bluuebunny/crossref_metadata_2025 huggingface dataset:
Reactive Oxygen Species-Related Ceftazidime Resistance Is Caused by the Pyruvate Cycle Perturbation and Reverted by Fe3 + in Edwardsiella tarda
Authors: Ye Jinzhou , Su Yubin , Peng Xuanxian , Li Hui
Published: April 2021

Reactive oxygen species (ROS) are related to antibiotic resistance and have been reported in bacteria. However, whether ROS contribute to ceftazidime resistance and plays a role in ceftazidime-mediated killing is unknown. The present study showed lower ROS production in ceftazidime-resistant Edwardsiella tarda (LTB4-RCAZ) than that in LTB4-sensitive E. tarda (LTB4-S), two isogenic E. tarda LTB4 strains, which was related to bacterial viability in the presence of ceftazidime. Consistently, ROS promoter Fe3+ and inhibitor thiourea elevated and reduced the ceftazidime-mediated killing, respectively. Further investigation indicated that the reduction of ROS is related to inactivation of the pyruvate cycle, which provides sources for ROS biosynthesis, but not superoxide dismutase (SOD) and catalase (CAT), which degrade ROS. Interestingly, Fe3+ promoted the P cycle, increased ROS biosynthesis, and thereby promoted ceftazidime-mediated killing. The Fe3+-induced potentiation is generalizable to cephalosporins and clinically isolated multidrug-resistant pathogens. These results show that ROS play a role in bacterial resistance and sensitivity to ceftazidime. More importantly, the present study reveals a previously unknown mechanism that Fe3+ elevates ROS production via promoting the P cycle.
Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor
Authors: Do Hung N. , Akhter Sana , Miao Yinglong
Published: April 2021

Caffeine (CFF) is a common antagonist to the four subtypes of adenosine G-protein-coupled receptors (GPCRs), which are critical drug targets for treating heart failure, cancer, and neurological diseases. However, the pathways and mechanism of CFF binding to the target receptors remain unclear. In this study, we have performed all-atom-enhanced sampling simulations using a robust Gaussian-accelerated molecular dynamics (GaMD) method to elucidate the binding mechanism of CFF to human adenosine A2A receptor (A2AAR). Multiple 500–1,000 ns GaMD simulations captured both binding and dissociation of CFF in the A2AAR. The GaMD-predicted binding poses of CFF were highly consistent with the x-ray crystal conformations with a characteristic hydrogen bond formed between CFF and residue N6.55 in the receptor. In addition, a low-energy intermediate binding conformation was revealed for CFF at the receptor extracellular mouth between ECL2 and TM1. While the ligand-binding pathways of the A2AAR were found similar to those of other class A GPCRs identified from previous studies, the ECL2 with high sequence divergence serves as an attractive target site for designing allosteric modulators as selective drugs of the A2AAR.
Foreign Language Learning as Cognitive Training to Prevent Old Age Disorders? Protocol of a Randomized Controlled Trial of Language Training vs. Musical Training and Social Interaction in Elderly With Subjective Cognitive Decline
Authors: Nijmeijer Saskia E. , van Tol Marie-José , Aleman André , Keijzer Merel
Published: April 2021

Introduction: With aging comes a reduction of cognitive flexibility, which has been related to the development of late-life depression and progression of general cognitive decline. Several factors have been linked to attenuating such decline in cognitive flexibility, such as education, physical exercise and stimulating leisure activities. Speaking two or more languages has recently received abundant attention as another factor that may build up cognitive reserve, thereby limiting the functional implications of compromised cognition that accompany old age. With the number of older adults reaching record levels, it is important to attenuate the development of old-age disorders. Learning to speak a foreign language might offer a powerful tool in promoting healthy aging, but up to date effect studies are sparse. Here, the protocol that forms the foundation of the current study is presented. The present study aims to: (1) examine the effects of a foreign language training on cognitive flexibility and its neural underpinnings, and on mental health; and (2) assess the unique role of foreign language training vs. other cognitive or social programs.

Method: One-hundred and ninety-eight Dutch elderly participants reporting subjective cognitive decline are included and randomized to either a language intervention, a music intervention, or a social control intervention. During 3 to 6 months, the language group learns English, the music group learns to play the guitar and the social group participates in social meetings where art workshops are offered. At baseline, at a 3-month follow-up, and at 6 months after termination of the training program, clinical, cognitive and brain activity measurements (combined EEG and fNIRS methods) are taken to assess cognitive flexibility and mental health.

