bluuebunny/crossref_metadata_2025 huggingface dataset:
A Regulatory Risk-Based Approach to ATMP/CGT Development: Integrating Scientific Challenges With Current Regulatory Expectations
Authors: Salazar-Fontana Laura I.
Published: May 2022

Cell and Gene Therapy Products (CGT), regulated as Advanced Therapy Medicinal Products (ATMP) in the European Union (EU), represent a novel and varied group of biotherapeutics developed to treat specific conditions for which there are limited or no effective treatments. The novelty and complexity of this product modality demands a regulatory risk-based approach to define a sound development plan, particularly, as most developers aim to target more than one market area simultaneously for clinical development and registration. This regulatory strategy should be built on solid scientific data that also addresses general regulatory recommendations to enable a benefit:risk analysis that is aligned with the particularities of each CGT product. This risk-based approach is especially helpful when no detailed product-specific regulatory guidelines are available. The goal of this article is to orient developers on how to build a combined EU/US regulatory strategy through the assessment of commonly understood quality (CMC), non-clinical, and clinical regulatory risks faced by ATMP/CGT.
Cytokine Profile in Aqueous Humor of Patients With Ocular Toxocariasis
Authors: Jiang Zhaoxin , Sun Limei , Ding Xiaohu , Zhang Ting , Li Songshan , Ding Xiaoyan
Published: May 2022

Purpose

Ocular toxocariasis (OT) is a vision-threatening disease with a largely unknown intraocular pathogenesis. Herein, we determined the cytokine expression profile in aqueous humor (AH) of patients with OT.

Methods

This is a retrospective case-control study of cytokine levels in AH of patients with OT and uveitis and control subjects. Thirty samples from eyes with OT, 23 from eyes with non-OT uveitis, and 25 from eyes with age-related cataract were analyzed using a multiplexed magnetic bead immunoassay. Thirty-one cytokines were detected and classified into 5 categories: T-helper type 1 (Th1) -associated cytokines, Th2-associated cytokines, Th17 cytokine, proinflammatory mediators, and growth factors.

Results

In the 31 cytokines, 9 cytokines were undetectable, including IL-1a, IL-1b, IL-2, IL-3, IL-12p70, IL-17A, TGF-a, TNF-β, and IFN-g. From the 22 cytokines, 13 exhibited significantly increased expression in the OT group than in the control group, including TNF-a, IFN-a2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, sCD40L, PDGF-AA, PDGF-AB/BB, FLT3l, and EGF. There were 5 cytokines exhibited significantly increased expression in the OT group than in non-OT group, including IL-5, IL-9, IL-10, IL-13, and PDGF-AA. There was no significantly decreased expression in any cytokines in the OT group when compared with control or non-OT groups. To the 5 cytokines that showed significant difference in OT group alone, IL-10 and IL-13 exhibited more than 13-fold increase, and IL-5 showed the most obvious as 27-fold increase in OT patients, when compared with that in control group.

Conclusion

The cytokine profile expression in aqueous humor from patients with ocular toxocariasis was investigated, and our findings suggest that Th1 and Th17 cytokine responses are not enhanced, whereas the cytokine status was polarized toward a Th2 response. Our findings also suggest the involvement of IL-5, IL-10, and IL-13 in the immunopathogenesis of ocular toxocariasis.
Diversity, Antimicrobial Activity, and Antibiotic Susceptibility Pattern of Endophytic Bacteria Sourced From Cordia dichotoma L
Authors: Sharma Mahima , Mallubhotla Sharada
Published: May 2022

Endophytic bacteria isolated from medicinal plants are crucial for the production of antimicrobial agents since they are capable of possessing bioactive compounds with diverse structures and activities. Cordia dichotoma, a plant of medicinal importance native to the Jammu region of India, was selected for the isolation and characterization of culturable endophytic bacteria and evaluation of their antimicrobial activities. Standardized surface sterilization methods were employed to isolate thirty-three phenotypically distinguishable endophytic bacteria from the root, stem, and leaf parts of the plant. Shannon Wiener diversity index clearly divulged diverse endophytes in roots (0.85), stem (0.61), and leaf (0.54) tissues. Physio-biochemical features of the isolates differentiated the distinct variations in their carbohydrate utilization profile and NaCl tolerance. The endophytes produced an array of enzymes, namely, catalase, oxidase, amylase, cellulase, nitrate reductase, and lipase. The bacterial isolates belong to the genera Bacillus, Pseudomonas, Paenibacillus, Acidomonas, Streptococcus, Ralstonia, Micrococcus, Staphylococcus, and Alcalignes predominantly. However, the antibiotic susceptibility pattern indicated that the isolates were mostly sensitive to erythromycin and streptomycin, while they were resistant to rifampicin, amoxicillin, and bacitracin. Interestingly, majority of the bacterial endophytes of C. dichotoma showed antimicrobial activity against Bacillus subtilis followed by Klebsiella pneumoniae. The 16S rRNA sequence of Bacillus thuringiensis has been deposited in the NCBI GenBank database under accession number OM320575. The major compounds of the crude extract derived from endophytic B. thuringiensis OM320575, according to the metabolic profile examination by GC-MS, are dibutyl phthalate, eicosane, tetrapentacontane, heneicosane, and hexadecane, which possessed antibacterial activities. In conclusion, results indicated the potential of C. dichotoma to host a plethora of bacterial endophytes that produce therapeutic bioactive metabolites.
An Intelligent Self-Driving Truck System for Highway Transportation
Authors: Wang Dawei , Gao Lingping , Lan Ziquan , Li Wei , Ren Jiaping , Zhang Jiahui , Zhang Peng , Zhou Pei , Wang Shengao , Pan Jia , Manocha Dinesh , Yang Ruigang
Published: May 2022

