bluuebunny/crossref_metadata_2025 huggingface dataset:
Escherichia coli BW25113 Competent Cells Prepared Using a Simple Chemical Method Have Unmatched Transformation and Cloning Efficiencies
Authors: Yang Yuqing , Yu Qiaoli , Wang Min , Zhao Rui , Liu Huaiwei , Xun Luying , Xia Yongzhen
Published: March 2022

Escherichia coli recA− strains are usually used for cloning to prevent insert instability via RecA-dependent recombination. Here, we report that E. coli BW25113 (recA+) competent cells prepared by using a previously reported transformation and storage solution (TSS) had 100-fold or higher transformation efficiency than the commonly used E. coli cloning strains, including XL1-Blue MRF’. The cloning success rates with E. coli BW25113 were 440 to 1,267-fold higher than those with E. coli XL1-Blue MRF’ when several inserts were assembled into four vectors by using a simple DNA assembly method. The difference was in part due to RecA, as the recA deletion in E. coli BW25113 reduced the transformation efficiency by 16 folds and cloning success rate by about 10 folds. However, the transformation efficiency and the cloning success rate of the recA deletion mutant of E. coli BW25113 are still 12- and >48-fold higher than those of E. coli XL1-Blue MRF’, which is a commonly used cloning strain. The cloned inserts with different lengths of homologous sequences were assembled into four vectors and transformed into E. coli BW25113, and they were stably maintained in BW25113. Thus, we recommend using E. coli BW25113 for efficient cloning and DNA assembly.
Dynamics of Bacterial Root Endophytes of Malus domestica Plants Grown in Field Soils Affected by Apple Replant Disease
Authors: Mahnkopp-Dirks Felix , Radl Viviane , Kublik Susanne , Gschwendtner Silvia , Schloter Michael , Winkelmann Traud
Published: March 2022

Apple replant disease (ARD) is a worldwide problem for tree nurseries and orchards leading to reduced plant growth and fruit quality. The etiology of this complex phenomenon is poorly understood, but shifts of the bulk soil and rhizosphere microbiome seem to play an important role. Since roots are colonized by microbes from the rhizosphere, studies of the endophytic microbiome in relation to ARD are meaningful. In this study, culture-independent and culture-dependent approaches were used in order to unravel the endophytic root microbiome of apple plants 3, 7, and 12 months after planting in ARD-affected soil and ARD-unaffected control soil at two different field sites. Next to a high diversity of Pseudomonas in roots from all soils, molecular barcoding approaches revealed an increase in relative abundance of endophytic Actinobacteria over time in plants grown in ARD and control plots. Furthermore, several amplicon sequence variants (ASVs) linked to Streptomyces, which had been shown in a previous greenhouse ARD biotest to be negatively correlated to shoot length and fresh mass, were also detected in roots from both field sites. Especially in roots of apple plants from control soil, these Streptomyces ASVs increased in their relative abundance over time. The isolation of 150 bacterial strains in the culture-dependent approach revealed a high diversity of members of the genus Pseudomonas, confirming the data of the molecular barcoding approach. However, only partial overlaps were found between the two approaches, underlining the importance of combining these methods in order to better understand this complex disease and develop possible countermeasures. Overall, this study suggests a key role of Streptomyces in the etiology of ARD in the field.
Evaluation of Potential Probiotic Properties of a Strain of Lactobacillus plantarum for Shrimp Farming: From Beneficial Functions to Safety Assessment
Authors: Wei Cong , Luo Kai , Wang Mingyang , Li Yongmei , Pan Miaojun , Xie Yumeng , Qin Guangcai , Liu Yijun , Li Li , Liu Qingbing , Tian Xiangli
Published: March 2022

In recent years the safety of probiotics has received increasing attention due to the possible transfer and spread of virulence factors (VFs) and antibiotic resistance genes (ARGs) among microorganisms. The safety of a strain of Lactobacillus plantarum named W2 was evaluated in phenotype and genotype in the present study. Its probiotic properties were also evaluated both in vivo and in vitro, including adherence properties, antibacterial properties and beneficial effects on the growth and immunity of Pacific white shrimp, Penaeus vannamei. Hemolysis tests, antibiotic resistance tests and whole genome sequence analysis showed that W2 had no significant virulence effects and did not carry high virulence factors. W2 was found to be sensitive to chloramphenicol, clindamycin, gentamicin, kanamycin and tetracycline, and to be resistant to ampicillin and erythromycin. Most ARGs have no transfer risk and a few have transfer risk but no significant enrichment in human-associated environments. The autoaggregation of W2 was 82.6% and the hydrophobicity was 81.0%. Coaggregation rate with Vibrio parahaemolyticus (24.9%) was significantly higher than Vibrio’s autoaggregation rate (17.8%). This suggested that W2 had adhesion potential to mucosal/intestinal surfaces and was able to attenuate the adherence of V. parahaemolyticus. In addition, several adhesion-related protein genes, including 1 S-layer protein, 1 collagen-binding protein and 9 mucus-binding proteins were identified in the W2 genome. W2 had efficiently antagonistic activity against 7 aquatic pathogenic strains. Antagonistic components analysis indicated that active antibacterial substances might be organic acids. W2 can significantly promote the growth of shrimp when supplemented with 1 × 1010 cfu/kg live cells. Levels of 7 serological immune indicators and expression levels of 12 hepatopancreatic immune-related genes were up-regulated, and the mortality of shrimp exposed to V. parahaemolyticus was significantly reduced. Based on the above, L. plantarum W2 can be applied safely as a potential probiotic to enhance the growth performance, immunity capacity and disease resistance of P. vannamei.
Transplantation of Gut Microbiota From High-Fat-Diet-Tolerant Cynomolgus Monkeys Alleviates Hyperlipidemia and Hepatic Steatosis in Rats
Authors: Gao Jiang-Mei , Rao Jun-Hua , Wei Zhi-Yuan , Xia Shou-Yue , Huang Li , Tang Ming-Tian , Hide Geoff , Zheng Ting-Ting , Li Jia-Huan , Zhao Guo-An , Sun Yun-Xiao , Chen Jian-Huan
Published: March 2022

