiber quality and cotton yield. In this study, initially, 22 cotton genotypes were screened for relative salt tolerance using germination test in Petri plates (growth chamber). Selected 11 genotypes were further tested in pot experiment (sand) with 0, 15, and 20 dS/m NaCl treatments under glass house conditions. At four-leaves stage, different morphological and physiological traits were measured for all genotypes while biochemical analysis was performed on selected seven highly tolerant and sensitive genotypes. NaCl treatment significantly reduced plant biomass in two genotypes IR-NIBGE-13 and BS-2018, while NIAB-135, NIAB-512, and GH-HADI had least difference in fresh weight between the control and NaCl-treated plants. Photosynthetic rate was maintained in all the genotypes with the exception of SITARA-16. In two sensitive genotypes (IR-NIBGE-13 and 6071/16), Na+ ion accumulated more in leaves as compared to K+ ion under stress conditions, and an increase in Na+/K+ ratio was also observed. The lesser accumulation of malondialdehyde (MDA) content and higher activity of enzymatic antioxidants such as superoxide dismutase (SOD), peroxidase (POD), and ascorbate peroxidase (APX) in stressed plants of NIAB-135, NIAB-512, and FH-152 indicated that these genotypes had adaption capacity for salinity stress in comparison with sensitive genotypes, i.e., IR-NIBGE-13 and 6071/16. The observed salt tolerance was corelated with plant biomass maintenance (morphological), photosynthetic rate, and ionic homeostasis (K+/Na+ ratio, physiological) and biochemical stress marker regulations. After a series of experiments, it was concluded that NIAB-135, NIAB-512, and FH-152 could be utilized in breeding programs aimed at improving salinity tolerance in cotton and can expand cotton cultivation in saline area.
Identification of Candidate Genes Conferring Cold Tolerance to Rice (Oryza sativa L.) at the Bud-Bursting Stage Using Bulk Segregant Analysis Sequencing and Linkage Mapping
Authors: Yang Luomiao , Lei Lei , Li Peng , Wang Jingguo , Wang Chao , Yang Fan , Chen Jiahui , Liu HuaLong , Zheng Hongliang , Xin Wei , Zou Detang
Published: March 2021

Low-temperature tolerance during the bud-bursting stage is an important characteristic of direct-seeded rice. The identification of cold-tolerance quantitative trait loci (QTL) in species that can stably tolerate cold environments is crucial for the molecular breeding of rice with such traits. In our study, high-throughput QTL-sequencing analyses were performed in a 460-individual F2:3 mapping population to identify the major QTL genomic regions governing cold tolerance at the bud-bursting (CTBB) stage in rice. A novel major QTL, qCTBB9, which controls seed survival rate (SR) under low-temperature conditions of 5°C/9 days, was mapped on the 5.40-Mb interval on chromosome 9. Twenty-six non-synonymous single-nucleotide polymorphism (nSNP) markers were designed for the qCTBB9 region based on re-sequencing data and local QTL mapping conducted using traditional linkage analysis. We mapped qCTBB9 to a 483.87-kb region containing 58 annotated genes, among which six predicted genes contained nine nSNP loci. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis revealed that only Os09g0444200 was strongly induced by cold stress. Haplotype analysis further confirmed that the SNP 1,654,225 bp in the Os09g0444200 coding region plays a key role in regulating the cold tolerance of rice. These results suggest that Os09g0444200 is a potential candidate for qCTBB9. Our results are of great significance to explore the genetic mechanism of rice CTBB and to improve the cold tolerance of rice varieties by marker-assisted selection.
“What If We Get Sick?”: Spanish Adaptation and Validation of the Fear of Illness and Virus Evaluation Scale in a Non-clinical Sample Exposed to the COVID-19 Pandemic
Authors: Cottin Marianne , Hernández Cristóbal , Núñez Catalina , Labbé Nicolás , Quevedo Yamil , Davanzo Antonella , Behn Alex
Published: March 2021