Discussion: This is the first trial addressing combined effects of language learning in elderly on cognition, language proficiency, socio-affective measures, and brain activity in the context of a randomized controlled trial. If successful, this study can provide insights into how foreign language training can contribute to more cognitively and mentally healthy years in older adulthood.

Clinical Trial Registration: The trial is registered at the Netherlands Trial Register, July 2, 2018, trial number NL7137. https://www.trialregister.nl/trial/7137.
Visual Deprivation Retards the Maturation of Dendritic Fields and Receptive Fields of Mouse Retinal Ganglion Cells
Authors: Chen Hui , Xu Hong-Ping , Wang Ping , Tian Ning
Published: April 2021

It was well documented that both the size of the dendritic field and receptive field of retinal ganglion cells (RGCs) are developmentally regulated in the mammalian retina, and visual stimulation is required for the maturation of the dendritic and receptive fields of mouse RGCs. However, it is not clear whether the developmental changes of the RGC receptive field correlate with the dendritic field and whether visual stimulation regulates the maturation of the dendritic field and receptive field of RGCs in a correlated manner. The present work demonstrated that both the dendritic and receptive fields of RGCs continuously develop after eye opening. However, the correlation between the developmental changes in the receptive field size and the dendritic field varies among different RGC types. These results suggest a continuous change of synaptic converging of RGC synaptic inputs in an RGC type-dependent manner. Besides, light deprivation impairs both the development of dendritic and receptive fields.
Retinal Thickness Analysis in Progressive Multiple Sclerosis Patients Treated With Epigallocatechin Gallate: Optical Coherence Tomography Results From the SUPREMES Study
Authors: Klumbies Katharina , Rust Rebekka , Dörr Jan , Konietschke Frank , Paul Friedemann , Bellmann-Strobl Judith , Brandt Alexander U. , Zimmermann Hanna G.
Published: April 2021

Background: Epigallocatechin gallate (EGCG) is an anti-inflammatory agent and has proven neuroprotective properties in animal models of multiple sclerosis (MS). Optical coherence tomography (OCT) assessed retinal thickness analysis can reflect treatment responses in MS.

Objective: To analyze the influence of EGCG treatment on retinal thickness analysis as secondary and exploratory outcomes of the randomized controlled Sunphenon in Progressive Forms of MS trial (SUPREMES, NCT00799890).

Methods: SUPREMES patients underwent OCT with the Heidelberg Spectralis device at a subset of visits. We determined peripapillary retinal nerve fiber layer (pRNFL) thickness from a 12° ring scan around the optic nerve head and thickness of the ganglion cell/inner plexiform layer (GCIP) and inner nuclear layer (INL) within a 6 mm diameter grid centered on the fovea from a macular volume scan. Longitudinal OCT data were available for exploratory analysis from 31 SUPREMES participants (12/19 primary/secondary progressive MS (PPMS/SPMS); mean age 51 ± 7 years; 12 female; mean time since disease onset 16 ± 11 years). We tested the null hypothesis of no treatment*time interaction using nonparametric analysis of longitudinal data in factorial experiments.

Results: After 2 years, there were no significant differences in longitudinal retinal thickness changes between EGCG treated and placebo arms in any OCT parameter (Mean change [confidence interval] ECGC vs. Placebo: pRNFL: −0.83 [1.29] μm vs. −0.64 [1.56] μm, p = 0.156; GCIP: −0.67 [0.67] μm vs. −0.14 [0.47] μm, p = 0.476; INL: −0.06 [0.58] μm vs. 0.22 [0.41] μm, p = 0.455).