Emerging evidence has been reported to support the involvement of the gut microbiota in the host’s blood lipid and hyperlipidemia (HLP). However, there remains unexplained variation in the host’s blood lipid phenotype. Herein a nonhuman primate HLP model was established in cynomolgus monkeys fed a high-fat diet (HFD) for 19 months. At month 19%, 60% (3/5) of the HFD monkeys developed HLP, but surprisingly 40% of them (2/5) exhibited strong tolerance to the HFD (HFD-T) with their blood lipid profiles returning to normal levels. Metagenomic analysis was used to investigate the compositional changes in the gut microbiota in these monkeys. Furthermore, the relative abundance of Megasphaera remarkably increased and became the dominant gut microbe in HFD-T monkeys. A validation experiment showed that transplantation of fecal microbiota from HFD-T monkeys reduced the blood lipid levels and hepatic steatosis in HLP rats. Furthermore, the relative abundance of Megasphaera significantly increased in rats receiving transplantation, confirming the successful colonization of the microbe in the host and its correlation with the change of the host’s blood lipid profiles. Our results thus suggested a potentially pivotal lipid-lowering role of Megasphaera in the gut microbiota, which could contribute to the variation in the host’s blood lipid phenotype.
Temporal Control of the WNT Signaling Pathway During Cardiac Differentiation Impacts Upon the Maturation State of Human Pluripotent Stem Cell Derived Cardiomyocytes
Authors: Tsoi Chantelle , Deng Ruixia , Kwok Maxwell , Yan Bin , Lee Carrie , Li Hung Sing , Ma Chloe Ho Yi , Luo Ruibang , Leung Kam Tong , Chan Godfrey Chi-Fung , Chow Larry Ming-cheung , Poon Ellen N.
Published: March 2022

Inefficient differentiation and insufficient maturation are barriers to the application of human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) for research and therapy. Great strides have been made to the former, and multiple groups have reported cardiac differentiation protocol that can generate hPSC-CMs at high efficiency. Although many such protocols are based on the modulation of the WNT signaling pathway, they differ in their timing and in the WNT inhibitors used. Little is currently known about whether and how conditions of differentiation affect cardiac maturation. Here we adapted multiple cardiac differentiation protocols to improve cost-effectiveness and consistency, and compared the properties of the hPSC-CMs generated. Our results showed that the schedule of differentiation, but not the choice of WNT inhibitors, was a critical determinant not only of differentiation efficiency, which was expected, but also CM maturation. Among cultures with comparable purity, hPSC-CMs generated with different differentiation schedules vary in the expression of genes which are important for developmental maturation, and in their structural, metabolic, calcium transient and proliferative properties. In summary, we demonstrated that simple changes in the schedule of cardiac differentiation could promote maturation. To this end, we have optimized a cardiac differentiation protocol that can simultaneously achieve high differentiation efficiency and enhanced developmental maturation. Our findings would advance the production of hPSC-CMs for research and therapy.
Microglia and Neuroinflammation: Crucial Pathological Mechanisms in Traumatic Brain Injury-Induced Neurodegeneration
Authors: Shao Fangjie , Wang Xiaoyu , Wu Haijian , Wu Qun , Zhang Jianmin
Published: March 2022

Traumatic brain injury (TBI) is one of the most common diseases in the central nervous system (CNS) with high mortality and morbidity. Patients with TBI usually suffer many sequelae in the life time post injury, including neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the pathological mechanisms connecting these two processes have not yet been fully elucidated. It is important to further investigate the pathophysiological mechanisms underlying TBI and TBI-induced neurodegeneration, which will promote the development of precise treatment target for these notorious neurodegenerative consequences after TBI. A growing body of evidence shows that neuroinflammation is a pivotal pathological process underlying chronic neurodegeneration following TBI. Microglia, as the immune cells in the CNS, play crucial roles in neuroinflammation and many other CNS diseases. Of interest, microglial activation and functional alteration has been proposed as key mediators in the evolution of chronic neurodegenerative pathology following TBI. Here, we review the updated studies involving phenotypical and functional alterations of microglia in neurodegeneration after injury, survey key molecules regulating the activities and functional responses of microglia in TBI pathology, and explore their potential implications to chronic neurodegeneration after injury. The work will give us a comprehensive understanding of mechanisms driving TBI-related neurodegeneration and offer novel ideas of developing corresponding prevention and treatment strategies for this disease.
Human Nmnat1 Promotes Autophagic Clearance of Amyloid Plaques in a Drosophila Model of Alzheimer’s Disease
Authors: Zhu Yi , Lobato Amanda G. , Zhai R. Grace , Pinto Milena
Published: March 2022