Distinct sources of stress have emerged during the COVID-19 pandemic. Particularly, fear is expected to generate significant psychological burden on individuals and influence on either unsafe behavior that may hinder recovery efforts or virus-mitigating behaviors. However, little is known about the properties of measures to capture them in research and clinical settings. To resolve this gap, we evaluated the psychometric properties of a novel measure of fear of illness and viruses and tested its predictive value for future development of distress. We extracted a random sample of 450 Chilean adult participants from a large cross-sectional survey panel and invited to participate in this intensive longitudinal study for 35 days. Of these, 163 ended up enrolling in the study after the demanding nature of the measurement schedule was clearly explained to them. For this final sample, we calculated different Confirmatory Factor Analyses (CFA) to evaluate the preliminary proposed structure for the instrument. Complementarily, we conducted a content analysis of the items to qualitatively extract its latent structure, which was also subject to empirical test via CFA. Results indicated that the original structure did not fit the data well; however, the new proposed structure based on the content analysis did. Overall, the modified instrument showed good reliability through all subscales both by its internal consistency with Cronbach’s alphas ranging from 0.814 to 0.913, and with test–retest correlations ranging from 0.715 to 0.804. Regarding its convergent validity, individuals who scored higher in fears tended to also score higher in depressive and posttraumatic stress symptoms at baseline. Furthermore, higher fears at baseline predicted a higher score in posttraumatic stress symptomatology 7 days later. These results provide evidence for the validity, reliability, and predictive performance of the scale. As the scale is free and multidimensional potentially not circumscribed to COVID-19, it might work as a step toward understanding the psychological impact of current and future pandemics, or further life-threatening health situations of similar characteristics. Limitations, practical implications, and future directions for research are discussed.
Mental Capacity, Decision-Making and Emotion Dysregulation in Severe Enduring Anorexia Nervosa
Authors: van Elburg Annemarie , Danner Unna Nora , Sternheim Lot Catharina , Lammers Mirjam , Elzakkers Isis
Published: March 2021

Severe and Enduring Anorexia Nervosa (SE-AN) is a chronic eating disorder characterized by long-term starvation and its physical and psychological sequelae, and severe loss of quality of life. Interactions between neurobiological changes caused by starvation, vulnerability (personality) traits, and eating behaviors play a role. Several other factors, such as increased fear and decreased social cognition, have also been found in relation to SE-AN. With this in mind, we aim to add to the understanding of SE-AN by introducing the concept of mental capacity (MC), which refers to the ability to understand and process information—both on a cognitive and an emotional level—and then make a well-informed choice. MC may be an important construct within the context of SE-AN. Furthermore, we will argue how impaired decision-making processes may underlie, fuel, or contribute to limited MC in SE-AN. We will speculate on the importance of dysfunctional emotion processing and anxiety-related processes (e.g., a high intolerance of uncertainty) and their potential interaction with decision-making. Lastly, we will propose how these aspects, which to our knowledge have previously received little attention, may advise research and treatment or help in dealing with the “want but cannot” situation of life-threatening AN.
REFOCUS-PULSAR Recovery-Oriented Practice Training in Adult Primary Mental Health Care: Exploratory Findings Including From a Pretest–Posttest Evaluation
Authors: Enticott Joanne C. , Shawyer Frances , Brophy Lisa Mary , Russell Grant , Mazza Danielle , Wilson-Evered Elisabeth , Weller Penelope June , Slade Mike , Edan Vrinda , Meadows Graham Nicholas
Published: March 2021

Objectives:Australian general practitioners (GPs) are pivotal in mental health care. The REFOCUS-PULSAR (Principles Unite Local Services Assisting Recovery) primary care study aimed to improve personal recovery outcomes in adults with mental health problems consulting GPs.

Design:Modified from an intended stepped-wedge cluster study, an exploratory (pre- and post-intervention) design employed cross-sectional surveys of patients consulting GPs.

Setting:Eighteen primary care sites (clusters) in Victoria, Australia in 2013–2017.

Participants:From 30 GPs recruited, 23 participated (76%), with 235 patient surveys returned from adults aged <75 years receiving mental health care.

Intervention:A co-delivered face-to-face training intervention for GPs in recovery-oriented practice (ROP), with personal recovery a key focus, used multimedia, mnemonics, and targeted interview schedules to encourage ROP—with availability of support sessions for 1 year.

Outcome Measures:Primary: the Questionnaire about the Process of Recovery full-scale score (outcome). Secondary: INSPIRE (experience), Warwick-Edinburgh Mental Well-being Scale (WEMWBS) and Kessler Psychological Distress Scale (K10) (outcomes). Other: General-practice-Users Perceived-need Inventory (experience).

Results:Small positive significant effects indicated primary-outcome post-intervention improvements [t-test (233) = −2.23,p= 0.01], also improvement in two secondary outcomes (WEMWBSt(233) = −2.12,p= 0.02 and K10t(233) = 2.44,p= 0.01). More patients post-intervention reported “no need” for further help from their GP; but in those reporting needs, there was greater unmet need for counseling.