Conclusion: Retinal thickness analysis did not reveal a neuroprotective effect of EGCG. While this is in line with the results of the main SUPREMES trial, our study was probably underpowered to detect an effect.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT00799890.
Volume Rendering of Angiographic Optical Coherence Tomography Angiography in Fovea Plana and Normal Foveal Pit
Authors: Fragiotta Serena , Ciancimino Chiara , Perdicchi Andrea , de Paula Alessandro , Abdolrahimzadeh Solmaz , Scuderi Gianluca
Published: April 2021

This paper aims to study adaptative vascular arrangements in idiopathic fovea plana with volume-rendered optical coherence tomography angiography (OCTA). A retrospective review of two cases of idiopathic fovea plana (mean age: 26.5 years) and two age-matched controls imaged with OCTA was conducted using spectral-domain OCTA (RTVue XR Avanti, Optovue, Inc., Fremont, CA) equipped with the AngioVue software. Both en face OCTA slabs and OCTA b scans were processed through Fiji software (http://fiji.sc; software version 2.0.0-rc-68/1.52e), and then extracted as image sequences for volume rendering reconstructions using the ImageVis3D volume rendering system (3.1.0 release). Eyes with idiopathic fovea plana demonstrated a regular superficial vascular plexus connecting to a single vascular monolayer representing the deeper vascular plexuses. At this location, several vertical short path connections were demonstrated, in contraposition with normal eyes where short path connections were infrequently observed. Advances in three-dimensional OCTA reconstruction increase the understanding of vascular connections and arrangement in retinal plexuses and possible anatomical variations that cannot be detected with conventional two-dimensional b scans.
Roles of Motor Cortex Neuron Classes in Reach-Related Modulation for Hemiparkinsonian Rats
Authors: Li Min , Wang Xuenan , Yao Xiaomeng , Wang Xiaojun , Chen Feiyu , Zhang Xiao , Sun Shuang , He Feng , Jia Qingmei , Guo Mengnan , Chen Dadian , Sun Yue , Li Yuchuan , He Qin , Zhu Zhiwei , Wang Min
Published: April 2021

Disruption of the function of the primary motor cortex (M1) is thought to play a critical role in motor dysfunction in Parkinson’s disease (PD). Detailed information regarding the specific aspects of M1 circuits that become abnormal is lacking. We recorded single units and local field potentials (LFPs) of M1 neurons in unilateral 6-hydroxydopamine (6-OHDA) lesion rats and control rats to assess the impact of dopamine (DA) cell loss during rest and a forelimb reaching task. Our results indicated that M1 neurons can be classified into two groups (putative pyramidal neurons and putative interneurons) and that 6-OHDA could modify the activity of different M1 subpopulations to a large extent. Reduced activation of putative pyramidal neurons during inattentive rest and reaching was observed. In addition, 6-OHDA intoxication was associated with an increase in certain LFP frequencies, especially those in the beta range (broadly defined here as any frequency between 12 and 35 Hz), which become pathologically exaggerated throughout cortico-basal ganglia circuits after dopamine depletion. Furthermore, assessment of different spike-LFP coupling parameters revealed that the putative pyramidal neurons were particularly prone to being phase-locked to ongoing cortical oscillations at 12–35 Hz during reaching. Conversely, putative interneurons were neither hypoactive nor synchronized to ongoing cortical oscillations. These data collectively demonstrate a neuron type-selective alteration in the M1 in hemiparkinsonian rats. These alterations hamper the ability of the M1 to contribute to motor conduction and are likely some of the main contributors to motor impairments in PD.
Signal Pathway of Estrogen and Estrogen Receptor in the Development of Thyroid Cancer
Authors: Liu Jian , Xu Tianmin , Ma Li , Chang Weiqin
Published: April 2021

The molecular mechanisms underlying the development of thyroid cancer (TC) have been examined through extensive experiments. A large number of studies have shown that the incidences of thyroid cancer in women is much higher than that in men, so estrogen plays a key role in the development of thyroid cancer. Estrogen plays its growth-promoting role through classical genomic and non-genomic pathways mediated by membrane-bound estrogen receptors. It also can affect tumor progression by regulating the tumor microenvironment. We summarize the understanding of molecular mechanisms of estrogen signaling pathways in thyroid cancer. Furthermore, it will provide a new target for the treatment of thyroid carcinoma by blocking estrogen and its related action pathway.
Conditional Relative Survival of Ovarian Cancer: A Korean National Cancer Registry Study
Authors: Shin Dong Wook , Bae Jaeman , Ha Johyun , Jung Kyu-Won
Published: April 2021

Objective

Conditional relative survival (CRS) rates, which take into account changes in prognosis over time, are useful estimates for survivors and their clinicians as they make medical and personal decisions. We aimed to present the 5-year relative conditional survival probabilities of patients diagnosed with ovarian cancer from 1997–2016.

