bluuebunny/crossref_metadata_2025 huggingface dataset:
Listeria monocytogenes: Investigation of Fitness in Soil Does Not Support the Relevance of Ecotypes
Authors: Sévellec Yann , Ascencio Eliette , Douarre Pierre-Emmanuel , Félix Benjamin , Gal Laurent , Garmyn Dominique , Guillier Laurent , Piveteau Pascal , Roussel Sophie
Published: June 2022

Listeria monocytogenes (Lm) is a ubiquitous bacterium that causes the serious foodborne illness listeriosis. Although soil is a primary reservoir and a central habitat for Lm, little information is available on the genetic features underlying the fitness of Lm strains in this complex habitat. The aim of this study was to identify (i) correlations between the strains fitness in soil, their origin and their phylogenetic position (ii) identify genetic markers allowing Lm to survive in the soil. To this end, we assembled a balanced panel of 216 Lm strains isolated from three major ecological compartments (outdoor environment, animal hosts, and food) and from 33 clonal complexes occurring worldwide. The ability of the 216 strains to survive in soil was tested phenotypically. Hierarchical clustering identified three phenotypic groups according to the survival rate (SR): phenotype 1 “poor survivors” (SR < 2%), phenotype 2 “moderate survivors” (2% < SR < 5%) and phenotype 3 “good survivors” (SR > 5%). Survival in soil depended neither on strains’ origin nor on their phylogenetic position. Genome-wide-association studies demonstrated that a greater number of genes specifically associated with a good survival in soil was found in lineage II strains (57 genes) than in lineage I strains (28 genes). Soil fitness was mainly associated with variations in genes (i) coding membrane proteins, transcription regulators, and stress resistance genes in both lineages (ii) coding proteins related to motility and (iii) of the category “phage-related genes.” The cumulative effect of these small genomic variations resulted in significant increase of soil fitness.
Development of a Lateral Flow Strip-Based Recombinase-Aided Amplification for Active Chlamydia psittaci Infection
Authors: Jiao Jun , Qi Yong , He Peisheng , Wan Weiqiang , OuYang Xuan , Yu Yonghui , Wen Bohai , Xiong Xiaolu
Published: June 2022

Chlamydia psittaci is the causative agent of psittacosis, a worldwide zoonotic disease. A rapid, specific, and sensitive diagnostic assay would be benefit for C. psittaci infection control. In this study, an assay combining recombinase-aided amplification and a lateral flow strip (RAA-LF) for the detection of active C. psittaci infection was developed. The RAA-LF assay targeted the CPSIT_RS02830 gene of C. psittaci and could be accomplished in 15 min at a single temperature (39°C). The analytical sensitivity of the assay was as low as 1 × 100 copies/μl and no cross-reaction with some other intracellular pathogens was observed. Moreover, all feces samples from mice infected with C. psittaci at day-1 post-infection were positive in the RAA-LF assay. In conclusion, the RAA-LF assay provides a convenient, rapid, specific and sensitive method for detection of active C. psittaci infection and it is also suitable for C. psittaci detection in field.
Exonuclease 1 is a Potential Diagnostic and Prognostic Biomarker in Hepatocellular Carcinoma
Authors: Ma Jiaxiu , Jin Jiapei , Lu Huishuang , Zhang Jin , Li Yalan , Cai Xuefei
Published: June 2022

Background: Hepatocellular carcinoma (HCC) represents a global health challenge. Effective biomarkers are required for an early diagnosis to improve the survival rates of HCC patients. Exonuclease 1 (EXO1) plays a significant role in the DNA repair and recombination mechanisms. This study aimed to investigate the diagnostic and prognostic roles of EXO1 in HCC.

Methods: We analyzed the EXO1 expression levels in various cancers including HCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. RNA sequencing data were analyzed using the R packages to determine differentially expressed genes (DEGs) between high- and low-EXO1 expressing HCC tissues from the TCGA–LIHC database. A Spearman’s correlation analysis was performed to determine the association between EXO1 expression and immune cell infiltration, and immune checkpoint genes and TP53. MethSurv and CBioPortal databases were used to evaluate the DNA methylation changes and genetic alterations in the EXO1 gene. A logistic regression analysis was performed to determine the association between EXO1 expression and the clinicopathological characteristics of the HCC patients. The diagnostic and prognostic predictive values of EXO1 were evaluated using the Kaplan–Meier (K-M) survival curves, diagnostic receiver operating characteristic (ROC) curves, nomogram model, and Cox regression analysis.

Results: EXO1 expression levels were significantly higher in the tumor tissues and serums of HCC patients compared to the corresponding controls. The DEGs associated with EXO1 were significantly enriched in the cell proliferation pathways. EXO1 expression levels significantly correlated with immune cell infiltration, immune checkpoint genes, and TP53 in the HCC tissues. The DNA methylation status in five CpG islands of the EXO1 gene was associated with the prognosis of HCC. EXO1 expression levels in the HCC tissues were associated with the tumor grades, alpha-fetoprotein (AFP) levels, and the tumor stages. Cox regression analysis showed that EXO1 was a potential independent risk factor for the overall survival (OS) and disease-specific survival (DSS) of HCC patients. ROC curve analysis showed that EXO1 expression levels accurately distinguished HCC tissues from the adjacent normal liver tissues.