Conclusions:ROP implementation, internationally influential in specialist mental health care, here is explored in primary care where it has had less attention. These exploratory findings suggest better patient outcomes followed introducing GPs to ROP in routine practice conditions. Higher unmet need for counseling post-intervention reported by patients might be a sign of limited supply despite ROP facilitating better identification of needs. Challenges in project implementation means that these findings carry risks of bias and flag the importance establishing research infrastructure in primary care.

Clinical Trial Registration:www.clinicaltrials.gov/, The Australian and New Zealand Clinical Trial Registry Identifier: ACTRN12614001312639.
Risk-Aware Model-Based Control
Authors: Yu Chen , Rosendo Andre
Published: March 2021

Model-Based Reinforcement Learning (MBRL) algorithms have been shown to have an advantage on data-efficiency, but often overshadowed by state-of-the-art model-free methods in performance, especially when facing high-dimensional and complex problems. In this work, a novel MBRL method is proposed, called Risk-Aware Model-Based Control (RAMCO). It combines uncertainty-aware deep dynamics models and the risk assessment technique Conditional Value at Risk (CVaR). This mechanism is appropriate for real-world application since it takes epistemic risk into consideration. In addition, we use a model-free solver to produce warm-up training data, and this setting improves the performance in low-dimensional environments and covers the shortage of MBRL’s nature in the high-dimensional scenarios. In comparison with other state-of-the-art reinforcement learning algorithms, we show that it produces superior results on a walking robot model. We also evaluate the method with an Eidos environment, which is a novel experimental method with multi-dimensional randomly initialized deep neural networks to measure the performance of any reinforcement learning algorithm, and the advantages of RAMCO are highlighted.
The Poor “Wealth” of Brazilian Football: How Poverty May Shape Skill and Expertise of Players
Authors: Uehara Luiz , Falcous Mark , Button Chris , Davids Keith , Araújo Duarte , de Paula Adelgício Ribeiro , Saunders John
Published: March 2021

Worldwide, 1.3 billion people live inPoverty, a socio-economic status that has been identified as a key determinant of a lack of sports participation. Still, numerous athletes around the world have grown up in underprivileged socio-economic conditions. This is the case in Brazil, a country with around 13.5 million impoverished citizens, yet, over decades, many of its best professional footballers have emerged from its favelas. In this article, we explore the role of the socio-cultural-economic constraints in shaping the development of skill and expertise of Brazilian professional football players. The methodological and epistemological assumptions of the “Contextualized Skill Acquisition Research” (CSAR) approach are used as an underpinning framework for organizing and analyzing data. Results suggested that, at the exosystemic level of Brazilian society,Povertyemerges as an influential constraint that can potentially enrich football development experiences of Brazilian players.Poverty, however, is not thedirectcausation of outstanding football skill development. Rather, from the perspective of ecological dynamics,Povertycreates specific contexts that can lead to the emergence of physical as well as socio-cultural environment constraints (e.g.,Pelada, Malandragem) that can shape affordances (opportunities) for skill acquisition. These ideas suggest the need to ensure that environmental constraints can support people to amuse themselves cheaply, gain access to employment opportunities and maintain health and well-being through (unstructured and more structured) sport and physical activities in dense urban environments such as favelas, inner city areas, and banlieues. For this purpose, design of open play areas and even parkour installations can provide affordances landscapes for physical activity and sports participation in urban settings.
Effects of Lean Thinking and Emerging Technologies on Breast Cancer Patients' Therapeutic Process During COVID-19 Pandemic: A Case-Control Matched Study
Authors: Pellini Francesca , Di Filippo Giacomo , Mirandola Sara , Deguidi Giulia , Filippi Elisa , Pollini Giovanni Paolo
Published: March 2021

Introduction: The advent of the COVID-19 pandemic has led to the sudden disruption of routine medical care, and the subsequent reorganization of hospital structures and therapeutic algorithms, aiming at protecting patients and health professionals. This was inevitably bound to affect our Breast Unit, dilating both pre- and post-operative times. The aim of this study was to evaluate the effect on patients' flow of organizational and logistic changes (key interventions) based on lean thinking implemented after the COVID-19 outbreak.