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by irreversible cognitive decline with limited therapeutic approaches. We characterized a Drosophila model of amyloid pathology that expresses human amyloid-beta precursor protein (APP695) and β-site APP cleaving enzyme (BACE) in the nervous system. Our model recapitulates in vivo the age-dependent accumulation of BACE-derived C-terminal fragment (CTF) and amyloid plaques in the brain, one of the key pathological hallmarks of AD. Using this model, we assessed the effects on plaque formation of Nicotinamide mononucleotide adenylyltransferase (Nmnat), an evolutionarily conserved nicotinamide adenine dinucleotide (NAD+) synthase involved in cellular metabolism and neuroprotection. We compared the effects of overexpression of Drosophila Nmnat (dNmnat), human Nmnat1 (hNmnat1), human Nmnat2 (hNmnat2), and human Nmnat3 (hNmnat3), and observed that hNmnat1 has the highest efficacy in reducing amyloid aggregation and APP-CTF accumulation. Interestingly, we demonstrated that overexpression of hNmnat1 reduces amyloid plaques by promoting autophagic clearance. Our findings uncover a role of hNmnat1 in amyloid clearance and suggest an exciting neuroprotective potential of hNmnat1 in amyloid pathology.
Neuroinflammation as the Underlying Mechanism of Postoperative Cognitive Dysfunction and Therapeutic Strategies
Authors: Li Zhichao , Zhu Youzhuang , Kang Yihan , Qin Shangyuan , Chai Jun
Published: March 2022

Postoperative cognitive dysfunction (POCD) is a common neurological complication following surgery and general anesthesia, especially in elderly patients. Severe cases delay patient discharge, affect the patient’s quality of life after surgery, and are heavy burdens to society. In addition, as the population ages, surgery is increasingly used for older patients and those with higher prevalences of complications. This trend presents a huge challenge to the current healthcare system. Although studies on POCD are ongoing, the underlying pathogenesis is still unclear due to conflicting results and lack of evidence. According to existing studies, the occurrence and development of POCD are related to multiple factors. Among them, the pathogenesis of neuroinflammation in POCD has become a focus of research in recent years, and many clinical and preclinical studies have confirmed the correlation between neuroinflammation and POCD. In this article, we reviewed how central nervous system inflammation occurred, and how it could lead to POCD with changes in peripheral circulation and the pathological pathways between peripheral circulation and the central nervous system (CNS). Furthermore, we proposed some potential therapeutic targets, diagnosis and treatment strategies at the cellular and molecular levels, and clinical applications. The goal of this article was to provide a better perspective for understanding the occurrence of POCD, its development, and preventive strategies to help manage these vulnerable geriatric patients.
Triglyceride-Glucose Index Is Related to Carotid Plaque and Its Stability in Nondiabetic Adults: A Cross-Sectional Study
Authors: Wang Anran , Li Yapeng , Zhou Lue , Liu Kai , Li Shaohua , Song Bo , Gao Yuan , Li Yusheng , Lu Jie , Tian Chuansheng , Xu Yuming , Wang Longde
Published: March 2022

Background

Carotid plaque plays an important role in the development of stroke. The triglyceride-glucose (TyG) index is a reliable alternative marker of insulin resistance. However, there are limited data regarding the relationship between TyG index and carotid plaque and its stability in nondiabetic adults.

Methods

This study was carried out on 24,895 urban workers (10,978 men and 13,917 women) aged 20 years or older who participated in a comprehensive health screening between January 2016 and December 2017 at the First Affiliated Hospital of Zhengzhou University, China. Carotid plaque was assessed using ultrasonography. TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL) /2]. Logistic regression models and restricted cubic spline (RCS) models were used to estimate the association of the TyG index with carotid plaque and its stability by odds ratios (ORs) and 95% confidence intervals (CIs).

Results

Carotid plaque was detected in 5,668 (22.8%) respondents, with stable and unstable plaque accounting for 2,511 (10.1%) and 3,158 (12.7%), respectively. There was a significant positive association between the prevalence of carotid plaque and TyG index quartile levels, and the same associations were observed for the prevalence of stable and unstable carotid plaque (P for trend <0.0001). The multivariable-adjusted ORs (95% CIs) for the highest vs. lowest quartile of TyG index were 1.30 (1.15–1.47) for carotid plaque, 1.38 (1.17–1.63) for stable carotid plaque, and 1.24 (1.07–1.43) for unstable carotid plaque. The RCS analysis showed a linear association between TyG index and carotid plaque, and linear associations were also observed between TyG index and both stable carotid plaque and unstable carotid plaque (P for linearity<0.05).

Conclusion

Our findings suggested that the TyG index was significantly associated with carotid plaque and might be a useful indicator for the early identification of carotid plaque in nondiabetic subjects.
Ring Finger Protein 213 in Moyamoya Disease With Pulmonary Arterial Hypertension: A Mini-Review
Authors: Luo Yuting , Cao Zhixin , Wu Shaoqing , Sun Xunsha
Published: March 2022

Moyamoya disease (MMD), most often diagnosed in children and adolescents, is a chronic cerebrovascular disease characterized by progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Recently, many investigators show a great interest in MMD with pulmonary arterial hypertension (PAH). Ring finger protein 213 (RNF213) is a major susceptibility gene for MMD and also has strong correlations with PAH. Therefore, this review encapsulates current cases of MMD with PAH and discusses MMD with PAH in the aspects of epidemiology, pathology, possible pathogenesis, clinical manifestations, diagnosis, and treatment.
Effects of Transcranial Pulse Stimulation (TPS) on Young Adults With Symptom of Depression: A Pilot Randomised Controlled Trial Protocol
Authors: Cheung Teris , Ho Yuen Shan , Yeung Jerry Wing-Fai , Leung Sau Fong , Fong Kenneth N. K. , Fong Tommy , Kranz Georg S. , Beisteiner Roland , Cheng Calvin Pak Wing
Published: March 2022