Recently, there have been many advances in autonomous driving society, attracting a lot of attention from academia and industry. However, existing studies mainly focus on cars, extra development is still required for self-driving truck algorithms and models. In this article, we introduce an intelligent self-driving truck system. Our presented system consists of three main components, 1) a realistic traffic simulation module for generating realistic traffic flow in testing scenarios, 2) a high-fidelity truck model which is designed and evaluated for mimicking real truck response in real world deployment, and 3) an intelligent planning module with learning-based decision making algorithm and multi-mode trajectory planner, taking into account the truck's constraints, road slope changes, and the surrounding traffic flow. We provide quantitative evaluations for each component individually to demonstrate the fidelity and performance of each part. We also deploy our proposed system on a real truck and conduct real world experiments which show our system's capacity of mitigating sim-to-real gap. Our code is available at https://github.com/InceptioResearch/IITS.
Long-Term Cost-Effectiveness of Severity-Based Triaging for Large Vessel Occlusion Stroke
Authors: Gao Lan , Moodie Marj , Yassi Nawaf , Davis Stephen M. , Bladin Christopher F. , Smith Karen , Bernard Stephen , Stephenson Michael , Churilov Leonid , Campbell Bruce C. V. , Zhao Henry
Published: May 2022

Background and Purpose:

Pre-hospital severity-based triaging using the Ambulance Clinical Triage For Acute Stroke Treatment (ACT-FAST) algorithm has been demonstrated to substantially reduce time to endovascular thrombectomy in Melbourne, Australia. We aimed to model the cost-effectiveness of an ACT-FAST bypass system from the healthcare system perspective.

Methods

A simulation model was developed to estimate the long-term costs and health benefits associated with diagnostic accuracy of the ACT-FAST algorithm. Three-month post stroke functional outcome was projected to the lifetime horizon to estimate the long-term cost-effectiveness between two strategies (ACT-FAST vs. standard care pathways). For ACT-FAST screened true positives (i.e., screened positive and eligible for EVT), a 52 mins time saving was applied unanimously to the onset to arterial time for EVT, while 10 mins delay in thrombolysis was applied for false-positive (i.e., screened positive but was ineligible for EVT) thrombolysis-eligible infarction. Quality-adjusted life year (QALY) was employed as the outcome measure to calculate the incremental cost-effectiveness ratio (ICER) between the ACT-FAST algorithm and the current standard care pathway.

Results

Over the lifetime, ACT-FAST was associated with lower costs (–$45) and greater QALY gains (0.006) compared to the current standard care pathway, resulting in it being the dominant strategy (less costly but more health benefits). Implementing ACT-FAST triaging led to higher proportion of patients received EVT procedure (30 more additional EVT performed per 10,000 patients). The total Net Monetary Benefit from ACT-FAST care estimated at A$0.76 million based on its implementation for a single year.

Conclusions

An ACT-FAST severity-triaging strategy is associated with cost-saving and increased benefits when compared to standard care pathways. Implementing ACT-FAST triaging increased the proportion of patients who received EVT procedure due to more patients arriving at EVT-capable hospitals within the 6-h time window (when imaging selection is less rigorous).
The CSF Vancomycin Concentration in Patients With Post-operative Intracranial Infection Can Be Predicted by the WBCs to Total Cells Ratio and the Serum Trough Concentration
Authors: Fan Ming-Chao , Sun Jia-Lin , Sun Jian , Ma Jun-Wei , Wang Nian , Fang Wei
Published: May 2022

Background

The pharmacokinetics of vancomycin in cerebrospinal fluid (CSF) is an important basis for evaluating the bactericidal effect. The accuracy of using serum vancomycin concentrations only to estimate the CSF concentrations remains controversial, may lead to underdosing.

Objectives

The aims of this study were to evaluate the vancomycin exposure in CSF, investigate the factors affecting the vancomycin blood–brain barrier (BBB) penetration, and to establish the prediction model of vancomycin concentration in CSF.

Methods

Eligible patients were included and given a standard dose of vancomycin. At the fifth dose, the blood and CSF samples were collected 0.5 h before the start of infusion of vancomycin, and 1, 2, 3, and 8 h from the start of infusion, and were measured by the enzyme-multiplied immunoassay technique using the Siemens Viva-E Drug Testing System.

Results

The AUCCSF/serum of patients with intracranial infection was higher than that of patients without (p = 0.001). The CSF concentration was relatively stable between dosing periods (p = 0.095). The area under the concentration–time curve (AUC) ratio of CSF to serum (AUCCSF/serum) in patients with intracranial infection ranged from 15.1 to 80.1% (33.23 ± 19.31%; median, 26.25%). The CSF vancomycin AUC levels were affected by the serum trough concentration (B: 5.23 ± 2.36, t = 2.22, p = 0.039), and were mainly affected by the CSF white blood cells (WBCs)/total cells (B: 113.96 ± 35.10, t = 3.25, p = 0.004) (Y = −17.86 + 5.23 × serum trough concentration + 113.96 × CSF [WBCs/total cells]; R2 = 0.473, F = 8.542, p = 0.002).