Materials and Methods: Clinical and demographic data were retrospectively collected from patients undergoing sentinel lymph node biopsy for breast cancer at the Verona University Hospital from January 2018 to June 2020. Patients enrolled (n = 341) were divided into two groups according to date of admission: before (Group A; n = 294) and after (Group B; n = 47) the implementation of key interventions. Each case in Group B was subsequently matched 1:1 by means of case-control matching with cases from Group A for age, comorbidities, and type of surgery (Subgroup A1; N = 47). Pre-admission time (T0) and length of stay (T1) were compared between the three groups.

Results: Median T0 was 312 h, whereas median T1 was 24 h. Patients in Group B had a higher frequency of comorbidities (57.4 vs. 25.2%, p = 0.001) and underwent mastectomy more often than patients in Group A (61.7 vs. 36.7%, p = 0.001). Both median T0 and T1 were higher in group B than in group A (384 vs. 300 h, p = 0.001, 48 vs. 24 h, p = 0.001, respectively). Median T0 and T1 did not significantly differ between Group B and Subgroup A1 (all p > 0.05).

Conclusions: Lean thinking and new technologies could prove useful to the optimization of preoperative and postoperative times during the current pandemic, minimizing healthcare personnel and patients' exposure to SARS-CoV-2, and promoting a rational use of limited resources, while complying with oncological principles.
Operation State Identification Method for Converter Transformers Based on Vibration Detection Technology and Deep Belief Network Optimization Algorithm
Authors: Wu Yongye , Zhang Zhanlong , Xiao Rui , Jiang Peiyu , Dong Zijian , Deng Jun
Published: March 2021

The converter transformer is a special power transformer that connects the converter bridge to the AC system in the HVDC transmission system. Due to the special structure of the converter transformer, it is necessary to test its operation state during its manufacture and processing to ensure the safety of its future connection to the grid. Numerous studies have shown that vibration signals in transformers can reflect their operating state. Therefore, in order to achieve an effective identification of the operation state of the converter transformer, this paper proposes a method for identifying the operation state of the converter transformer based on vibration detection technology and a deep belief network optimization algorithm. This paper firstly describes the background, principle and application of vibration detection technology, using vibration measurement systems with piezoelectric acceleration sensors, piezoelectric actuators and data acquisition instruments to collect vibration signals at different measurement points on the converter transformer in states of no-load and on-load. By analyzing the time-frequency characteristics of the vibration signals, fast Fourier transform (FFT), wavelet packet decomposition (WPD) and time domain indexes (TDI) are combined into a fused feature extraction method to extract the eigenvalues of the vibration signals, so that the fused eigenvectors of the signals can be constructed. Considering the excellent performance of deep learning in classification, the deep belief network is used to classify the signals’ eigenvectors. To effectively improve the network classification efficiency, the sparrow search algorithm was introduced to build a mathematical model based on the behavioral characteristics of sparrow populations and combine the model with a deep belief network, so as to achieve adaptive parameter optimization of the network and accurate classification of the signals’ eigenvectors. The proposed method is applied to a 500 kV converter transformer for experimental verification. The experimental results show that the fused feature extraction method was able to fully extract the features of the vibration signal, and the deep belief network optimization algorithm had higher classification accuracy and better operational efficiency, and was able to effectively achieve accurate identification of the operation state of the converter transformer. In addition, the method achieved a precision response to the detection results of the vibration sensors, contributing to future improvements in converter transformer manufacturing technology.
Genome-Wide Identification of WRKY Gene Family and Expression Analysis under Abiotic Stress in Barley
Authors: Zheng Junjun , Zhang Ziling , Tong Tao , Fang Yunxia , Zhang Xian , Niu Chunyu , Li Jia , Wu Yuhuan , Xue Dawei , Zhang Xiaoqin
Published: March 2021

The WRKY gene family consists of transcription factors that are widely distributed in plants and play a key role in plant growth and development, secondary metabolite synthesis, biotic and abiotic stress responses, and other biological processes. In this study, 86 WRKY proteins were identified from the barley genome database using bioinformatics and were found to be distributed unevenly on seven chromosomes. According to the structure and phylogenetic relationships, the proteins could be classified into three groups and seven subgroups. The multiple sequence alignment results showed that WRKY domains had different conserved sites in different groups or subgroups, and some members had a special heptapeptide motif. Protein and gene structure analysis indicated that there were significant differences between the groups in terms of the distribution of WRKY motifs and the number of introns in barley. Tissue expression pattern analysis demonstrated that the transcription levels of most genes exhibited tissue and growth-stage specificity. In addition, the analysis of cis-elements in the promoter region revealed that almost all HvWRKYs had plant hormone or stress response cis-elements, and there were differences in the numbers between groups. Finally, the transcriptional levels of 15 HvWRKY genes under drought, cadmium, or salt stress were analyzed by quantitative real-time PCR. It was found that most of the gene expression levels responded to one or more abiotic stresses. These results provide a foundation for further analysis of the function of WRKY gene family members in abiotic stress.
Application of Plant Growth Promoting Microorganism and Plant Growth Regulators in Agricultural Production and Research
Authors: Khan Naeem
Published: March 2021