Background

Since the emergence of the COVID-19 pandemic, there have been lots of published work examining the association between COVID-19 and mental health, particularly, anxiety and depression in the general populations and disease subpopulations globally. Depression is a debilitating disorder affecting individuals' level of bio-psychological-social functioning across different age groups. Since almost all studies were cross-sectional studies, there seems to be a lack of robust, large-scale, and technological-based interventional studies to restore the general public's optimal psychosocial wellbeing amidst the COVID-19 pandemic. Transcranial pulse stimulation (TPS) is a relatively new non-intrusive brain stimulation (NIBS) technology, and only a paucity of studies was conducted related to the TPS treatment on older adults with mild neurocognitive disorders. However, there is by far no study conducted on young adults with major depressive disorder nationwide. This gives us the impetus to execute the first nationwide study evaluating the efficacy of TPS on the treatment of depression among young adults in Hong Kong.

Methods

This study proposes a two-armed single-blinded randomised controlled trial including TPS as an intervention group and a waitlist control group. Both groups will be measured at baseline (T1), immediately after the intervention (T2), and at the 3- month follow-up (T3).

Recruitment

A total of 30 community-dwelling subjects who are aged 18 and above and diagnosed with major depressive disorder (MDD) will be recruited in this study. All subjects will be computer randomised into either the intervention group or the waitlist control group, balanced by gender and age on a 1:1 ratio.

Intervention

All subjects in each group will have to undertake functional MRI (fMRI) before and after six 30-min TPS sessions, which will be completed in 2 weeks' time.

Outcomes

Baseline measurements and post-TPS evaluation of the psychological outcomes (i.e., depression, cognition, anhedonia, and instrumental activities of daily living) will also be conducted on all participants. A 3-month follow-up period will be used

to assess the long-term sustainability of the TPS intervention. For statistical analysis, ANOVA with repeated measures will be used to analyse data. Missing data were managed by multiple mutations. The level of significance will be set to p < 0.05.

Significance of the Study

Results of this study will be used to inform health policy to determine whether TPS could be considered as a top treatment option for MDD.

Clinical Trial Registration

ClinicalTrials.gov, identifier: NCT05006365.
Understanding Pharmaco-Epigenomic Response of Antipsychotic Drugs Using Genome-Wide MicroRNA Expression Profile in Liver Cell Line
Authors: Swathy Babu , Banerjee Moinak
Published: March 2022

Interindividual variability in drug response is a major concern among patients undergoing antipsychotic drug treatment. Apart from genetic and physiological factors, this variability in drug response could also be attributed to epigenetic mechanisms. The microRNAs (miRNAs) are key epigenetic markers that play an important role in pathogenesis and drug response. Several studies have shown that miRNAs are implicated in regulating the expression of various genes involved in drug metabolism and transport. In a conventional clinical setup, it is extremely difficult to distinguish the role of miRNA in pathogenesis and drug response as it is difficult to obtain drug naïve patients. To resolve this issue, we aimed to identify the role of antipsychotic drug treatment in inducing miRNA expression under an in vitro condition using a hepatic cell line. A liver cell line was treated with a maximum tolerable drug dosage model for haloperidol, clozapine in monotherapy, and their combination in polytherapy. Genome-wide miRNA profiling was performed using 60,000 miRNA probes in the microarray format in different treatment groups. Several miRNAs were observed to be differentially expressed impacting the pharmacokinetic, pharmacodynamics, and epigenomics properties of antipsychotic drug treatment. Interestingly, some of these miRNA expression patterns were similar to reported miRNA observations on schizophrenia pathogenesis. This study unravels the potential role of miRNAs in the mechanism of action of the antipsychotic drug and could also reflect in drug-induced side effects. This study also signifies the importance of pharmacoepigenomics approach while evaluating the role of miRNAs in pathogenesis.
The Application of in silico Methods for Prediction of Blood-Brain Barrier Permeability of Small Molecule PET Tracers
Authors: Stéen E. Johanna L. , Vugts Danielle J. , Windhorst Albert D.
Published: March 2022

Designing positron emission tomography (PET) tracers for targets in the central nervous system (CNS) is challenging. Besides showing high affinity and high selectivity for their intended target, these tracers have to be able to cross the blood-brain barrier (BBB). Since only a small fraction of small molecules is estimated to be able to cross the BBB, tools that can predict permeability at an early stage during the development are of great importance. One such tool isin silicomodels for predicting BBB-permeability. Thus far, such models have been built based on CNS drugs, with one exception. Herein, we sought to discuss and analyze ifin silicopredictions that have been built based on CNS drugs can be applied for CNS PET tracers as well, or if dedicated models are needed for the latter. Depending on what is taken into account in the prediction, i.e., passive diffusion or also active influx/efflux, there may be a need for a model build on CNS PET tracers. Following a brief introduction, an overview of a few selectedin silicoBBB-permeability predictions is provided along with a short historical background to the topic. In addition, a combination of previously reported CNS PET tracer datasets were assessed in a couple of selected models and guidelines for predicting BBB-permeability. The selected models were either predicting only passive diffusion or also the influence of ADME (absorption, distribution, metabolism and excretion) parameters. To conclude, we discuss the potential need of a prediction model dedicated for CNS PET tracers and present the key issues in respect to setting up a such a model.
Comparing the Profiles of Raw and Cooked Donkey Meat by Metabonomics and Lipidomics Assessment
Authors: Li Mengmeng , Ren Wei , Chai Wenqiong , Zhu Mingxia , Man Limin , Zhan Yandong , Qin Huaxiu , Sun Mengqi , Liu Jingjing , Zhang Demin , Wang Yonghui , Wang Tianqi , Shi Xiaoyuan , Wang Changfa
Published: March 2022