Conclusions

After intravenous administration of vancomycin, the CSF concentration curve was fluctuated gently. The CSF vancomycin concentration in patients with postoperative intracranial infection can be predicted by the WBCs to total cells ratio and the serum trough concentration, and help to adjust the administration of vancomycin.
Architectural Narrative Shapes Brain Activities Underlying Approach-Avoidance Response: A Case Study of the Stadium
Authors: Zhang Weixia , Wei Hongyang , Chen Xiaowen , Hou Yuyang , Zhang Yujie , Huang Qian
Published: May 2022

Each great architecture tells a story to make its space meaningful. What the stadium tells matters how the individual interacts with it. The potent influence of narrative in shaping our cognitive processing has been revealed and widely used. This influence, however, has not been the focus of researchers in stadium operations. The present study aimed at investigating the influence of the stadium narrative on approach-avoidance responses and the corresponding neural correlates. Participants were presented with a sequence of pictures expressing a story congruent or incongruent with the general profile of the stadium, and were required to make an enter or exit response. Results showed larger amplitudes of N400 for incongruent trials than congruent trials at the end of the narrative, indicating the feasibility of continuity editing procedure for the study of narratives. Moreover, larger amplitudes of LPP were observed in response to the stadium preceded by congruent trials than incongruent trials. This effect was more pronounced in the left than right frontal sites. The LPP suggested that a congruent narrative imparted the stadium approaching affective features, and induced approaching responses, which was consistent with the behavioral and correlational results. Our findings suggested that changes in narrative were sufficient to shape the approach-avoidance responses and the underlying neural correlates. Implications for stadium management and buildings are provided.
Long March Toward Safe and Effective Analgesia by Enhancing Gene Expression of Kcc2: First Steps Taken
Authors: Liedtke Wolfgang
Published: May 2022

Low intraneuronal chloride in spinal cord dorsal horn pain relay neurons is critical for physiologic transmission of primary pain afferents because low intraneuronal chloride dictates whether GABA-ergic and glycin-ergic neurotransmission is inhibitory. If the neuronal chloride elevates to pathologic levels, then spinal cord primary pain relay becomes leaky and exhibits the behavioral hallmarks of pathologic pain, namely hypersensitivity and allodynia. Low chloride in spinal cord dorsal horn neurons is maintained by proper gene expression of Kcc2 and sustained physiologic function of the KCC2 chloride extruding electroneutral transporter. Peripheral nerve injury and other forms of neural injury evoke greatly diminished Kcc2 gene expression and subsequent corruption of inhibitory neurotransmission in the spinal cord dorsal horn, thus causing derailment of the gate function for pain. Here I review key discoveries that have helped us understand these fundamentals, and focus on recent insights relating to the discovery of Kcc2 gene expression enhancing compounds via compound screens in neurons. One such study characterized the kinase inhibitor, kenpaullone, more in-depth, revealing its function as a robust and long-lasting analgesic in preclinical models of nerve injury and cancer bone pain, also elucidating its mechanism of action via GSK3β inhibition, diminishing delta-catenin phosphorylation, and facilitating its nuclear transfer and subsequent enhancement of Kcc2 gene expression by de-repressing Kaiso epigenetic transcriptional regulator. Future directions re Kcc2 gene expression enhancement are discussed, namely combination with other analgesics and analgesic methods, such as spinal cord stimulation and electroacupuncture, gene therapy, and leveraging Kcc2 gene expression-enhancing nanomaterials.
Genetically Modified Mouse Models of Congenital Diaphragmatic Hernia: Opportunities and Limitations for Studying Altered Lung Development
Authors: Friedmacher Florian , Rolle Udo , Puri Prem
Published: May 2022

Congenital diaphragmatic hernia (CDH) is a relatively common and life-threatening birth defect, characterized by an abnormal opening in the primordial diaphragm that interferes with normal lung development. As a result, CDH is accompanied by immature and hypoplastic lungs, being the leading cause of morbidity and mortality in patients with this condition. In recent decades, various animal models have contributed novel insights into the pathogenic mechanisms underlying CDH and associated pulmonary hypoplasia. In particular, the generation of genetically modified mouse models, which show both diaphragm and lung abnormalities, has resulted in the discovery of multiple genes and signaling pathways involved in the pathogenesis of CDH. This article aims to offer an up-to-date overview on CDH-implicated transcription factors, molecules regulating cell migration and signal transduction as well as components contributing to the formation of extracellular matrix, whilst also discussing the significance of these genetic models for studying altered lung development with regard to the human situation.
Adenosine in Acute Myocardial Infarction-Associated Reperfusion Injury: Does it Still Have a Role?
Authors: De Marco Corrado , Charron Thierry , Rousseau Guy
Published: May 2022

The mainstay of acute myocardial infarction has long been timely reperfusion of the culprit obstruction. Reperfusion injury resulting from a multitude of pathophysiological processes has been demonstrated to negatively affect myocardial recovery and function post-infarction. Adenosine interacts directly with the sequential pathophysiological processes culminating in reperfusion injury by inhibiting them upstream. The evidence for adenosine’s benefit in acute myocardial infarction has produced mixed results with regards to myocardial salvage and long-term mortality. The heterogenous evidence with regards to benefits on clinical outcomes has resulted in modest uptake of adenosine in the clinical setting. However, it is critical to analyze the variability in study methodologies. The goal of this review is to evaluate how adenosine dose, route of administration, timing of administration, and site of administration play essential roles in the molecule’s efficacy. The benefits of adenosine, as highlighted in the following review, are clear and its role in the treatment of acute myocardial infarction should not be discounted
The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy
Authors: Wiesinger Anna-Maria , Bigger Brian , Giugliani Roberto , Scarpa Maurizio , Moser Tobias , Lampe Christina , Kampmann Christoph , Lagler Florian B.
Published: May 2022