Plant growth-promoting microorganisms (PGPM) are rhizosphere microorganisms that colonize the root environment [...]
Pharmacokinetics of Meropenem in People with Cystic Fibrosis—A Proof of Concept Clinical Trial
Authors: Kamp Jan C. , Fuge Jan , Ringshausen Felix C. , Grote-Koska Denis , Brand Korbinian , Graalmann Lukas , Vonberg Ralf-Peter , Welte Tobias , Rademacher Jessica
Published: March 2021

Anti-infective treatment of pulmonary exacerbations is a major issue in people with cystic fibrosis (CF). Individualized dosing strategies and adaptation of infusion times are important concepts to optimize anti-infective therapy. In this prospective non-randomized controlled open-label trial, we compared pharmacokinetics of meropenem in 12 people with CF experiencing a pulmonary exacerbation, of whom six received parenteral meropenem 2 g tid as short infusion over 30 min and six extended infusion over 120 min. We measured blood concentrations of meropenem at five predetermined time points over 240 min and calculated differences in the percentages of the time above the minimal inhibitory concentration (fT > MIC) for meropenem concentrations >16 and >32 mg/L, respectively. Mean percentages of fT > 16 and fT > 32 mg/L were higher in the extended compared to the short infusion group (83 and 56% vs. 59% and 34%), with a statistically significant prolongation of the fT > 32 mg/L (mean 134 vs. 82 min; p = 0.037). Our results demonstrate that, in people with CF, longer fT > MIC can be achieved with a simple modification of meropenem dosing. Further studies are needed to clarify if this may translate into improved microbiological and clinical outcomes, in particular in adults with difficult-to-treat chronic infection by carbapenem-resistant Pseudomonas aeruginosa.
Design and Comprehensive Characterization of Tetramethylpyrazine (TMP) for Targeted Lung Delivery as Inhalation Aerosols in Pulmonary Hypertension (PH): In Vitro Human Lung Cell Culture and In Vivo Efficacy
Authors: Muralidharan Priya , Acosta Maria F. , Gomez Alexan I. , Grijalva Carissa , Tang Haiyang , Yuan Jason X.-J. , Mansour Heidi M.
Published: March 2021

This is the first study reporting on the design and development innovative inhaled formulations of the novel natural product antioxidant therapeutic, tetramethylpyrazine (TMP), also known as ligustrazine. TMP is obtained from Chinese herbs belonging to the class of Ligusticum. It is known to have antioxidant properties. It can act as a Nrf2/ARE activator and a Rho/ROCK inhibitor. The present study reports for the first time on the comprehensive characterization of raw TMP (non-spray dried) and spray dried TMP in a systematic manner using thermal analysis, electron microscopy, optical microscopy, and Raman spectroscopy. The in vitro aerosol dispersion performance of spray dried TMP was tested using three different FDA-approved unit-dose capsule-based human dry powder inhaler devices. In vitro human cellular studies were conducted on pulmonary cells from different regions of the human lung to examine the biocompatibility and non-cytotoxicity of TMP. Furthermore, the efficacy of inhaled TMP as both liquid and dry powder inhalation aerosols was tested in vivo using the monocrotaline (MCT)-induced PH rat model.
Experimental Assessment of RANS Models for Wind Load Estimation over Solar-Panel Arrays
Authors: Güemes Alejandro , Fajardo Pablo , Raiola Marco
Published: March 2021