Conclusion: Our study demonstrated that EXO1 was a potential diagnostic and prognostic biomarker, and a promising therapeutic target in HCC.
Recent Molecular Insights into Agonist-specific Binding to the Mu-Opioid Receptor
Authors: Zádor Ferenc , Király Kornél , Essmat Nariman , Al-Khrasani Mahmoud
Published: June 2022

Opioid agonists produce their analgesic effects primarily by acting at the µ-opioid receptor (µOR). µOR agonists with different efficacies exert diverse molecular changes in the µOR which dictate the faith of the receptor’s signaling pathway and possibly it’s the degree of desensitization. Since the development of the active conformations of the µOR, growing data have been published in relation to ligand-specific changes in µOR activation. In this regard, this review summarizes recent data regarding the most studied opioid agonists in in silico µOR activation, including how these ligands are recognized by the µOR, how their binding signal is transmitted toward the intracellular parts of the µOR, and finally, what type of large-scale movements do these changes trigger in the µOR’s domains.
Phosphorylated Tau 181 Serum Levels Predict Alzheimer’s Disease in the Preclinical Stage
Authors: Qin Wei , Li Fangyu , Jia Longfei , Wang Qi , Li Ying , Wei Yiping , Li Yan , Jin Hongmei , Jia Jianping
Published: June 2022

Background

There is an urgent need for cost-effective, easy-to-measure biomarkers to identify subjects who will develop Alzheimer’s disease (AD), especially at the pre-symptomatic stage. This stage can be determined in autosomal dominant AD (ADAD) which offers the opportunity to observe the dynamic biomarker changes during the life-course of AD stages. This study aimed to investigate serum biomarkers during different AD stages and potential novel protein biomarkers of presymptomatic AD.

Methods

In the first stage, 32 individuals [20 mutation carriers including 10 with AD, and 10 with mild cognitive impairment (MCI), and 12 healthy controls] from ADAD families were analyzed. All subjects underwent a complete clinical evaluation and a comprehensive neuropsychological battery. Serum samples were collected from all subjects, and antibody arrays were used to analyze 170 proteins in these samples. The most promising biomarkers were identified during this screening and were then measured in serum samples of 12 subjects with pre-MCI and 20 controls.

Results

The serum levels of 13 proteins were significantly different in patients with AD or MCI compared to controls. Of the 13 proteins, cathepsin D, immunoglobulin E, epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP-9), von Willebrand factor (vWF), haptoglobin, and phosphorylated Tau-181 (p-Tau181) correlated with all cognitive measures (R2 = −0.69–0.76). The areas under the receiver operating characteristic curve of these seven proteins were 0.71–0.93 for the classification of AD and 0.57–0.95 for the classification of MCI. Higher levels of p-Tau181 were found in the serum of pre-MCI subjects than in the serum of controls. The p-Tau181 serum level might detect AD before symptoms occur (area under the curve 0.85, sensitivity 75%, specificity 81.67%).

Conclusions

A total of 13 serum proteins showed significant differences between subjects with AD and MCI and healthy controls. The p-Tau181 serum level might be a broadly available and cost-effective biomarker to identify individuals with preclinical AD and assess the severity of AD.
The Brilliance of the Zebrafish Model: Perception on Behavior and Alzheimer’s Disease
Authors: Shenoy Avinash , Banerjee Meheli , Upadhya Archana , Bagwe-Parab Siddhi , Kaur Ginpreet
Published: June 2022

Alzheimer’s disease (AD) has become increasingly prevalent in the elderly population across the world. It’s pathophysiological markers such as overproduction along with the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFT) are posing a serious challenge to novel drug development processes. A model which simulates the human neurodegenerative mechanism will be beneficial for rapid screening of potential drug candidates. Due to the comparable neurological network with humans, zebrafish has emerged as a promising AD model. This model has been thoroughly validated through research in aspects of neuronal pathways analogous to the human brain. The cholinergic, glutamatergic, and GABAergic pathways, which play a role in the manifested behavior of the zebrafish, are well defined. There are several behavioral models in both adult zebrafish and larvae to establish various aspects of cognitive impairment including spatial memory, associative memory, anxiety, and other such features that are manifested in AD. The zebrafish model eliminates the shortcomings of previously recognized mammalian models, in terms of expense, extensive assessment durations, and the complexity of imaging the brain to test the efficacy of therapeutic interventions. This review highlights the various models that analyze the changes in the normal behavioral patterns of the zebrafish when exposed to AD inducing agents. The mechanistic pathway adopted by drugs and novel therapeutic strategies can be explored via these behavioral models and their efficacy to slow the progression of AD can be evaluated.
Harmonic Noise-Tolerant ZNN for Dynamic Matrix Pseudoinversion and Its Application to Robot Manipulator
Authors: Liao Bolin , Wang Yuyan , Li Jianfeng , Guo Dongsheng , He Yongjun
Published: June 2022