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs). GAG storage-induced inflammatory processes are a driver of cytopathology in MPS and pharmacological immunomodulation can bring improvements in brain, cartilage and bone pathology in rodent models. This manuscript reviews current knowledge with regard to inflammation in MPS patients and provides hypotheses for the therapeutic use of immunomodulators in MPS. Thus, we aim to set the foundation for a rational repurposing of the discussed molecules to minimize the clinical unmet needs still remaining despite enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).
Analysis of Students' Sports Exercise Behavior and Health Education Strategy Using Visual Perception–Motion Recognition Algorithm
Authors: Chen Minwei , Zhou Yunzheng
Published: May 2022

This study aims to explore the future development path of the college health education and health education's impact on students' sports exercise. Specifically, artificial intelligence (AI) algorithm is combined with intelligent robotics technology to acquire and analyze students' sports exercise behaviors. As a result, a new development model is formulated for college health education. First, it explores students' sports exercise and health education situation in Chinese higher institutions and uncovers the underlying problems. Then it puts forward the corresponding modification suggestions. Second, the AI algorithm and the Kinect sensor-mounted intelligent robot capture the human skeleton features to obtain smooth skeleton joint points data. At the same time, a visual perception human motion recognition (HMR) algorithm is established based on the Hidden Markov Model (HMM). Afterward, the proposed HMM-based HMR algorithm is used to recognize students' sports exercise motions by analyzing human motion skeleton images. The experimental outcomes suggest that the maximum reconstruction error of the HMR algorithm is 10 mm, and the compression ratio is between 5 and 10; the HMR rate is more than 96%. Compared with similar algorithms, the proposed visual perception HMR algorithm depends less on the number of training samples. It can achieve a high recognition rate given only a relatively few samples. Therefore, the proposed (AI + intelligent robot)-enabled HMM-based HMR algorithm can effectively identify the behavior characteristics of students in sports exercise. This study can provide a reference for exploring college students' health education development path.
Knowledge Sharing Types as Predictors of Job Performance Mediated by Problem-Solving Self-Efficacy in the Information System Integration Service Industry
Authors: Hong Jon-Chao , Lee Yi-Fang , Chen Hsin-Han , Nguyen Hoang Bao Ngoc
Published: May 2022

Knowledge sharing is an essential approach to creative problem solving in technology firms, but few studies have considered the information system integration service industry. To address this gap, drawing on the micro-ecology theory, we developed a research model to explore the mediating role of four types of knowledge sharing (i.e., automatic response, rational reflection, ridiculed reflection, and stolen reflection) in the relationship between problem solving self-efficacy (PSSE) and IT workers’ job performance. Data were collected from 307 System Integration IT workers by using the snowball sampling methodviaa Google questionnaire. Structural equation modeling was used to test the hypotheses of the relationships between the variables. The results showed that PSSE can positively predict four knowledge sharing types; except for stolen reflection, the others can positively predict job performance. The implication of this study is that automatic response systems and rational reflection systems in knowledge sharing can enhance job performance, supported by PSSE. It is hoped that managers can generate System Integration workers’ rational reflection to effectively evoke knowledge sharing.
The Relationship Between Sleep Duration and Blood Lipids Among Chinese Middle-Aged and Older Adults: Cross-Lagged Path Analysis From CHARLS
Authors: Chen Ziwei , Zhang Xia , Duan Yanran , Mo Tingting , Liu Wenli , Ma Yilei , Yin Ping
Published: May 2022

This study used data from the China Health and Retirement Longitudinal Study to investigate the temporal relationship between blood lipids and sleep duration in Chinese middle-aged and older adults. We used medical examinations and questionnaire data of 5,016 Chinese middle-aged and older adults (age 45+) in 2011 and 2015. Cross-lagged path analysis was performed to examine the bidirectional relationships between blood lipids and sleep duration. Sleep duration and lipids data were analyzed as continuous variables. Temporal relationships between sleep duration and HDL-cholesterol, LDL-cholesterol, total cholesterol, and triglycerides were different. Sleep duration was negatively associated with HDL-cholesterol 4 year later (β1 = −0.171, P = 0.005), and HDL-cholesterol was negatively associated with sleep duration 4 year later (β2 = −0.006, P = 0.002). Longer sleep duration was associated lower levels of LDL-cholesterol (β1 = −0.275, P = 0.097) and total cholesterol (β1 = −0.329, P = 0.096) 4 year later. There was a positive correlation between triglycerides and sleep duration. The path coefficient from triglycerides to sleep duration 4 year later (β2 = 0.001, P = 0.018) was greater than that from sleep duration to triglycerides 4 year later (β1 = 0.109, P = 0.847), with P = 0.030 for the difference between β1 and β2. In stratified analysis, we found that the strength and direction of the relationships may be related to age and BMI. Effects of sleep duration on blood lipids were only observed among participants aged <60 years, while the effect in the opposite direction was observed in older adults (age 60+), and the cross-lagged path coefficients were more significant in adults with BMI > 25.
Impact of Employees' Workplace Environment on Employees' Performance: A Multi-Mediation Model
Authors: Zhenjing Gu , Chupradit Supat , Ku Kuo Yen , Nassani Abdelmohsen A. , Haffar Mohamed
Published: May 2022