This paper reports a comparison between wind-tunnel measurements and numerical simulations to assess the capabilities of Reynolds-Averaged Navier-Stokes models to estimate the wind load over solar-panel arrays. The free airstream impinging on solar-panel arrays creates a complex separated flow at large Reynolds number, which is severely challenging for the current Reynolds-Averaged Navier-Stokes models. The Reynolds-Averaged Navier-Stokes models compared in this article are k-ϵ, Shear-Stress Transport k-ω, transition and Reynolds Shear Model. Particle Image Velocimetry measurements are performed to investigate the mean flow-velocity and turbulent-kinetic-energy fields. Pressure taps are located in the surface of the solar panel model in order to obtain static pressure measurements. All the Reynolds-Averaged Navier-Stokes models predict accurate average velocity fields when compared with the experimental ones. One of the challenging factor is to predict correctly the thickness of the turbulent wake. In this aspect, Reynolds Shear provides the best results, reproducing the wake shrink observed on the 3rd panel in the experiment. On the other hand, some other features, most notably the blockage encountered by the flow below the panels, are not correctly reproduced by any of the models. The pressure distributions over the 1st panel obtained from the different Reynolds-Averaged Navier-Stokes models show good agreement with the pressure measurements. However, for the rest of the panels Reynolds-Averaged Navier-Stokes fidelity is severely challenged. Overall, the Reynolds Shear model provides the best pressure estimation in terms of pressure difference between the front and back sides of the panels.
A Decision Support System Based on BI-RADS and Radiomic Classifiers to Reduce False Positive Breast Calcifications at Digital Breast Tomosynthesis: A Preliminary Study
Authors: Alì Marco , D’Amico Natascha Claudia , Interlenghi Matteo , Maniglio Marina , Fazzini Deborah , Schiaffino Simone , Salvatore Christian , Castiglioni Isabella , Papa Sergio
Published: March 2021

Digital breast tomosynthesis (DBT) studies were introduced as a successful help for the detection of calcification, which can be a primary sign of cancer. Expert radiologists are able to detect suspicious calcifications in DBT, but a high number of calcifications with non-malignant diagnosis at biopsy have been reported (false positives, FP). In this study, a radiomic approach was developed and applied on DBT images with the aim to reduce the number of benign calcifications addressed to biopsy and to give the radiologists a helpful decision support system during their diagnostic activity. This allows personalizing patient management on the basis of personalized risk. For this purpose, 49 patients showing microcalcifications on DBT images were retrospectively included, classified by BI-RADS (Breast Imaging-Reporting and Data System) and analyzed. After segmentation of microcalcifications from DBT images, radiomic features were extracted. Features were then selected with respect to their stability within different segmentations and their repeatability in test–retest studies. Stable radiomic features were used to train, validate and test (nested 10-fold cross-validation) a preliminary machine learning radiomic classifier that, combined with BI-RADS classification, allowed a reduction in FP of a factor of 2 and an improvement in positive predictive value of 50%.
Cerebroprotective Effects of 2-Ethyl-6-methyl-3-hydroxypyridine-2,6-dichlorophenyl(amino)phenylethanoic Acid in the Treatment of Purulent Meningitis
Authors: Agarkova Alina , Pokrovskii Mikhail , Kolesnichenko Pavel , Gureev Vladimir , Gudyrev Oleg , Peresypkina Anna , Soldatov Vladislav , Nesterov Arkadii , Denisyuk Tatyana , Korokin Mikhail
Published: March 2021

Purulent meningitis (PM) is a severe disease, characterized by high mortality and a formation of a residual neurological deficit. Loss of treatment of PM leads to the lethal outcome in 100% of cases. In addition, death and the development of residual neurological complications are possible despite adequate therapy. The aim of the study was to evaluate the cerebroprotective effects of a new pharmacological compound 2-ethyl-6-methyl-3-hydroxypyridine-2,6-dichlorophenyl(amino)phenylethanoic acid (EMHDPA) on the bacterial purulent meningitis in a model of experimental pneumococcal meningitis. Meningitis was simulated by intrathecal injection of the suspension containing Streptococcus pneumoniae at the concentration of 5 × 109 CFU/mL. The cerebroprotective effect was evaluated by survival rates, the severity of neurological deficit, investigatory behaviors, and results of short-term and long-term memory tests. The group administered with EMHDPA showed high survival rates, 80%. Animals treated with the studied compound showed a higher clinical assessment of the rat health status and specific force, and a lesser intensity of neurological deficit compared to the control group (p < 0.05). Locomotor activity of the animals treated with EMHDPA was significantly higher compared to the control group (p < 0.05). There is a decrease in the activity of all estimated indicators of oxidative stress in the group administered with 2-ethyl-6-methyl-3-hydroxypyridine-2,6-dichlorophenyl(amino)phenylethanoic acid relative to the control group: a decrease in the activity of catalase—17%, superoxide dismutase—34%, malondialdehyde and acetylhydroperoxides—50%, and nitric oxide—85% (p < 0.05). Analysis of the data obtained during the experiment leads to the conclusion about the effectiveness of 2-ethyl-6-methyl-3-hydroxypyridine-2,6-dichlorophenyl(amino)phenylethanoic acid in the treatment of the experimental PM.
Kappa Free Light Chains in the Context of Blood Contamination, and Other IgA- and IgM-Related Cerebrospinal Fluid Disease Pattern
Authors: Hannich Malte Johannes , Dressel Alexander , Budde Kathrin , Petersmann Astrid , Nauck Matthias , Süße Marie
Published: March 2021