As we know, harmonic noises widely exist in industrial fields and have a crucial impact on the computational accuracy of the zeroing neural network (ZNN) model. For tackling this issue, by combining the dynamics of harmonic signals, two harmonic noise-tolerant ZNN (HNTZNN) models are designed for the dynamic matrix pseudoinversion. In the design of HNTZNN models, an adaptive compensation term is adopted to eliminate the influence of harmonic noises, and a Li activation function is introduced to further improve the convergence rate. The convergence and robustness to harmonic noises of the proposed HNTZNN models are proved through theoretical analyses. Besides, compared with the ZNN model without adaptive compensation term, the HNTZNN models are more effective for tacking the problem of dynamic matrix pseudoinverse under harmonic noises environments. Moreover, HNTZNN models are further applied to the kinematic control of a four-link planar robot manipulator under harmonic noises. In general, the experimental results verify the effectiveness, superiority, and broad application prospect of the models.
Clinical Value and Prognosis of C Reactive Protein to Lymphocyte Ratio in Severe Aneurysmal Subarachnoid Hemorrhage
Authors: Zhang Qingqing , Zhang Gaoqi , Wang Lintao , Zhang Wanwan , Hou Fandi , Zheng Zhanqiang , Guo Yong , Chen Zhongcan , Hernesniemi Juha , Andrade-Barazarte Hugo , Feng Guang , Gu Jianjun
Published: June 2022

Objective

To investigate the relationship between CLR and disease severity and clinical prognosis of aSAH.

Methods

The authors retrospectively analyzed the clinical data of 221 patients with aSAH, who were admitted to the intensive care unit from January 2017 to December 2020. The indicators of inflammatory factors in the first blood routine examination within 48 h of bleeding were obtained. The prognosis was evaluated by mRS score at discharge, mRS>2 was a poor outcome. Through the receiver operating characteristic (ROC) curve, the area under the curve was calculated and the predicted values of inflammatory factors (CLR, CRP, WBC, and neutrophils) were compared. Univariate and multivariable logistic regression analyses were used to evaluate the relationship between CLR and the clinical prognosis of patients. ROC curve analysis was performed to determine the optimal cut-off threshold, sensitivity, and specificity of CLR in predicting prognosis at admission.

Results

According to the mRS score at discharge, 139 (62.90%) patients were classified with poor outcomes (mRS>2). The inflammatory factor with the best predictive value was CLR, which had an optimal cut-off threshold of 10.81 and an area under the ROC curve of 0.840 (95%CI.788–0.892, P < 0.001). Multivariable Logistic regression analysis showed that the Modified Fisher grade, Hunt-Hess grade, and CLR at admission were independent risk factors for poor outcomes of patients with aSAH (P < 0.05). According to Hunt-Hess grade, patients were divided into a mild group (Hunt-Hess ≤ 3) and a severe group (Hunt-Hess > 3), and the CLR value was significantly higher in severe patients with aSAH than in mild patients. The optimal cut-off threshold of CLR in the severe group was 6.87, and the area under the ROC curve was 0.838 (95% CI.752–0.925, P < 0.001).

Conclusions

The CLR value at the admission of patients with aSAH was significantly associated with Hunt-Hess grade, The higher Hunt-Hess grade, the higher the CL R-value, and the worse the prognosis. Early CLR value can be considered as a feasible biomarker to predict the clinical prognosis of patients with aSAH.
Non-invasive Liver Fibrosis Scores Are Associated With Recurrence of Postoperative Chronic Subdural Hematoma
Authors: Zhang Peng , Wang Hua , Bao Han , Wang Ning , Chen Zhen , Tu Qi , Lin Xiao , Li Yun , Zheng Zezheng , Chen Yu , Ruan Linhui , Zhuge Qichuan
Published: June 2022

Objective

Although liver diseases have already been identified as a risk factor for increased recurrence and mortality in patients with chronic subdural hematoma (CSDH), the association between subclinical liver disease, specifically liver fibrosis (LF), and CSDH remains unknown. In the present study, we aimed to investigate the association between the LF scores and CSDH recurrence.

Methods

We retrospectively analyzed consecutive patients with CSDH who underwent burr-hole irrigation in the First Affiliated Hospital of Wenzhou Medical University between January 2015 and December 2018. The clinical data were collected, and the LF scores were calculated including aspartate aminotransferase–platelet ratio index (APRI), fibrosis-4 (FIB-4), and Forns index. Multivariable logistic regression analysis was applied to identify the association between the LF scores and CSDH recurrence, and Cox regression model and Fine–Gray competing risks model were performed to calculate hazard ratios (HRs) for CSDH recurrence based on time-to-event outcomes. The C-statistic, the integrated discrimination improvement (IDI), and the net reclassification improvement (NRI) evaluated the additive value of the LF scores to predict the recurrence of CSDH.

Results

A total of 419 patients with CSDH were included, hematoma recurrence was observed in 62 patients (14.80%) within 1 year after surgery. The LF scores were significantly higher in those who recurred, whereas the standard hepatic assays were mostly normal. The patients were assigned to groups of high and low LF scores based on the validated cut-offs; compared with the subjects with low scores, those with high score levels had significantly higher recurrence rates. After adjusting for potential confounders, the LF scores were independently associated with CSDH recurrence, multivariable-adjusted HRs (95% CI) for those with higher levels of APRI, FIB-4, and Forns score were 4.32 (1.37–13.60), 2.56 (1.20–5.43), and 2.02 (1.07–3.79) for the recurrence of CSDH, respectively. Moreover, adding the APRI to the conventional model improved the C-statistic from 0.731 to 0.763, with an NRI and IDI of 7.50 and 1.35%, respectively. Two further commonly-used LF score indices (FIB-4 score and Forns index) yielded comparable results.