Methods

This nationwide retrospective cohort study used data from the Korean Central Cancer Registry. Patients diagnosed with ovarian cancer between 1997 and 2016 were included. CRS rates were calculated stratified by age at diagnosis, cancer stage, histology, treatment received, year of diagnosis, and social deprivation index.

Results

The 5-year relative survival rate at the time of diagnosis was 61.1% for all cases. The probability of surviving an additional 5 years, conditioned on having already survived 1, 2, 3, 4, and 5 years after diagnosis was 65.0, 69.5, 74.6, 79.3, and 83.9%, respectively. Patients with poorer initial survival estimates (older, distant stage, serous histology) generally showed the largest increases in CRS over time. The probability of death was highest in the first year after diagnosis (11.8%), and the conditional probability of death in the 2nd, 3rd, 4th, and 5th years declined to 9.4%, 7.9%, 6.1%, and 5.2%, respectively.

Conclusion

CRS rates for patients with ovarian cancer increased with each year they survived, but this did not reach the level of ‘no excess mortality’ even 5 years after diagnosis. The largest improvements in CRS were observed in patients with poorer initial prognoses. Our findings provide updated prognosis to ovarian cancer survivors and clinicians.
Long Non-Coding RNA LINC00467 Correlates to Poor Prognosis and Aggressiveness of Breast Cancer
Authors: Zhang Ying , Sun Yi , Ding Lin , Shi Wenjing , Ding Keshuo , Zhu Yong
Published: April 2021

Breast cancer remains the leading cause of female cancer-related mortalities worldwide. Long non-coding RNAs (LncRNAs) have been increasingly reported to play pivotal roles in tumorigenesis and cancer progression. Herein, we focused on LINC00467, which has never been studied in breast cancer. Silence of LINC00467 suppressed proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of breast cancer cells in vitro, whereas forced expression of LINC00467 exhibited the opposite effects. Furthermore, we demonstrated overexpression of LINC00467 promoted tumor growth, while knockdown of LINC00467 inhibited pulmonary metastasis in vivo. Mechanistically, LINC00467 down-regulated miR-138-5p by acting as a miRNA “sponge”. Besides, LINC00467 also up-regulated the protein level of lin-28 homolog B (LIN28B) via a direct interaction. A higher expression level of LINC00467 was observed in breast cancer tissues as compared to the adjacent normal counterparts and elevated LINC00467 predicted poor overall survival. Our findings suggest LINC00467 promotes progression of breast cancer through interacting with miR-138-5p and LIN28B directly. LINC00467 may serve as a potential candidate for the diagnosis and treatment of breast cancer.
Circulating Tumor DNA Analyses Predict Disease Recurrence in Non-Muscle-Invasive Bladder Cancer
Authors: Zhang Jinghua , Dai Daofeng , Tian Junqiang , Li Lifeng , Bai Jing , Xu Yaping , Wang Zhiping , Tang Aifa
Published: April 2021

Circulating tumor DNA (ctDNA) can be a prognostic biomarker for non-muscle-invasive bladder cancer (NMIBC); however, targeted sequencing has not been performed to detect ctDNA in NMIBC. We applied targeted sequencing based on an 861-gene panel to determine mutations in tumor tissue DNA and plasma ctDNA in 82 NMIBC patients receiving transurethral resection (TUR) of bladder followed by immunotherapy. We detected 476 and 165 somatic variants in tumor DNA from 82 NMIBC patients (100%) and ctDNA from 54 patients (65.85%), respectively. Patients with high heterogeneity in tumor DNA had a significantly shorter disease-free survival than those with low heterogeneity. Tumor-derived alterations were detectable in plasma of 43 patients (52.44%). The concordance of somatic variants between tumor DNA and plasma ctDNA were higher in patients with T1 stage (p < 0.0001) and tumor size ≥3 cm (p = 0.0002). Molecular tumor burden index (mTBI) in ctDNA positively correlated with larger tumor size (p = 0.0020). A higher mTBI was an independent predictor of recurrence after TUR of bladder followed by immunotherapy. Analysis of ctDNA based on targeted sequencing is a promising approach to predict disease recurrence for NMIBC patients receiving TUR of bladder followed by immunotherapy.
Early Postnatal Metabolic Profile in Neonates With Different Birth Weight Status: A Pilot Study
Authors: Beken Serdar , Abali Saygin , Yildirim Saral Neslihan , Guner Bengisu , Dinc Taha , Albayrak Eda , Ersoy Melike , Kilercik Meltem , Halici Muge , Bulbul Ezgi , Kaya Didem , Karabay Melis , Ay Zeynep Alize , Eksi Gulten Zeynep , Benli Aksungar Fehime , Korkmaz Ayse , Serteser Mustafa
Published: April 2021