In this retrospective, monocentric cohort study, we tested if an intrathecal free light chain kappa (FLC-k) synthesis reflects not only an IgG but also IgA and IgM synthesis. We also analysed if FLC-k can help to distinguish between an inflammatory process and a blood contamination of cerebrospinal fluid (CSF). A total of 296 patient samples were identified and acquired from patients of the department of Neurology, University Medicine Greifswald (Germany). FLC-k were analysed in paired CSF and serum samples using the Siemens FLC-k kit. To determine an intrathecal FLC-k and immunoglobulin (Ig) A/-M-synthesis we analysed CSF/serum quotients in quotient diagrams, according to Reiber et al. Patient samples were grouped into three cohorts: cohort I (n = 41), intrathecal IgA and/or IgM synthesis; cohort II (n = 16), artificial blood contamination; and the control group (n = 239), no intrathecal immunoglobulin synthesis. None of the samples had intrathecal IgG synthesis, as evaluated with quotient diagrams or oligoclonal band analysis. In cohort I, 98% of patient samples presented an intrathecal synthesis of FLC-k. In cohort II, all patients lacked intrathecal FLC-k synthesis. In the control group, 6.5% presented an intrathecal synthesis of FLC-k. The data support the concept that an intrathecal FLC-k synthesis is independent of the antibody class produced. In patients with an artificial intrathecal Ig synthesis due to blood contamination, FLC-k synthesis is lacking. Thus, additional determination of FLC-k in quotient diagrams helps to discriminate an inflammatory process from a blood contamination of CSF.
Adaptation of Kirkpatrick’s Four-Level Model of Training Criteria to Evaluate Training Programmes for Head Teachers
Authors: Alsalamah Aljawharah , Callinan Carol
Published: March 2021

Training programmes are evaluated to verify their effectiveness, assess their ability to achieve their goals and identify the areas that require improvement. Therefore, the target of evaluators is to develop an appropriate framework for evaluating training programmes. This study adapted Kirkpatrick’s four-level model of training criteria published in 1959 to evaluate training programmes for head teachers according to their own perceptions and those of their supervisors. The adapted model may help evaluators to conceptualise the assessment of learning outcomes of training programmes with metrics and instruments. The model also helps to determine the strengths and weaknesses of the training process. The adaptation includes concrete metrics and instruments for each of the four levels in the model: reaction criteria, learning criteria, behaviour criteria and results criteria. The adapted model was applied to evaluate 12 training programmes for female head teachers in Saudi Arabia. The study sample comprised 250 trainee head teachers and 12 supervisors. The results indicated that the adapted Kirkpatrick evaluation model was very effective in evaluating educational training for head teachers.
A 40-nm CMOS Piezoelectric Energy Harvesting IC for Wearable Biomedical Applications
Authors: Wang Chua-Chin , Tolentino Lean Karlo S. , Chen Pin-Chuan , Hizon John Richard E. , Yen Chung-Kun , Pan Cheng-Tang , Hsueh Ya-Hsin
Published: March 2021

This investigation presents an energy harvesting IC (integrated circuit) for piezoelectric materials as a substitute for battery of a wearable biomedical device. It employs a voltage multiplier as first stage which uses water bucket fountain approach to boost the very low voltage generated by the piezoelectric. The boosted voltage was further improved by the boost DC/DC converter which follows a predefined timing control directed by the digital logic for the said converter to be operated efficiently. TSMC 40-nm CMOS process was used for implementation and fabrication of the energy harvesting IC. The chip’s core has an area of 0.013 mm2. With an output of 1 V which is enough to supply the wearable biomedical devices, it exhibited the highest pump gain and accommodated the lowest piezoelectric generated voltage among recent related works.
Over-Size Pill-Box Window for Sub-Terahertz Vacuum Electronic Devices
Authors: Yang Tongbin , Guan Xiaotong , Fu Wenjie , Lu Dun , Zhang Chaoyang , Xie Jie , Yuan Xuesong , Yan Yang
Published: March 2021