Conclusions

The data from this study first indicated that the high LF scores were significantly associated with the recurrence of CSDH and that careful follow-up in these patients may be needed.
Association of White Blood Cell Count With Clinical Outcome Independent of Treatment With Alteplase in Acute Ischemic Stroke
Authors: Barow Ewgenia , Quandt Fanny , Cheng Bastian , Gelderblom Mathias , Jensen Märit , Königsberg Alina , Boutitie Florent , Nighoghossian Norbert , Ebinger Martin , Endres Matthias , Fiebach Jochen B. , Thijs Vincent , Lemmens Robin , Muir Keith W. , Pedraza Salvador , Simonsen Claus Z. , Gerloff Christian , Thomalla Götz
Published: June 2022

Introduction

Higher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase.

Methods

WAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22–36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group.

Results

Of 503 randomized patients, WBC count and baseline parameters were available in 437 patients (μ = 64.7 years, 35.2% women) on admission and 355 patients (μ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 109/L (interquartile range, IQR, 6.1–9.4 × 109/L) and 8.2 × 109/L (IQR, 6.7–9.7 × 109/L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78–0.94 and aOR 0.88, 95% CI 0.79–0.97). No interaction between WBC count and treatment group was observed (p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05–1.24 and aOR 1.13, 95% CI 1.00–1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08–6.07).

Conclusion

Higher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested.

Trial Registration

ClinicalTrials.gov Identifier: NCT01525290.
From End to End: Gaining, Sorting, and Employing High-Density Neural Single Unit Recordings
Authors: Bod Réka Barbara , Rokai János , Meszéna Domokos , Fiáth Richárd , Ulbert István , Márton Gergely
Published: June 2022

The meaning behind neural single unit activity has constantly been a challenge, so it will persist in the foreseeable future. As one of the most sourced strategies, detecting neural activity in high-resolution neural sensor recordings and then attributing them to their corresponding source neurons correctly, namely the process of spike sorting, has been prevailing so far. Support from ever-improving recording techniques and sophisticated algorithms for extracting worthwhile information and abundance in clustering procedures turned spike sorting into an indispensable tool in electrophysiological analysis. This review attempts to illustrate that in all stages of spike sorting algorithms, the past 5 years innovations' brought about concepts, results, and questions worth sharing with even the non-expert user community. By thoroughly inspecting latest innovations in the field of neural sensors, recording procedures, and various spike sorting strategies, a skeletonization of relevant knowledge lays here, with an initiative to get one step closer to the original objective: deciphering and building in the sense of neural transcript.
The Role of Brain Activity in Characterizing Successful Reading Intervention in Children With Dyslexia
Authors: Krafnick Anthony J. , Napoliello Eileen M. , Flowers D. Lynn , Eden Guinevere F.
Published: June 2022

Studies of reading intervention in dyslexia have shown changes in performance and in brain function. However, there is little consistency in the location of brain regions associated with successful reading gains in children, most likely due to variability/limitations in methodologies (study design, participant criteria, and neuroimaging procedures). Ultimately for the results to be meaningful, the intervention has to be successful, be assessed against a control, use rigorous statistics, and take biological variables (sex) into consideration. Using a randomized, crossover design, 31 children with dyslexia were assigned to a phonological- and orthographic-based tutoring period as well as a within-subjects control period to examine: (1) intervention-induced changes in behavior (reading performance) and in brain activity (during reading); and (2) behavioral and brain activity pre-intervention data that predicted intervention-induced gains in reading performance. We found gains in reading ability following the intervention, but not following the control period, with no effect of participants’ sex. However, there were no changes in brain activity following the intervention (regardless of sex), suggesting that individual brain changes are too variable to be captured at the group level. Reading gains were not predicted by pre-intervention behavioral data, but were predicted by pre-intervention brain activity in bilateral supramarginal/angular gyri. Notably, some of this prediction was only found in females. Our results highlight the limitations of brain imaging in detecting the neural correlates of reading intervention in this age group, while providing further evidence for its utility in assessing eventual success of intervention, especially if sex is taken into consideration.
Alterations of Cerebral Perfusion and Functional Connectivity in Children With Idiopathic Generalized Epilepsy
Authors: Chen Guiqin , Hu Jie , Ran Haifeng , Nie Lei , Tang Wenying , Li Xuhong , Li Qinhui , He Yulun , Liu Junwei , Song Ganjun , Xu Gaoqiang , Liu Heng , Zhang Tijiang
Published: June 2022

Background

Studies have demonstrated that adults with idiopathic generalized epilepsy (IGE) have functional abnormalities; however, the neuropathological pathogenesis differs between adults and children. This study aimed to explore alterations in the cerebral blood flow (CBF) and functional connectivity (FC) to comprehensively elucidate the neuropathological mechanisms of IGE in children.