Heat cooking of meat gives it a specific taste and flavor which are favored by many consumers. While the characteristic taste components of chicken, duck, pig, and seafood have been studied, there is a lack of information about the molecular components that give donkey meat its unique taste. Here, the characterization profiles of raw donkey meat (RDM) and cooked donkey meat (CDM) meat by metabonomics and lipidomics. The results showed that a total of 186 metabolites belonging to 8 subclasses were identified in CDM and RDM, including carbohydrates (27.42%), amino acids (17.20%), lipids (13.44%), and nucleotides (9.14%). In total, 37 differential metabolites were identified between CDM and RDM. Among these, maltotriose, L-glutamate, and L-proline might predominantly contribute to the unique umami and sweet taste of donkey meat. Comprehensive biomarker screening detected 9 potential metabolite markers for the discrimination among RDM and CDM, including L-glutamate, gamma-aminobutyric acid, and butane-1, 2, 3, 4-tetrol. Moreover, a total of 992 and 1,022 lipids belonging to 12 subclasses were identified in RDM and CDM, respectively, mainly including triglycerides (TGs) and glycerophospholipids (GPs). Of these lipids, 116 were significantly different between CDM and RDM. The abundances of 61 TGs rich in saturated and monounsaturated fatty acids were retained in CDM, whereas the abundances of 37 GPs rich in polyunsaturated fatty acids were reduced, suggesting that TGs and GPs might be the predominant lipids for binding and generating aroma compounds, respectively. A total of 13 lipids were determined as potential markers for the discrimination among RDM and CDM, including PC(O-16:2/2:0), LPE(22:5/0:0), and PC(P-16:0/2:0). In conclusion, this study provided useful information about the metabolic and lipid profiles of donkey meat which may explain its unique taste and flavor, which could serve as a basis for the development and quality control of donkey meat and its products.
The Mechanism of Acrylamide-Induced Neurotoxicity: Current Status and Future Perspectives
Authors: Zhao Mengyao , Zhang Boya , Deng Linlin
Published: March 2022

Acrylamide (ACR), a potential neurotoxin, is produced by the Maillard reaction between reducing sugars and free amino acids during food processing. Over the past decade, the neurotoxicity of ACR has caused increasing concern, prompting many related studies. This review summarized the relevant literature published in recent years and discussed the exposure to occupational, environmental, and daily ACR contamination in food. Moreover, ACR metabolism and the potential mechanism of ACR-induced neurotoxicity were discussed, with particular focus on the axonal degeneration of the nervous system, nerve cell apoptosis, oxidative stress, inflammatory response, and gut-brain axis homeostasis. Additionally, the limitations of existing knowledge, as well as new perspectives, were examined, specifically regarding the connection between the neurotoxicity caused by ACR and neurodegenerative diseases, NOD-like receptor protein 3 (NLRP3) inflammasome-related neuroinflammation, and microbiota-gut-brain axis signaling. This review might provide systematic information for developing an alternative pathway approach to assess ACR risk.
Natural Flavonoids Derived From Fruits Are Potential Agents Against Atherosclerosis
Authors: Li Ruo-Lan , Wang Ling-Yu , Liu Shuqin , Duan Hu-Xinyue , Zhang Qing , Zhang Ting , Peng Wei , Huang Yongliang , Wu Chunjie
Published: March 2022

Atherosclerosis, as a chronic inflammatory response, is one of the main causes of cardiovascular diseases. Atherosclerosis is induced by endothelial cell dysfunction, migration and proliferation of smooth muscle cells, accumulation of foam cells and inflammatory response, resulting in plaque accumulation, narrowing and hardening of the artery wall, and ultimately leading to myocardial infarction or sudden death and other serious consequences. Flavonoid is a kind of natural polyphenol compound widely existing in fruits with various structures, mainly including flavonols, flavones, flavanones, flavanols, anthocyanins, isoflavones, and chalcone, etc. Because of its potential health benefits, it is now used in supplements, cosmetics and medicines, and researchers are increasingly paying attention to its role in atherosclerosis. In this paper, we will focus on several important nodes in the development of atherosclerotic disease, including endothelial cell dysfunction, smooth muscle cell migration and proliferation, foam cell accumulation and inflammatory response. At the same time, through the classification of flavonoids from fruits, the role and potential mechanism of flavonoids in atherosclerosis were reviewed, providing a certain direction for the development of fruit flavonoids in the treatment of atherosclerosis drugs.
Severe and Enduring' Stage in Anorexia Nervosa: Comparing Eating Attitudes, Impairment and Associated Psychopathology
Authors: Ramos Rita , Vaz Ana , Rodrigues Tânia F. , Pinto-Bastos Ana , Brandão Isabel , Neves António , Conceição Eva , Machado Paulo P. P.
Published: March 2022