Introduction:Restricted or enhanced intrauterine growth is associated with elevated risks of early and late metabolic problems in humans. Metabolomics based on amino acid and carnitine/acylcarnitine profile may have a role in fetal and early postnatal energy metabolism. In this study, the relationship between intrauterine growth status and early metabolomics profile was evaluated.

Materials and Methods:A single-center retrospective cohort study was conducted. Three hundred and sixty-one newborn infants were enrolled into the study, and they were grouped according to their birth weight percentile as small for gestational age (SGA,n= 69), appropriate for gestational age (AGA,n= 168), and large for gestational age (LGA,n= 124) infants. In all infants, amino acid and carnitine/acylcarnitine profiles with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were recorded and compared between groups.

Results:LGA infants had higher levels of glutamic acid and lower levels of ornithine, alanine, and glycine (p< 0.05) when compared with AGA infants. SGA infants had higher levels of alanine and glycine levels when compared with AGA and LGA infants. Total carnitine, C0, C2, C4, C5, C10:1, C18:1, C18:2, C14-OH, and C18:2-OH levels were significantly higher and C3 and C6-DC levels were lower in SGA infants (p< 0.05). LGA infants had higher C3 and C5:1 levels and lower C18:2 and C16:1-OH levels (p< 0.05). There were positive correlations between free carnitine and phenylalanine, arginine, methionine, alanine, and glycine levels (p< 0.05). Also, a positive correlation between ponderal index and C3, C5-DC, C14, and C14:1 and a negative correlation between ponderal index and ornithine, alanine, glycine, C16:1-OH, and C18:2 were shown.

Conclusion:We demonstrated differences in metabolomics possibly reflecting the energy metabolism in newborn infants with intrauterine growth problems in the early postnatal period. These differences might be the footprints of metabolic disturbances in future adulthood.
Efficacy of Non-pharmacologic Auxiliary Treatments in Improving Defecation Function in Children With Chronic Idiopathic Constipation: A Systematic Review and Network Meta-analysis
Authors: Tang Jie , Li Huijuan , Tang Weibing
Published: April 2021

Background: Non-pharmacologic auxiliary treatments have been considered crucial therapies for treating chronic idiopathic constipation (CIC) during the past decades worldwide. Several treatment patterns are available, but their relative efficacy is obscure because there are no head-to-head randomized controlled trials, especially in children. We conducted this network meta-analysis to evalute the effectiveness of these therapies in improving defecation function based on their direct comparisons with standard medical care.

Methods: Medline, Embase, and Cochrane Central were searched for randomized controlled trials (RCTs) published in English from inception to October 2020, assessing the efficacy of auxiliary therapies (behavior therapy, physiotherapy, biofeedback, or anorectal manometry) in children with CIC. We extracted data for endpoints, risk of bias, and evidence quality. Eligible studies in the meta-analysis reported the data of a dichotomous assessment of overall response to treatment (response or not) or defecation frequency per week after treatment. The hierarchical Bayesian network meta-analysis was used in the study. We chose a conservative methodology, random effects model, to pool data which could handle the heterogeneity well. The relative risk (RR) with 95% confidence intervals (CIs) was calculated for dichotomous outcomes. For continuous results, weighted mean difference (WMD) with related CIs was calculated. The included treatments were ranked to define the probability of being the best treatment.

Results: Seven RCTs (838 patients) met inclusion and endpoint criteria. Based on an endpoint of the absence of constipation (Rome criteria) with laxatives allowed, physiotherapy plus standard medical care (SMC) had the highest probability (84%) to bethe most effective therapy. When the treatment response was defined as an absence of constipation with not laxatives allowed, biofeedback plus SMC ranked first (probability 52%). Physiotherapy plus SMC ranked first when the endpoint was based on defecation frequency per week with laxatives allowed (probability 86%).