This study examined the impact of workplace environment on employee task performance under the mediating role of employee commitment and achievement-striving ability. For this purpose, data were collected from the academic staff under a cross-sectional research design, and they were approached through convenience sampling technique. As per recommendations of established sample size criteria, we distributed a sum of 420 questionnaires among the respondents. Among these distributed questionnaires, only 330 were received back. The returned questionnaires were checked for missing and incomplete responses and after discarding the missing responses useable responses were 314 which were used for the data analysis. Data had been analyzed through structural equation modeling (SEM) by using Smart PLS 3. The SEM was done based on measurement models and structural models. The results indicated that a positive work environment had the power to improve employee performance. Similarly, a positive work environment also improved the employee commitment level and achievement-striving ability significantly. Both employee commitment and achievement-striving ability also improved employee performance. While in the case of mediation, it had also been observed that workplace environment triggered employee commitment and employee achievement-striving ability which further improved employee performance.
Knowledge Needs in Rehabilitation: Perspectives of Service Users and Professionals
Authors: Sipari Salla , Tammelin Mia , Helenius Sari , Janhunen Eija , Rantakokko Merja , Vänskä Nea , Harra Toini
Published: May 2022

Applying rehabilitation research knowledge in practice is challenging due to a gap between scientific knowledge produced by researchers and the needs of practical rehabilitation. This study describes the current and future knowledge needs of rehabilitation research from the perspectives of professionals and service users. We conducted a qualitative study with inductive content analysis from nine focus group interviews with rehabilitation stakeholders. The results show that current knowledge needs are strongly related to the meaningful and inclusive life of service users, the promotion of multi- and interprofessionalism in rehabilitation, and transdisciplinary applied research on rehabilitation. The future knowledge needs were related to the changing needs of rehabilitation and remote rehabilitation based on rapid change in society and digitalisation and on different rehabilitation practices and contexts. The results of the study can be used to enable favorable conditions for reciprocal research, development, and innovation (RDI) activities and research networks in transdisciplinary rehabilitation.
Acute Appendicitis: What Is It and How Do Doctors Treat It?
Authors: Gonçalves Nuno , Oliveira Olga , Pereira Joaquim Costa
Published: May 2022

Acute appendicitis is the medical term for inflammation of the appendix, which is a tubular structure located at the beginning of the large intestine. Acute appendicitis is usually caused by a blockage of the appendix, increasing the pressure inside it and decreasing its blood supply. Acute appendicitis is a very common disease, mostly affecting people 10–20 years old. The usual symptoms are abdominal pain, located at the center of the abdomen and moving to the lower right quadrant, accompanied by fever and loss of appetite. The best available treatment is surgery to remove the appendix. Surgery can be done in a way that leaves only a small scar. The patient is usually discharged from the hospital 2–3 days after surgery, and most people have a full and fast recovery.
Formamide-Based Post-impact Thermal Prebiotic Synthesis in Simulated Craters: Intermediates, Products and Mechanism
Authors: Ferus Martin , Knížek Antonín , Petera Lukáš , Pastorek Adam , Hrnčířová Jana , Jankovič Luboš , Ivanek Ondřej , Šponer Jiří , Křivková Anna , Saeidfirozeh Homa , Civiš Svatopluk , Chatzitheodoridis Elias , Mráziková Klaudia , Nejdl Lukáš , Saija Franz , Šponer Judit E. , Cassone Giuseppe
Published: May 2022

Influx of matter from impacting meteoroids and hydrothermal crater weathering are important factors modifying the rock and mineral inventory of young planets undergoing heavy bombardment. These processes may have influenced not only the geochemical environment of, e.g., early Mars and other planets, but also the peculiar prebiotic chemistry on early Earth. Here, we present a synergistic experimental and computational investigation of the intermediates of chemical reactions of the formamide-based synthesis of canonical and non-canonical nucleobases by thermochemistry in hot hydrothermal crater environments. We put our findings into context with previously investigated plasma-initiated synthesis occuring directly during impact. Both processes result into the formation of all canonical nucleobases, hypoxanthine, purine, and into the onset of the simplest amino acid glycine. Furthermore, it turns out that radical species such as CN and H play a key role in the plasma-assisted impact chemistry. However, post-impact thermochemistry is essential for the origin of formamidine and 2-aminoacetonitrile, intermediate species detected in this study by means of FTIR spectroscopy.
Innovative Technical Solution Using the Renal Artery Stump after Nephrectomy as an Inflow Artery for Lower Limb Revascularization—A Case Report
Authors: Russu Eliza , Mureșan Adrian Vasile , Kaller Reka , Toma Lucian , Coșarcă Cătălin Mircea , Chibelean Călin Bogdan , Arbănași Emil Marian , Arbănași Eliza Mihaela
Published: May 2022

We present the case of a 56-year-old patient admitted to the vascular unit of the Targu Mures County Emergency Clinical Hospital after a computed tomography angiography performed for critical limb ischemia showed a tumor of the right kidney of 11.3/12/11 cm anteroposterior/later-lateral/craniocaudal, accompanied by an abdominal aortic aneurysm (AAA) (3 cm diameter) and right iliac artery occlusion. An interdisciplinary team formed of urological and vascular surgeons decided and performed a one-step operation. The right kidney was removed, and the limb revascularization was achieved by performing a bypass that used the right renal arterial stump as an inflow artery, thus called a reno-femoral bypass. The AAA had no indication for reconstruction. The final pathology interpretation of the kidney tumor revealed a clear cell renal cell carcinoma, excised with oncological safety margins. A short-term follow-up found the patient without ischemic symptomatology and a fully functional graft.
Diagnostic Accuracy of Magnetic Resonance Enterography for the Evaluation of Active and Fibrotic Inflammation in Crohn’s Disease
Authors: Loch Florian N. , Kamphues Carsten , Beyer Katharina , Klauschen Frederick , Schineis Christian , Weixler Benjamin , Lauscher Johannes C. , Dorenbeck Marc , Bayerl Christian , Reiter Rolf
Published: May 2022