This study aimed to assess differences in eating attitudes, impairment, and related psychopathology at treatment presentation for patients with “Non-severe and enduring Anorexia Nervosa” (illness duration of <7 years) and patients with “severe and enduring Anorexia Nervosa” (illness duration of 7 years or more). One hundred and thirty-nine patients diagnosed with Anorexia Nervosa participated in this study. Participants were interviewed with the Eating Disorder Examination (EDE) and asked to complete several questionnaires at the end of the first treatment appointment. We also explored differences at treatment presentation by considering alternative criteria to define groups, namely a composite of illness duration and clinical impairment (≥16 CIA total score). No differences were found when comparing participants based on illness duration. However, when participants were classified into a different classification scheme: “Non-severe and enduring Anorexia Nervosa” (illness duration <7 years and a CIA total score <16) vs. “severe and enduring Anorexia Nervosa” (illness duration ≥7 years and CIA total score ≥16), significant differences were found in terms of eating pathology, depressive symptomatology, psychological distress, and emotion dysregulation. Further research is needed to better understand the role of illness duration and clinical impairment in informing the course of AN.
Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives
Authors: Abdel-Razeq Hikmat , Tamimi Faris , Abujamous Lama , Abdel-Razeq Rashid , Abunasser Mahmoud , Edaily Sara , Abdulelah Hazem , Khashabeh Razan Abu , Bater Rayan
Published: March 2022

Purpose

Contrary to BRCA pathogenic variants, recommendations for management of variants of uncertain significance (VUS) are not clear and focus more on the patient’s family and personal history of cancer. Local and regional data on VUS are scarce. In this paper, we study patterns and frequency of VUS among breast cancer patients undergoing genetic testing.

Patients and Methods

Patients with breast cancer at high risk for pathogenic variants, as per the National Comprehensive Cancer Network (NCCN) guidelines, were tested at reference laboratories. Related surgical interventions were reviewed.

Results

Among a group of 1,197 patients with breast cancer who underwent genetic testing and counseling, 110 (9.2%) had VUS; most (n = 79, 71.8%) were in BRCA2. Median age (range) was 39 (25–66) years with 65 (59.1%) patients who were 40 years or younger at diagnosis. Among 103 patients with non-metastatic disease, 48 (46.6%) had breast-conserving surgery (BCS) while only 5 (4.9%) had bilateral mastectomies; all were due to bilateral disease and not prophylactic. VUS diagnosis was known prior to initial surgery in 34 (33.0%) patients; 11 (32.4%) of them had BCS only. Over the study period, only one VUS variant was upgraded to “likely positive.” The recent introduction of multiple-gene panel testing had resulted in a surge in VUS rate (22.2%) in genes other than BRCA1 or BRCA2, like PALB2, CHEK2, and ATM.

Conclusions

Rates of VUS are relatively high and increasing, mostly in non-BRCA1 or BRCA2, and this had no impact on the therapeutic or prophylactic surgical decisions. Adherence to guidelines is extremely important to avoid unnecessary procedures.
Enhanced Cancer Therapy Using an Engineered Designer Cytokine Alone and in Combination With an Immune Checkpoint Inhibitor
Authors: Pradhan Anjan K. , Bhoopathi Praveen , Maji Santanu , Kumar Amit , Guo Chunqing , Mannangatti Padmanabhan , Li Jiong , Wang Xiang-Yang , Sarkar Devanand , Emdad Luni , Das Swadesh K. , Fisher Paul B.
Published: March 2022

melanoma differentiation associated gene-7 or Interleukin-24 (mda-7, IL-24) displays expansive anti-tumor activity without harming corresponding normal cells/tissues. This anticancer activity has been documented in vitro and in vivo in multiple preclinical animal models, as well as in patients with advanced cancers in a phase I clinical trial. To enhance the therapeutic efficacy of MDA-7 (IL-24), we engineered a designer cytokine (a “Superkine”; IL-24S; referred to as M7S) with enhanced secretion and increased stability to engender improved “bystander” antitumor effects. M7S was engineered in a two-step process by first replacing the endogenous secretory motif with an alternate secretory motif to boost secretion. Among four different signaling peptides, the insulin secretory motif significantly enhanced the secretion of MDA-7 (IL-24) protein and was chosen for M7S. The second modification engineered in M7S was designed to enhance the stability of MDA-7 (IL-24), which was accomplished by replacing lysine at position K122 with arginine. This engineered “M7S Superkine” with increased secretion and stability retained cancer specificity. Compared to parental MDA-7 (IL-24), M7S (IL-24S) was superior in promoting anti-tumor and bystander effects leading to improved outcomes in multiple cancer xenograft models. Additionally, combinatorial therapy using MDA-7 (IL-24) or M7S (IL-24S) with an immune checkpoint inhibitor, anti-PD-L1, dramatically reduced tumor progression in murine B16 melanoma cells. These results portend that M7S (IL-24S) promotes the re-emergence of an immunosuppressive tumor microenvironment, providing a solid rationale for prospective translational applications of this therapeutic designer cytokine.
Transcriptomic Portraits and Molecular Pathway Activation Features of Adult Spinal Intramedullary Astrocytomas
Authors: Konovalov Nikolay , Timonin Stanislav , Asyutin Dmitry , Raevskiy Mikhail , Sorokin Maxim , Buzdin Anton , Kaprovoy Stanislav
Published: March 2022