Conclusion: Almost all auxiliary therapies are effective complementary therapies for treating CIC, but they needed to be used simultaneously with SMC. Nevertheless, because of the small number of eligible studies and their small sample sizes, the differences in treatment duration and the endpoints, large sample RCTs with long-term follow-up are required for further investigation.
Intensive Care and Treatment of Severe Guillain–Barré Syndrome
Authors: Shang Pei , Feng Jiachun , Wu Wei , Zhang Hong-Liang
Published: April 2021

Guillain–Barré syndrome (GBS) is an acute polyneuropathy mostly characterized by acute flaccid paralysis with or without sensory/autonomous nerve dysfunction. Current immuno therapies including intravenous immunoglobulin (IVIg), plasma exchange (PE), and newly developed biological drugs benefit patients by alleviating hyperreactive immune responses. Up to 30% of patients develop respiratory failure during hospitalization and require mechanical ventilation and intensive care. Immunotherapies, mechanical ventilation, supportive care, and complication management during the intensive care unit (ICU) stay are equally emphasized. The most important aspect of intensive care and treatment of severe GBS, that is, mechanical ventilation, has been extensively reviewed elsewhere. In contrast to immunotherapies, care and treatment of GBS in the ICU setting are largely empirical. In this review, we intend to stress the importance of intensive care and treatment, other than mechanical ventilation in patients with severe GBS. We summarize the up-to-date knowledge of pharmacological therapies and ICU management of patients with severe GBS. We aim to answer some key clinical questions related to the management of severe GBS patients including but not limited to: Is IVIg better than PE or vice versa? Whether combinations of immune therapies benefit more? How about the emerging therapies promising for GBS? When to perform tracheal intubation or tracheostomy? How to provide multidisciplinary supportive care for severe cases? How to avert life-threatening complications in severe cases?
Berberine Attenuates Cerebral Ischemia-Reperfusion Injury Induced Neuronal Apoptosis by Down-Regulating the CNPY2 Signaling Pathway
Authors: Zhao Lina , Li Huanming , Gao Qian , Xu Jin , Zhu Yongjie , Zhai Meili , Zhang Peijun , Shen Na , Di Yanbo , Wang Jinhui , Chen Tie , Huang Meina , Sun Jinglai , Liu Chong
Published: April 2021

Berberine (BBR) has a neuroprotective effect against ischemic stroke, but its specific protective mechanism has not been clearly elaborated. This study explored the effect of BBR on the canopy FGF signaling regulator 2 (CNPY2) signaling pathway in the ischemic penumbra of rats. The model of cerebral ischemia-reperfusion injury (CIRI) was established by the thread embolization method, and BBR was gastrically perfused for 48 h or 24 h before operation and 6 h after operation. The rats were randomly divided into four groups: the Sham group, BBR group, CIRI group, and CIRI + BBR group. After 2 h of ischemia, followed by 24 h of reperfusion, we confirmed the neurologic dysfunction and apoptosis induced by CIRI in rats (p < 0.05). In the ischemic penumbra, the expression levels of CNPY2-regulated endoplasmic reticulum stress-induced apoptosis proteins (CNPY2, glucose-regulated protein 78 (GRP78), double-stranded RNA-activated protein kinase-like ER kinase (PERK), C/EBP homologous protein (CHOP), and Caspase-3) were significantly increased, but these levels were decreased after BBR treatment (p < 0.05). To further verify the inhibitory effect of BBR on CIRI-induced neuronal apoptosis, we added an endoplasmic reticulum-specific agonist and a PERK inhibitor to the treatment. BBR was shown to significantly inhibit the expression of apoptotic proteins induced by endoplasmic reticulum stress agonist, while the PERK inhibitor partially reversed the ability of BBR to inhibit apoptotic protein (p < 0.05). These results confirm that berberine may inhibit CIRI-induced neuronal apoptosis by downregulating the CNPY2 signaling pathway, thereby exerting a neuroprotective effect.
Yi–Qi–Jian–Pi–Xiao–Yu–Xie–Zhuo Formula Improves Muscle Atrophy via Modulating the IGF-1/PI3K/Akt Signaling Pathway in 5/6 Nephrectomized Rats
Authors: Xia Hong , Zhang Bingbing , Yang Dan , Zhu Chengyue , Zhang Jiudan , Chen Hongbo , Ma Hongzhen , Hu Shouci , Xu Chao , Shi Chengqian , Lu Keda , Zhang Peipei
Published: April 2021