Methods

We obtained arterial spin labeling (ASL) and resting state functional magnetic resonance imaging data of 28 children with IGE and 35 matched controls. We used ASL to determine differential CBF regions in children with IGE. A seed-based whole-brain FC analysis was performed for regions with significant CBF changes. The mean CBF and FC of brain areas with significant group differences was extracted, then its correlation with clinical variables in IGE group was analyzed by using Pearson correlation analysis.

Results

Compared to controls, children with IGE had CBF abnormalities that were mainly observed in the right middle temporal gyrus, right middle occipital gyrus (MOG), right superior frontal gyrus (SFG), left inferior frontal gyrus (IFG), and triangular part of the left IFG (IFGtriang). We observed that the FC between the left IFGtriang and calcarine fissure (CAL) and that between the right MOG and bilateral CAL were decreased in children with IGE. The CBF in the right SFG was correlated with the age at IGE onset. FC in the left IFGtriang and left CAL was correlated with the IGE duration.

Conclusion

This study found that CBF and FC were altered simultaneously in the left IFGtriang and right MOG of children with IGE. The combination of CBF and FC may provide additional information and insight regarding the pathophysiology of IGE from neuronal and vascular integration perspectives.
Microphysiological Modeling of the Structure and Function of Neuromuscular Transmitter Release Sites
Authors: Laghaei Rozita , Meriney Stephen D.
Published: June 2022

The general mechanism of calcium-triggered chemical transmitter release from neuronal synapses has been intensely studied, is well-known, and highly conserved between species and synapses across the nervous system. However, the structural and functional details within each transmitter release site (or active zone) are difficult to study in living tissue using current experimental approaches owing to the small spatial compartment within the synapse where exocytosis occurs with a very rapid time course. Therefore, computer simulations offer the opportunity to explore these microphysiological environments of the synapse at nanometer spatial scales and on a sub-microsecond timescale. Because biological reactions and physiological processes at synapses occur under conditions where stochastic behavior is dominant, simulation approaches must be driven by such stochastic processes. MCell provides a powerful simulation approach that employs particle-based stochastic simulation tools to study presynaptic processes in realistic and complex (3D) geometries using optimized Monte Carlo algorithms to track finite numbers of molecules as they diffuse and interact in a complex cellular space with other molecules in solution and on surfaces (representing membranes, channels and binding sites). In this review we discuss MCell-based spatially realistic models of the mammalian and frog neuromuscular active zones that were developed to study presynaptic mechanisms that control transmitter release. In particular, these models focus on the role of presynaptic voltage-gated calcium channels, calcium sensors that control the probability of synaptic vesicle fusion, and the effects of action potential waveform shape on presynaptic calcium entry. With the development of these models, they can now be used in the future to predict disease-induced changes to the active zone, and the effects of candidate therapeutic approaches.
Knowledge Mapping of Olfactory Dysfunction: A Bibliometric Study
Authors: Hu Wen , Chen Na , Yan Weiheng , Pei Pei , Wei Yongxiang , Zhan Xiaojun
Published: June 2022

Background

Olfaction is one of the five basic senses of human beings. As such, olfactory dysfunction seriously affects patients' quality of life and can even endanger them. In recent years, olfactory dysfunction has attracted greater research interest, and numerous studies have been published on olfactory dysfunction. However, there are few studies on olfactory dysfunction through bibliometric analysis. This study aims to describe the current situation and identify the foci and potential new research directions of olfactory dysfunction using a bibliometric approach.

Methods

Articles related to olfactory dysfunction published from 2002 to 2021 were located in the Web of Science Core Collection of Clarivate Analytics (London, UK). Bibliometric analyses were conducted with the CiteSpace (Chaomei Chen, Drexel University, Philadelphia, PA, USA) and VOSviewer (Center for Science and Technology Studies, Leiden University, Leiden, Netherlands) software programs.

Results

The number of articles published each year showed an upward trend, especially in 2020, where a sharp increase had occurred due to the coronavirus disease 2019 (COVID-19) pandemic. The United States was the country with the most publications and the strongest international cooperation. In terms of institutions, the greatest number of publications from a single institution came from Dresden University of Technology. Thomas Hummel was the author who had contributed the most articles. An analysis of co-citation networks and burst keywords in the field revealed a shift from “gonadotropin-releasing hormone” and “apoptosis” earlier on to “olfactory training,” “COVID-19,” and “Parkinson's disease” more recently. “Outcome,” “COVID-19,” “infection,” and “pathogenesis” are topics of the research frontier and hotspots.