In this study, we report 31 spinal intramedullary astrocytoma (SIA) RNA sequencing (RNA-seq) profiles for 25 adult patients with documented clinical annotations. To our knowledge, this is the first clinically annotated RNA-seq dataset of spinal astrocytomas derived from the intradural intramedullary compartment. We compared these tumor profiles with the previous healthy central nervous system (CNS) RNA-seq data for spinal cord and brain and identified SIA-specific gene sets and molecular pathways. Our findings suggest a trend for SIA-upregulated pathways governing interactions with the immune cells and downregulated pathways for the neuronal functioning in the context of normal CNS activity. In two patient tumor biosamples, we identified diagnostic KIAA1549-BRAF fusion oncogenes, and we also found 16 new SIA-associated fusion transcripts. In addition, we bioinformatically simulated activities of targeted cancer drugs in SIA samples and predicted that several tyrosine kinase inhibitory drugs and thalidomide analogs could be potentially effective as second-line treatment agents to aid in the prevention of SIA recurrence and progression.
Neonatologists’ Resuscitation Decisions at Birth for Extremely Premature Infants. A Belgian Qualitative Study
Authors: Cavolo Alice , Dierckx de Casterlé Bernadette , Naulaers Gunnar , Gastmans Chris
Published: March 2022

Objective

Deciding whether initiating or withholding resuscitation at birth for extremely preterm infants (EPIs) can be difficult due to uncertainty on outcomes. Clinical uncertainty generates ethical uncertainty. Thus, physicians’ attitudes and perspectives on resuscitation of EPIs might influence resuscitation decisions. We aimed at understanding how neonatologists make clinical-ethical decisions for EPI resuscitation and how they perceive these decisions.

Methods

We performed a qualitative study using a constructivist account of grounded theory. Face-to-face, semi-structured in-depth interviews with neonatologists comprised data collection. For data analysis, we used the Qualitative Analysis Guide of Leuven.

Results

We interviewed 20 neonatologists working in 10 hospitals in Belgium. Participants’ decision-making can be described as consensus-based, gestational age-based, contextualized, progressive, and shared. All participants agreed on the importance of using the consensus expressed in guidelines as a guidance for the decision-making, i.e., consensus-based. Consequently, all 20 participants use GA thresholds indicated in the guidelines, i.e., GA-based. However, they use these thresholds differently in their decisions. Few participants rigidly follow established thresholds. The vast majority reported using additional contextual factors as birthweight or parents’ wishes in the decision-making, rather than only the EPIs’ GA, i.e., contextualized. All participants agreed on the importance of involving the parents in the decision-making, i.e., shared, and indeed parents’ wishes were among the most valued factors considered in the decision-making. However, the extent to which parents were involved in the decision-making depended on the infant’s GA. Participants described a gray zone in which parents’ were viewed as the main decision-makers due to the high clinical uncertainty. This mean that participants tend to follow parents’ request even when they disagree with it. Outside the gray zone, physicians were viewed as the main decision-makers. This mean that, although parents’ wishes were still considered, counseling was more directive and the final decision was made by the physician.

Conclusion

Although an EPI’s GA remains the main factor guiding neonatologists’ resuscitation decisions, other factors are seriously considered in the decision-making process. All neonatologist participants agreed on the importance of involving parents in the decision-making. However, they involve parents differently depending on the EPI’s GA.
Honeysuckle (Lonicera japonica) and Huangqi (Astragalus membranaceus) Suppress SARS-CoV-2 Entry and COVID-19 Related Cytokine Storm in Vitro
Authors: Yeh Yuan-Chieh , Doan Ly Hien , Huang Zi-Yi , Chu Li-Wei , Shi Tzu-Hau , Lee Ying-Ray , Wu Cheng-Tao , Lin Chao-Hsiung , Chiang Shu-Tuan , Liu Hui-Kang , Chuang Tsung-Hsien , Ping Yueh-Hsin , Liu Hsiao-Sheng , Huang Chi-Ying F.
Published: March 2022

COVID-19 is threatening human health worldwide but no effective treatment currently exists for this disease. Current therapeutic strategies focus on the inhibition of viral replication or using anti-inflammatory/immunomodulatory compounds to improve host immunity, but not both. Traditional Chinese medicine (TCM) compounds could be promising candidates due to their safety and minimal toxicity. In this study, we have developed a novel in silico bioinformatics workflow that integrates multiple databases to predict the use of honeysuckle (Lonicera japonica) and Huangqi (Astragalus membranaceus) as potential anti-SARS-CoV-2 agents. Using extracts from honeysuckle and Huangqi, these two herbs upregulated a group of microRNAs including let-7a, miR-148b, and miR-146a, which are critical to reduce the pathogenesis of SARS-CoV-2. Moreover, these herbs suppressed pro-inflammatory cytokines including IL-6 or TNF-α, which were both identified in the cytokine storm of acute respiratory distress syndrome, a major cause of COVID-19 death. Furthermore, both herbs partially inhibited the fusion of SARS-CoV-2 spike protein-transfected BHK-21 cells with the human lung cancer cell line Calu-3 that was expressing ACE2 receptors. These herbs inhibited SARS-CoV-2 Mpro activity, thereby alleviating viral entry as well as replication. In conclusion, our findings demonstrate that honeysuckle and Huangqi have the potential to be used as an inhibitor of SARS-CoV-2 virus entry that warrants further in vivo analysis and functional assessment of miRNAs to confirm their clinical importance. This fast-screening platform can also be applied to other drug discovery studies for other infectious diseases.
Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS
Authors: Wu Bin , Luo Min , Wu Fengbo , He Zhiyao , Li Yuwen , Xu Ting
Published: March 2022