Background

Despite the success of standard magnetic resonance enterography (MRE) in detecting Crohn’s disease (CD), characterization of strictures and, thus, therapy guidance is still limited. The aim of the study was to determine diagnostic accuracy of MRE in detecting or ruling out active inflammation and identifying fibrotic lesions in patients with terminal ileal CD with histopathology as reference.

Methods

Sixty-seven consecutive patients (median age 32 years, range 19–79 years) with terminal ileal CD were retrospectively enrolled between January 2015 and October 2020. The median interval between MRE and surgery was 9 days (range 0–86 days). Sensitivity, specificity, positive and negative predictive value (PPV and NPV, respectively), and area under the curve (AUC) with 95% confidence intervals (CIs) were calculated for the MRE-based AIS (acute inflammation score) using the histopathology of surgical specimens as the reference standard.

Results

Sensitivity, specificity, PPV, and NPV for detecting or ruling out active inflammation were 100% (CI, 0.94–1.00; 0.44–1.00; 0.93–1.00; 0.31–1.00) using an AIS cut-off of >4.1. AUC was 1.00 (CI, 1.00–1.00; p < 0.01). In all patients with fibrotic changes only and no active inflammation, AIS was <4.1. Interobserver agreement was substantial (κ = 0.65, p < 0.01).

Conclusion

Our study has shown an excellent diagnostic performance of the MRE-based AIS for determining whether active inflammation is present or lesions are due to chronic changes in ileal CD using the histopathology of surgical specimens as reference. These findings indicate that the MRE-based AIS allows a better determination of the inflammatory stage of terminal ileal CD, which facilitates the decision to perform surgery.
Antimicrobial Resistance and Comparative Genomic Analysis of Elizabethkingia anophelis subsp. endophytica Isolated from Raw Milk
Authors: Andriyanov Pavel A. , Zhurilov Pavel A. , Kashina Daria D. , Tutrina Anastasia I. , Liskova Elena A. , Razheva Irina V. , Kolbasov Denis V. , Ermolaeva Svetlana A.
Published: May 2022

Elizabethkingia anophelis is an emerging multidrug-resistant pathogen that causes severe nosocomial and community-acquired infections worldwide. We report the first case of E. anophelis isolation in Russia and the first isolation from raw cow’s milk. The ML-44 demonstrated resistance to 28 antimicrobials of 33 tested in the disk-diffusion test. Whole genome-based phylogeny showed ML-44 strain clustered together with the F3201 strain isolated from a human patient in Kuwait in 1982. Both strains were a part of the “endophytica” clade. Another clade was formed by subsp. anophelis strains. Each of the E. anophelis compared genomes carried 18 to 21 antibiotic resistance determinants. The ML-44 chromosome harbored nine efflux system genes and three beta-lactamase genes, along with six other antimicrobial resistance genes. In total, 72 virulence genes were revealed. The set of virulence factors was quite similar between different E. anophelis strains and included LPS and capsule encoded genes, type IV pili, oxidative stress response genes, and genes encoding TIVSS and TVISS effectors. The particular interest caused the mip and zmp1 gene homologs, which can be essential for intracellular survival. In sum, our findings suggest that raw milk might be a source of E. anophelis harboring a set of virulence factors and a broad resistance to generally used antimicrobials.
Nitric Oxide Production and Regulation in the Teleost Cardiovascular System
Authors: Giordano Daniela , Verde Cinzia , Corti Paola
Published: May 2022

Nitric Oxide (NO) is a free radical with numerous critical signaling roles in vertebrate physiology. Similar to mammals, in the teleost system the generation of sufficient amounts of NO is critical for the physiological function of the cardiovascular system. At the same time, NO amounts are strictly controlled and kept within basal levels to protect cells from NO toxicity. Changes in oxygen tension highly influence NO bioavailability and can modulate the mechanisms involved in maintaining the NO balance. While NO production and signaling appears to have general similarities with mammalian systems, the wide range of environmental adaptations made by fish, particularly with regards to differing oxygen availabilities in aquatic habitats, creates a foundation for a variety of in vivo models characterized by different implications of NO production and signaling. In this review, we present the biology of NO in the teleost cardiovascular system and summarize the mechanisms of NO production and signaling with a special emphasis on the role of globin proteins in NO metabolism.
Bee Pollen Extracts: Chemical Composition, Antioxidant Properties, and Effect on the Growth of Selected Probiotic and Pathogenic Bacteria
Authors: Ilie Cornelia-Ioana , Oprea Eliza , Geana Elisabeta-Irina , Spoiala Angela , Buleandra Mihaela , Gradisteanu Pircalabioru Gratiela , Badea Irinel Adriana , Ficai Denisa , Andronescu Ecaterina , Ficai Anton , Ditu Lia-Mara
Published: May 2022