Conclusion

More attention has been paid to olfactory dysfunction as the understanding of it has improved in the past 20 years. This study provides researchers with an objective, systematic, and comprehensive analysis of the literature on olfactory dysfunction. The current frontier areas and hotspots in the field focus on the pathological mechanisms of olfactory dysfunction after infection with COVID-19 and its different prognoses. The pathophysiological mechanism of olfactory dysfunction in neurodegenerative diseases and COVID-19 will be a primary future research direction.
Cell Line Characteristics Predict Subsequent Resistance to Androgen Receptor-Targeted Agents (ARTA) in Preclinical Models of Prostate Cancer
Authors: Moll Jan Matthijs , Teubel Wilma J. , Erkens Sigrun E. , Jozefzoon-Agai Ashraf , Dits Natasja F. , van Rijswijk Angelique , Jenster Guido W. , van Weerden Wytske M.
Published: June 2022

Treatment of prostate cancer (PCa) has changed considerably in the last decade due to the introduction of novel androgen receptor (AR)-targeted agents (ARTAs) for patients progressing on androgen deprivation therapy (ADT). Preclinical research however still relies heavily on AR-negative cell line models. In order to investigate potential differences in castration-resistant PCa (CRPC) growth, we set out to create a comprehensive panel of ARTA-progressive models from 4 androgen-responsive AR wild-type PCa cell lines and analyzed its androgen response as opposed to its ADT-progressive counterparts. Parallel cultures of VCaP, DuCaP, PC346C, and LAPC4 were established in their respective culture media with steroid-stripped fetal calf serum (FCS) [dextran-coated charcoal-stripped FCS (DCC)] without androgen (ADT) or in DCC plus 1 μM of the ARTAs bicalutamide, OH-flutamide, or RD162 (an enzalutamide/apalutamide analog). Cell growth was monitored and compared to those of parental cell lines. Short-term androgen response was measured using cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. qRT-PCR was performed to assess the mRNA expression of markers for AR signaling, steroidogenesis, glucocorticoid receptor (GR) signaling, epithelial-mesenchymal transition (EMT), and WNT signaling. Out of 35 parallel cultures per cell line, a total of 24, 15, 34, and 16 CRPC sublines emerged for VCaP, DuCaP, PC346C, and LAPC4, respectively. The addition of bicalutamide or OH-flutamide significantly increased CRPC growth compared to ADT or RD162. VCaP, DuCaP, and PC346C CRPC clones retained an AR-responsive phenotype. The expression of AR and subsequent androgen response were completely lost in all LAPC4 CRPC lines. Markers for EMT and WNT signaling were found to be elevated in the resilient PC346C model and CRPC derivatives of VCaP, DuCaP, and LAPC4. Although the resistant phenotype is pluriform between models, it seems consistent within models, regardless of type of ARTA. These data suggest that the progression to and the phenotype of the CRPC state might already be determined early in carcinogenesis.
Body Mass Index and Prognosis of Patients With Stage II/III Gastric Cancer After Curative Gastrectomy: Completion of Perioperative Adjuvant Chemotherapy May Be a Confounding Factor
Authors: Peng Wei , Dai Jing , Liu Chao-chan , Liu Dian , Xiao Hua
Published: June 2022

Objective

To investigate the association between body mass index (BMI) and overall survival (OS) of patients with stage II/III gastric cancer (GC) after radical gastrectomy, and evaluate the potential influence of perioperative adjuvant chemotherapy (PAC).

Methods

Medical records of 2,510 consecutive stage II/III GC patients who underwent curative resection between November 2010 and December 2020 were retrospectively reviewed. The optimal cutoff value of BMI for OS was determined by X-tile. The independent predictive factors for completeness of PAC were identified using univariate and multivariate logistic regression analyses. Cox regression analyses assessed the association among BMI, completeness of PAC, and OS.

Results

Of the 2,510 patients, 813 cases with BMI < 20.3 kg/m2 were classified as belonging in the low BMI group. Further analyses confirmed that low BMI was an independent predictor for incomplete PAC (< 6 cycles, n = 920) and poorer OS (hazard ratio: 1.317, 95% confidence interval: 1.162-1.494, P < 0.001), but neo-adjuvant chemotherapy (NAC) was a protective factor. An additive effect was found in those with both low BMI and incomplete PAC, as they had even worse OS. However, in patients with low BMI, completion of PAC (≥ 6 cycles) significantly improved OS, which became comparable to that in the high BMI group (P = 0.143).

Conclusions

Low preoperative BMI independently affects completion of PAC and prognosis of patients with stage II/III GC, but completing PAC can compensate for the adverse influence of low BMI on OS. Thus, strategies designed to ensure the completion of PAC, such as NAC and nutritional support, should be further investigated.
Endothelial Activin Receptor-Like Kinase 1 (ALK1) Regulates Myofibroblast Emergence and Peritubular Capillary Stability in the Early Stages of Kidney Fibrosis
Authors: Martínez-Salgado Carlos , Sánchez-Juanes Fernando , López-Hernández Francisco J. , Muñoz-Félix José M.
Published: June 2022

Renal tubulo-interstitial fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) in the tubular interstitium during chronic kidney disease. The main source of ECM proteins are emerging and proliferating myofibroblasts. The sources of myofibroblasts in the renal tubular interstitium have been studied during decades, in which the epithelial contribution of the myofibroblast population through the epithelial-to-mesenchymal (EMT) process was assumed to be the major mechanism. However, it is now accepted that the EMT contribution is very limited and other mechanisms such as the proliferation of local resident fibroblasts or the transdifferentiation of endothelial cells seem to be more relevant. Activin receptor-like kinase 1 (ALK1) is a type I receptor which belongs to the transforming growth factor beta (TGF-β) superfamily, with a key role in tissue fibrosis and production of ECM by myofibroblast. Predominantly expressed in endothelial cells, ALK1 also plays an important role in angiogenesis and vessel maturation, but the relation of these processes with kidney fibrosis is not fully understood. We show that after 3 days of unilateral ureteral obstruction (UUO), ALK1 heterozygous mice (Alk1+/−) display lower levels of kidney fibrosis associated to a lower number of myofibroblasts. Moreover, Alk1+/− mice have a lower degree of vascular rarefaction, showing improved peritubular microvasculature after UUO. All these data suggest an important role of ALK1 in regulating vascular rarefaction and emergence of myofibroblasts.
New Drugs for Hepatic Fibrosis
Authors: Shan Liang , Wang Fengling , Zhai Dandan , Meng Xiangyun , Liu Jianjun , Lv Xiongwen
Published: June 2022