Acute kidney injury (AKI) is a common complication among patients with the novel coronavirus (COVID-19). COVID-19 along with AKI usually resulted in a poor prognosis for those affected. Remdesivir is a novel antiviral drug that was urgently approved for the treatment of COVID-19. In the current study, safety data of remdesivir were limited. We gathered information on COVID-19 cases in patients with adverse events that were reported to the U.S. Food and Drug Administration (US FDA) Adverse Event Reporting System (FAERS) database. We employed the reporting odds ratio (ROR) method to perform disproportionality analysis. Finally, we identified 12,869 COVID-19 cases. A total of 3,991 of these cases reported remdesivir as a primary suspected drug, while 8,878 cases were treated with other drugs. More AKI events occurred in cases of male patients and those above the age of 65 years. We detected a significant association between remdesivir and AKI: ROR = 2.81, 95% CI (2.48, 3.18). The association was stronger after the propensity score matching ROR = 3.85, 95% CI (3.11, 4.78). The mean time to AKI event onset was 4.91 ± 7.25 days in COVID-19 cases with remdesivir therapy. The fatality proportion was 36.45% in AKI cases with remdesivir treatment. This pharmacovigilance study identified a significant association between AKI events and remdesivir treatment in COVID-19 patients by mining FAERS real-world big data. Although causality was not confirmed, the association between remdesivir and AKI should not be ignored, especially in the older, male COVID-19 inpatients.
Identifying Potential Drug-Related Problems Among Geriatric Patients With Use of an Integrated Clinical Decision Support Tool
Authors: Bobrova Veera , Fialová Daniela , Desselle Shane , Heinämäki Jyrki , Volmer Daisy
Published: March 2022

Background: Drug-related problems (DRPs) which arise from potentially inappropriate medications (PIMs) are a common problem in older people with multi-morbidity and polypharmacy.

Aim: To develop an integrated PIM clinical decision support tool for identification of DRPs in geriatric multi-morbid polypharmacy patients, using the EU(7)-PIM and EURO-FORTA lists, with a focus on high-risk medications.

Methods: The integrated PIM tool used the information on PIMs in both databases—the EU(7)-PIM and EURO-FORTA. PIMs were classified into four color groups based on risk profile: high-risk PIMs (should be avoided in older patients) as red, moderate-risk PIMs (require dose and/or treatment duration adjustment) as yellow, low-risk PIMs (low DRP risk) as green, and questionable PIMs (incomplete/missing information) as grey.

Results: The summarized list of the high-risk (red and some grey) PIMs contained 81 active substances and medication classes. According to the ATC classification, most of the high-risk PIMs (n = 60, 74.1%) belong to the A, C, and N medication groups and 50.6% (n = 41) of the high-risk PIMs have currently marketing authorization in Estonia. The preliminary list of the moderate- and low-risk (yellow, green, and other grey) PIMs contained 240 active substances and medication classes, but sub-classification of this category into one or another group depends mainly on an individual patient´s clinical characteristics in a concrete analyzed study sample and needs further research.

Conclusion: The integrated clinical decision support tool based on the EU(7)-PIM and EURO-FORTA criteria addresses the need for more efficient identification of DRPs. It can be applied to identify PIMs and geriatric prescribing problems in different health care settings, and also in a context of little clinical information available.
Reveal the Antimigraine Mechanism of Chuanxiong Rhizoma and Cyperi Rhizoma Based on the Integrated Analysis of Metabolomics and Network Pharmacology
Authors: Zhu Zhiyao , Wu Sha , Wang Yuxuan , Wang Jiayi , Zhang Yujia
Published: March 2022

Migraine is a common neurological disorder that manifests as recurrent attacks of unilateral and throbbing headache. Conioselinum anthriscoides “Chuanxiong” (Apiaceae; Chuanxiong rhizoma) and Cyperus rotundus L. (Cyperaceae; Cyperi rhizoma) (CRCR), is a classic prescription for treating migraine. This study aimed to reveal the potential mechanisms of CRCR extract against migraine using integrated analysis of metabolomics and network pharmacology. Behavioral changes in the nitroglycerin rat migraine model were determined from von Frey withdrawal response. Untargeted serum metabolomics was used to identify the differentially expressed metabolites and metabolic pathways. The differentially expressed metabolites were analyzed to obtain the corresponding targets by a compound–reaction–enzyme–gene network. Network pharmacology was used to construct a compound–target–pathway network. The common targets of metabolomics and network pharmacology were further analyzed. Metabolomics analysis identified 96 differentially expressed metabolites and 77 corresponding targets. Network pharmacology analysis identified 201 potential targets for CRCR against migraine. By intersecting 77 targets with 201 targets, monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), and catechol-O-methyltransferase (COMT) were identified as the common targets, and MAO-A, MAO-B, and COMT were involved in the tyrosine metabolism pathway. Further experiments demonstrated that the contents of MAO-A and COMT were significantly increased in serum and brainstem tissue of the migraine rats. CRCR extract significantly decreased the contents of MAO-A and COMT, while no significant difference was found in MAO-B. Metabolomics analysis indicated that the contents of 3,4-dihydroxyphenylacetate (DOPAC) and 3-(4-hydroxyphenyl)pyruvate (HPP) were significantly increased in the migraine rats, and CRCR extract caused significant decreases in DOPAC and HPP. Interestingly, DOPAC and HPP were two differentially expressed metabolites involved in the tyrosine metabolism pathway. Correlation analysis showed that DOPAC and HPP were highly positively correlated with MAO-A and COMT. Taken together, two key differentially expressed metabolites (DOPAC and HPP), two key targets (MAO-A and COMT), and one relevant metabolic pathway (tyrosine metabolism) showed great importance in the treatment of migraine. This research could provide a new understanding of the potential mechanism of CRCR against migraine. More attentions should be paid into the tyrosine metabolism pathway in future studies.