This paper evaluated the chemical and biological properties of bee pollen samples from Romania. Firstly, the bee pollen alcoholic extracts (BPEs) were obtained from raw bee pollen harvested by Apis mellifera carpatica bees. The chemical composition of BPE was obtained by determination of total phenol content and total flavonoid content, UHPLC-DAD-ESI/MS analysis of phenolic compounds, and GC-MS analysis of fatty acids, esters, and terpenes. Additionally, the antioxidant activity was evaluated by the Trolox Equivalent Antioxidant Capacity method. Furthermore, the biological properties of BPE were evaluated (antimicrobial and cytotoxic activity). The raw BP samples studied in this paper had significant phenolic acid and flavonoid content, and moderate fatty acid, ester, and terpene content. P1, P2, and P4 have the highest TPC and TFC levels, and the best antioxidant activity. All BPEs studied had antimicrobial activity on pathogenic strains isolated from the clinic or standard strains. A synergistic antimicrobial effect of the BPEs was observed along with the soluble compounds of L. rhamnosus MF9 and E. faecalis 2M17 against some pathogenic (clinical) strains and, considering the tumour proliferation inhibitory activity, makes BP a potential prebiotic and antitumour agent for the gut environment.
18β-Glycyrrhetinic Acid Protects against Cholestatic Liver Injury in Bile Duct-Ligated Rats
Authors: Pan Pin-Ho , Wang Ya-Yu , Lin Shih-Yi , Liao Su-Lan , Chen Yu-Fang , Huang Wei-Chi , Chen Chun-Jung , Chen Wen-Ying
Published: May 2022

18β-Glycyrrhetinic acid is a nutraceutical agent with promising hepatoprotective effects. Its protective mechanisms against cholestatic liver injury were further investigated in a rodent model of extrahepatic cholestasis caused by Bile Duct Ligation (BDL) in rats. The daily oral administration of 18β-Glycyrrhetinic acid improved liver histology, serum biochemicals, ductular reaction, oxidative stress, inflammation, apoptosis, impaired autophagy, and fibrosis. 18β-Glycyrrhetinic acid alleviated the BDL-induced hepatic and systemic retention of bile acids, matrix-producing cell activation, hepatic collagen deposition, Transforming Growth Factor beta-1/Smad activation, malondialdehyde elevation, glutathione reduction, High Mobility Group Box-1/Toll-Like Receptor-4 activation, NF-κB activation, inflammatory cell infiltration/accumulation, Interleukin-1β expression, Signal Transducer and Activator of Transcription-1 activation, Endoplasmic Reticulum stress, impairment autophagy, and caspase 3 activation. Conversely, the protein expression of Sirt1, Farnesoid X Receptor, nuclear NF-E2-Related Factor-2, Transcription Factor EB, bile acid efflux transporters, and LC3-II, as well as the protein phosphorylation of AMP-Activated Protein Kinase, was promoted in 18β-Glycyrrhetinic acid-treated BDL rats. The hepatoprotective effects of 18β-Glycyrrhetinic acid in the present investigation correlated well with co-activation and possible interactions among Sirt, FXR, and Nrf2. The concurrent or concomitant activation of Sirt1, FXR, and Nrf2 not only restored the homeostatic regulation of bile acid metabolism, but also alleviated oxidative stress, inflammation, apoptosis, impaired autophagy, and fibrosis.
Morin Disrupts Cytoskeleton Reorganization in Osteoclasts through an ROS/SHP1/c-Src Axis and Grants Protection from LPS-Induced Bone Loss
Authors: Park Hyun-Jung , Park Jung-Nam , Yoon Sun-Young , Yu Rina , Suh Jae-Hee , Choi Hye-Seon
Published: May 2022

Morin is a naturally occurring flavonoid with anti-inflammatory and antioxidative properties. Therefore, we hypothesized that morin may prevent inflammatory bone loss by reducing oxidative stress. To investigate the effect of morin on inflammatory bone loss, mice were injected with lipopolysaccharide (LPS). Osteoclasts (OCs) were analyzed by tartrate-resistant acid phosphatase (TRAP) staining and actin ring formation. Micro-computerized tomography analysis indicated that morin prevented LPS-induced bone loss in mice. In vivo TRAP staining indicated that morin decreased the number and surface of the OCs that were increased in LPS-treated mice. Furthermore, in vitro experiments indicated that morin decreased the number and activity of OCs upon LPS stimulation. Morin decreased actin ring-containing OCs with decreased activation of c-Src (Y416)/vav guanine nucleotide exchange factor 3/Ras-related C3 botulinum toxin substrate 1 compared with LPS alone. Morin decreased cytosolic reactive oxygen species (ROS), thus preventing the oxidation of Src homology region 2 domain-containing phosphatase 1 (SHP-1), followed by the inactivation of c-Src via direct interaction with SHP1. Conversely, SHP1 knockdown abolished the inhibitory effect of morin on OCs. Therefore, our findings suggest that morin disrupted cytoskeletal reorganization via an ROS/SHP1/c-Src axis in OCs, thereby granting protection from LPS-induced bone loss, which demonstrates its therapeutic potential against inflammatory bone loss.
Selenium Nanoparticles (SeNPs) Immunomodulation Is More Than Redox Improvement: Serum Proteomics and Transcriptomic Analyses
Authors: Xia Ivan Fan , Kong Hang-Kin , Wu Margaret M. H. , Lu Yishan , Wong Ka-Hing , Kwok Kevin W. H.
Published: May 2022