The morbidity and mortality of hepatic fibrosis caused by various etiologies are high worldwide, and the trend is increasing annually. At present, there is no effective method to cure hepatic fibrosis except liver transplantation, and its serious complications threaten the health of patients and cause serious medical burdens. Additionally, there is no specific drug for the treatment of hepatic fibrosis, and many drugs with anti-hepatic fibrosis effects are in the research and development stage. Recently, remarkable progress has been made in the research and development of anti-hepatic fibrosis drugs targeting different targets. We searched websites such as PubMed, ScienceDirect, and Home-ClinicalTrials.gov and found approximately 120 drugs with anti-fibrosis properties, some of which are in phase Ⅱ or Ⅲ clinical trials. Additionally, although these drugs are effective against hepatic fibrosis in animal models, most clinical trials have shown poor results, mainly because animal models do not capture the complexity of human hepatic fibrosis. Besides, the effect of natural products on hepatic fibrosis has not been widely recognized at home and abroad. Furthermore, drugs targeting a single anti-hepatic fibrosis target are prone to adverse reactions. Therefore, currently, the treatment of hepatic fibrosis requires a combination of drugs that target multiple targets. Ten new drugs with potential for development against hepatic fibrosis were selected and highlighted in this mini-review, which provides a reference for clinical drug use.
Isolation and Quantification of the Hepatoprotective Flavonoids From Scleromitron diffusum (Willd.) R. J. Wang With Bio-Enzymatic Method Against NAFLD by UPLC–MS/MS
Authors: Qin Yuxi , Zhao Baojin , Deng Huifang , Zhang Mengjiao , Qiao Yanan , Liu Qiling , Shi Chuandao , Li Yunlan
Published: June 2022

Flavonoids were the major phytochemicals against hepatic peroxidative injury in Scleromitron diffusum (Willd.) R. J. Wang with an inventive bio-enzymatic method by our group (LU500041). Firstly, the total flavonoids from Scleromitron diffusum (Willd.) R. J. Wang were extracted by reflux, ultrasonic, ultrasound-assisted enzymatic methods (TFH), and the bio-enzymatic method (Ey-TFH). Then 24 flavonoid compounds were isolated and quantified in the extracts by UPLC-MS/MS. Next, six representative differential compounds in Ey-TFH were further screened out by multivariate statistical analysis compared with those in TFH. In a further step, Ey-TFH presented a higher protective rate (59.30 ± 0.81%) against H2O2-damaged HL-02 hepatocytes than TFH. And six representative differential compounds at 8 and 16 μmol/L all exerted significant hepatoprotective effects (p < 0.05 or p < 0.01). Finally, the therapeutic action of Ey-TFH for nonalcoholic fatty liver disease (NAFLD) was processed by a rat’s model induced with a high-fat diet. Ey-TFH (90, 120 mg/kg) significantly ameliorated the lipid accumulation in the rat model (p < 0.05). Meanwhile, Ey-TFH relieved liver damage. The levels of ALT, ALP, AST, LDH, and γ-GT in rats’ serum were also significantly reduced (p < 0.05 or p < 0.01). In addition to this, the body’s antioxidant capacity was improved with elevated SOD and GSH levels (p < 0.05) and down-regulated MDA content (p < 0.01) after Ey-TFH administration. Histopathological observations of staining confirmed the hepatic-protective effect of Ey-TFH.
Icariside II Restores Vascular Smooth Muscle Cell Contractile Phenotype by Enhancing the Focal Adhesion Signaling Pathway in the Rat Vascular Remodeling Model
Authors: Lv Junyuan , Li Xintong , Wu Hongyu , Li Jiayang , Luan Boyang , Li Yiqi , Li Yeli , Yang Danli , Wen Hao
Published: June 2022