The pill-box window is one of the important components of microwave vacuum electronic devices (VEDs), and research into it is of great significance. As the operating frequency increases, the problems associated with the reduction in the structure size include the reduction of the brazing plane and the reduction in the tolerance of the pill-box window. These problems will cause traditional pill-box windows to be unsuitable in high-frequency bands, especially in terahertz and sub-terahertz regions. The most influential factor is the length of the circular waveguide in the box window. The welding plane of the over-size pill-box window is the annular bottom surface on both sides of the dielectric sheet, which is larger than the circular waveguide, and the operating frequency does not directly affect the area of the brazing surface. Choosing a suitable diameter for the dielectric sheet can effectively increase the tolerance to the length of the pill-box window circular waveguide. Therefore, an over-size pill-box window would be a practicable approach to improve the performance compared to the traditional pillow-box in high-frequency bands. This paper describes, in detail, the theoretical design, simulation optimization and experimental process of this improved pill-box window. An over-size pill-box window suitable for G band VEDs was successfully developed. The experimental result in the 215–225 GHz band is that the maximum transmission loss is −1 dB, and the overall transmission loss is close to −0.5 dB. The overall reflection is less than −11 dB.
Assessing Early Heterogeneity in Doubling Times of the COVID-19 Epidemic across Prefectures in Mainland China, January–February, 2020
Authors: Fung Isaac Chun-Hai , Zhou Xiaolu , Cheung Chi-Ngai , Ofori Sylvia K. , Muniz-Rodriguez Kamalich , Cheung Chi-Hin , Lai Po-Ying , Liu Manyun , Chowell Gerardo
Published: March 2021

To describe the geographical heterogeneity of COVID-19 across prefectures in mainland China, we estimated doubling times from daily time series of the cumulative case count between 24 January and 24 February 2020. We analyzed the prefecture-level COVID-19 case burden using linear regression models and used the local Moran’s I to test for spatial autocorrelation and clustering. Four hundred prefectures (~98% population) had at least one COVID-19 case and 39 prefectures had zero cases by 24 February 2020. Excluding Wuhan and those prefectures where there was only one case or none, 76 (17.3% of 439) prefectures had an arithmetic mean of the epidemic doubling time <2 d. Low-population prefectures had a higher per capita cumulative incidence than high-population prefectures during the study period. An increase in population size was associated with a very small reduction in the mean doubling time (−0.012, 95% CI, −0.017, −0.006) where the cumulative case count doubled ≥3 times. Spatial analysis revealed high case count clusters in Hubei and Heilongjiang and fast epidemic growth in several metropolitan areas by mid-February 2020. Prefectures in Hubei and neighboring provinces and several metropolitan areas in coastal and northeastern China experienced rapid growth with cumulative case count doubling multiple times with a small mean doubling time.
Qualitative Fire Vulnerability Assessments for Museums and Their Collections: A Case Study from Kosovo
Authors: Fafet Charlotte , Mulolli Zajmi Erinë
Published: March 2021

Fires are among the most frequently recurring hazards affecting museums and cultural heritage sites. The fires of the National Museum of Brazil in 2018 and of Notre Dame de Paris in 2019 showed that the consequences of such events can be heavy and lead to irreversible heritage losses. In Kosovo, few studies were made about the risks that can affect cultural heritage sites. A project led by the NGO Kosovo Foundation for Cultural Heritage without Borders (CHwB Kosova) in 2018 explored the most prevalent risks for the cultural heritage sites of the country and highlighted fire as a predominant risk in Kosovo. In order to better understand it, vulnerability assessments were conducted in several museums in Kosovo. Data were collected through field visits in the different museums, in which interviews with staff members as well as observations were conducted. The aim of this paper is to present the main results of the fire vulnerability assessments conducted in Kosovo’s museums in 2018. An important aspect of this project is the approach to collect information in data-scarce environments. It is believed that the questionnaires used to lead interviews with museums’ staff members could help other practitioners to collect data in such contexts and evaluate more easily the risk of fire for the museums and their collections. In the context of Kosovo, one of the main findings is the identification and prioritisation of measures to ensure better protection of Kosovar museums. Structural mitigation measures such as alarm and fire suppression systems are not the only elements necessary to improve the resilience of Kosovar museums to fire. Indeed, the promotion of risk awareness, the training of staff members and the realisation of crisis simulation exercises are just as important in order to prevent and detect a fire, and above all, to respond quickly and accurately if a fire occurs.