Selenium nanoparticles (SeNPs) are a novel elemental form selenium and often reported to possess beneficial bioactivities such as anticancer, promoting bone growth and immunomodulation. Our previous study demonstrated that chitosan-stabilized SeNPs have strong activity in immunomodulation. However, the mechanism underlying the immunomodulation of SeNPs is still unknown. The aim of this study is to identify the molecular mechanisms involved in SeNP-induced immunomodulation. Using zebrafish, as a common immunological animal model with a highly conserved molecular mechanism with other vertebrates, we conducted serum proteomic and tissue transcriptome analyses on individuals fed with SeNP in healthy or disease conditions. We also compared differences between SeNPs and an exogenous antioxidant Trolox in immune activity and redox regulation. Our results suggest that the immunomodulation activity was highly related to antioxidant activity and lipid metabolism. Interestingly, the biological functions enhanced by SeNP were almost identical in the healthy and disease conditions. However, while the SeNP was suppressing ROS in healthy individuals, it promoted ROS formation during disease condition. This might be related to the defense mechanism against pathogens. SOD and NFkβ appeared to be the key molecular switch changing effect of SeNPs when individuals undergo infection, indicating the close relationship between immune and redox regulation.
Redox Balance in β-Thalassemia and Sickle Cell Disease: A Love and Hate Relationship
Authors: Bou-Fakhredin Rayan , De Franceschi Lucia , Motta Irene , Eid Assaad A. , Taher Ali T. , Cappellini Maria Domenica
Published: May 2022

β-thalassemia and sickle cell disease (SCD) are inherited hemoglobinopathies that result in both quantitative and qualitative variations in the β-globin chain. These in turn lead to instability in the generated hemoglobin (Hb) or to a globin chain imbalance that affects the oxidative environment both intracellularly and extracellularly. While oxidative stress is not among the primary etiologies of β-thalassemia and SCD, it plays a significant role in the pathogenesis of these diseases. Different mechanisms exist behind the development of oxidative stress; the result of which is cytotoxicity, causing the oxidation of cellular components that can eventually lead to cell death and organ damage. In this review, we summarize the mechanisms of oxidative stress development in β-thalassemia and SCD and describe the current and potential antioxidant therapeutic strategies. Finally, we discuss the role of targeted therapy in achieving an optimal redox balance.
Adenosine, Adenosine Receptors and Neurohumoral Syncope: From Molecular Basis to Personalized Treatment
Authors: Guieu Régis , Degioanni Clara , Fromonot Julien , De Maria Lucille , Ruf Jean , Deharo Jean , Brignole Michele
Published: May 2022

Adenosine is a ubiquitous nucleoside that is implicated in the occurrence of clinical manifestations of neuro-humoral syncope (NHS). NHS is characterized by a drop in blood pressure due to vasodepression together with cardio inhibition. These manifestations are often preceded by prodromes such as headaches, abdominal pain, feeling of discomfort or sweating. There is evidence that adenosine is implicated in NHS. Adenosine acts via four subtypes of receptors, named A1 (A1R), A2A (A2AR), A2B (A2BR) and A3 (A3R) receptors, with all subtypes belonging to G protein membrane receptors. The main effects of adenosine on the cardiovascular system occurs via the modulation of potassium ion channels (IK Ado, K ATP), voltage-gate calcium channels and via cAMP production inhibition (A1R and A3R) or, conversely, through the increased production of cAMP (A2A/BR) in target cells. However, it turns out that adenosine, via the activation of A1R, leads to bradycardia, sinus arrest or atrioventricular block, while the activation of A2AR leads to vasodilation; these same manifestations are found during episodes of syncope. The use of adenosine receptor antagonists, such as theophylline or caffeine, should be useful in the treatment of some forms of NHS. The aim of this review was to summarize the main data regarding the link between the adenosinergic system and NHS and the possible consequences on NHS treatment by means of adenosine receptor antagonists.
Significantly Altered Serum Levels of NAD, AGE, RAGE, CRP, and Elastin as Potential Biomarkers of Psoriasis and Aging—A Case-Control Study
Authors: Karas Adam , Holmannova Drahomira , Borsky Pavel , Fiala Zdenek , Andrys Ctirad , Hamakova Kvetoslava , Svadlakova Tereza , Palicka Vladimir , Krejsek Jan , Rehacek Vit , Esterkova Monika , Kovarikova Helena , Borska Lenka
Published: May 2022

Background: This study aims to investigate potential markers of psoriasis and aging, and to elucidate possible connections between these two processes. Methods: The serum samples of 60 psoriatic patients and 100 controls were analysed, and the levels of four selected parameters (AGEs, RAGE, NAD, and elastin) were determined using commercial ELISA kits. Serum C-reactive protein was assayed using an immune-nephelometry method. Findings: Among the patients, the levels of CRP, AGEs, and RAGE were all increased, while the levels of NAD were reduced when compared to the control group. A negative correlation between the levels of AGEs and NAD was found. A negative correlation between age and the NAD levels among the control group was observed, however among the patients the relationship was diminished. While there was no difference in the levels of native elastin between the patients and the controls, a positive correlation between the levels of native elastin and age and a negative correlation between the levels of native elastin and the severity of psoriasis were found. Conclusions: The results of our study support the notion of psoriasis and possibly other immune-mediated diseases accelerating the aging process through sustained systemic damage. The serum levels of CRP, NAD, AGEs, and RAGE appear to be promising potential biomarkers of psoriasis. The decrease in the serum levels of NAD is associated with (pro)inflammatory states. Our analysis indicates that the levels of native elastin might strongly reflect both the severity of psoriasis and the aging process.