Vascular smooth muscle cell (VSMC) phenotypic transition represents the fundamental pathophysiological alteration in the vascular remodeling process during the initiation and progression of cardiovascular diseases. Recent studies have revealed that Icariside II (ICS-II), a flavonol glycoside derived from the traditional Chinese medicine Herba Epimedii, exhibited therapeutic effects in various cardiovascular diseases. However, the therapeutic efficacy and underlying mechanisms of ICS-II regarding VSMC phenotypic transition were unknown. In this study, we investigated the therapeutic effects of ICS-Ⅱ on vascular remodeling with a rat’s balloon injury model in vivo. The label-free proteomic analysis was further implemented to identify the differentially expressed proteins (DEPs) after ICS-II intervention. Gene ontology and the pathway enrichment analysis were performed based on DEPs. Moreover, platelet-derived growth factor (PDGF-BB)-induced primary rat VSMC was implemented to verify the restoration effects of ICS-II on the VSMC contractile phenotype. Results showed that ICS-II could effectively attenuate the vascular remodeling process, promote SMA-α protein expression, and inhibit OPN expression in vivo. The proteomic analysis identified 145 differentially expressed proteins after ICS-II intervention. Further, the bioinformatics analysis indicated that the focal adhesion signaling pathway was enriched in the ICS-II group. In vitro studies showed that ICS-II suppressed VSMC proliferation and migration, and promoted VSMC contractile phenotype by modulating the focal adhesion signaling pathway. Taken together, our results suggest that ICS-II attenuates the vascular remodeling process and restores the VSMC contractile phenotype by promoting the focal adhesion pathway.
Drug-Related Hospital Admissions via the Department of Emergency Medicine: A Cross-Sectional Study From the Czech Republic
Authors: Očovská Zuzana , Maříková Martina , Kočí Jaromír , Vlček Jiří
Published: June 2022

Background: Drug-related hospital admissions (DRAs) represent a significant problem affecting all countries worldwide. This study aimed to determine the prevalence and preventability of DRAs, identify the most common medications involved in DRAs, the most common clinical manifestations of DRAs and describe the preventability aspects of DRAs.

Methods: This cross-sectional study examined unplanned hospital admissions to the University Hospital Hradec Králové via the department of emergency medicine in August–November 2018. Data were obtained from electronic medical records. The methodology of DRA identification was adapted from the OPERAM DRA adjudication guide.

Results: Out of 1252 hospital admissions, 195 DRAs have been identified (145 related to treatment safety, 50 related to treatment effectiveness). The prevalence of DRAs was 15.6% (95% CI 13.6–17.6). The most common medication classes involved in DRAs related to treatment safety were Antithrombotic agents, Antineoplastic agents, Diuretics, Corticosteroids for systemic use, and Beta blocking agents. The most common medication classes involved in DRAs related to treatment effectiveness included Diuretics, Antithrombotic agents, Drugs used in diabetes, Agents acting on the renin-angiotensin system, and Lipid modifying agents. Gastrointestinal disorders were the leading causes of DRAs related to treatment safety, while Cardiac disorders were the leading causes of DRAs related to treatment effectiveness. The potential preventability of DRAs was 51%. The highest share of potential preventability in medication classes repeatedly involved in DRAs related to treatment safety was observed for Anti-inflammatory and antirheumatic products, Psycholeptics, and Drugs used in diabetes. Potentially preventable DRAs related to treatment safety were most commonly associated with inappropriate drug selection, inappropriate monitoring, inappropriate dose selection, and inappropriate lifestyle measures. On the contrary, DRAs related to treatment effectiveness were more commonly associated with medication nonadherence.

Conclusion: It should be emphasized that in most DRAs, medications were only a contributory reason of hospital admissions and that benefits and risks have to be carefully balanced. It is highlighted by the finding that the same medication classes (Antithrombotic agents and Diuretics) were among the most common medication classes involved in DRAs related to treatment safety and simultaneously in DRAs related to treatment effectiveness. The study highlighted that apart from problems related to prescribing, problems related to monitoring and patient-related problems represent significant preventability aspects.
Effect of Bufalin-PLGA Microspheres in the Alleviation of Neuropathic Pain via the CCI Model
Authors: Long Lina , Zhong Wenwei , Guo Liwei , Ji Jing , Nie Hong
Published: June 2022

The treatment of neuropathic pain (NPP) is considered challenging, while the search for alternative medication is striving. NPP pathology is related with the expression of both the purinergic 2X7 (P2X7) receptor and the transient receptor potential vanilloid 1 receptor (TRPV1). Bufalin is a traditional Chinese medication derived from toad venom with pronounced antitumor, analgesic, and anti-inflammatory properties. However, poor solubility, rapid metabolism, and the knowledge gap on its pain alleviation mechanism have limited the clinical application of bufalin. Hence, the purpose of this study is to illustrate the NPP alleviation mechanism of bufalin via chronic constriction injury (CCI). To address the concern on fast metabolism, bufalin-PLGA microspheres (MS) were prepared via membrane emulsification to achieve prolonged pain-relieving effects. Western blot, real-time PCR, immunofluorescence, and molecular docking were employed to demonstrate the therapeutic action of bufalin on NPP. The results showed enhanced thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) after the administration of both bufalin and bufalin-PLGA MS in the CCI rats. Prolonged pain-relieving effects for up to 3 days with reduced dose frequency was achieved via bufalin-PLGA MS. In the CCI rats treated with bufalin-PLGA MS, the expression levels of protein and mRNA in TRPV1 and P2X7, both localized in the dorsal root ganglion (DRG), were reduced. Moreover, bufalin-PLGA MS effectively reduced the levels of IL-1β, IL-18, IL-6, and TNF-α in the CCI group. The results from molecular docking suggested a possible mechanism of NPP alleviation of bufalin through binding to P2X7 receptors directly. The administration of bufalin-PLGA MS prepared by membrane emulsification demonstrated promising applications for sustained effect on the alleviation of NPP.