The Yi–Qi–Jian–Pi–Xiao–Yu–Xie–Zhuo (YQJPXYXZ) formula has been used for treating chronic kidney disease (CKD) for many years with good efficiency based on the cumulative empirical experience of previous practitioners. Impairment of the IGF-1/PI3K/Akt signaling pathway plays an important role in mediating muscle wasting. This study aimed to observe effects of the YQJPXYXZ formula on muscle atrophy in CKD rats and investigate its possible mechanism on regulation of the IGF-1/PI3K/Akt signaling pathway. The 5/6 nephrectomized rats were randomly allocated into 3 groups: the CKD group, the KT (compound α-ketoacid tablets) group, and the YQJPXYXZ group. Besides, sham-operated rats were included as the sham group. All rats were treated for 12 weeks. Results showed that administration of the YQJPXYXZ formula prevented body weight loss and muscle fiber size decrease. Moreover, the YQJPXYXZ formula increased the IGF-1 level of serum and skeletal muscle in CKD rats and enhanced the phosphorylation level of Akt. Furthermore, the YQJPXYXZ formula decreased the Atrogin1 and MuRF1 mRNA and MuRF1 proteins. In conclusion, our data demonstrated that the YQJPXYXZ formula improves muscle wasting in CKD rats, which might be associated with the modulation of the IGF-1/PI3K/Akt signaling pathway and inhibition of the ubiquitin–proteasome system (UPS).
A Palmitoylethanolamide Producing Lactobacillus paracasei Improves Clostridium difficile Toxin A-Induced Colitis
Authors: Esposito Giuseppe , Corpetti Chiara , Pesce Marcella , Seguella Luisa , Annunziata Giuseppe , Del Re Alessandro , Vincenzi Martina , Lattanzi Roberta , Lu Jie , Sanseverino Walter , Sarnelli Giovanni
Published: April 2021

Genetically engineered probiotics, able to in situ deliver therapeutically active compounds while restoring gut eubiosis, could represent an attractive therapeutic alternative in Clostridium difficile infection (CDI). Palmitoylethanolamide is an endogenous lipid able to exert immunomodulatory activities and restore epithelial barrier integrity in human models of colitis, by binding the peroxisome proliferator–activated receptor-α (PPARα). The aim of this study was to explore the efficacy of a newly designed PEA-producing probiotic (pNAPE-LP) in a mice model of C. difficile toxin A (TcdA)-induced colitis. The human N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), a key enzyme involved in the synthesis of PEA, was cloned and expressed in a Lactobacillus paracasei that was intragastrically administered to mice 7 days prior the induction of the colitis. Bacteria carrying the empty vector served as negative controls (pLP).In the presence of palmitate, pNAPE-LP was able to significantly increase PEA production by 27,900%, in a time- and concentration-dependent fashion. Mice treated with pNAPE-LP showed a significant improvement of colitis in terms of histological damage score, macrophage count, and myeloperoxidase levels (−53, −82, and −70.4%, respectively). This was paralleled by a significant decrease both in the expression of toll-like receptor-4 (−71%), phospho-p38 mitogen-activated protein kinase (−72%), hypoxia-inducible factor-1-alpha (−53%), p50 (−74%), and p65 (−60%) and in the plasmatic levels of interleukin-6 (−86%), nitric oxide (−59%), and vascular endothelial growth factor (−71%). Finally, tight junction protein expression was significantly improved by pNAPE-LP treatment as witnessed by the rescue of zonula occludens-1 (+304%), Ras homolog family member A-GTP (+649%), and occludin expression (+160%). These protective effects were mediated by the specific release of PEA by the engineered probiotic as they were abolished in PPARα knockout mice and in wild-type mice treated with pLP. Herein, we demonstrated that pNAPE-LP has therapeutic potential in CDI by inhibiting colonic inflammation and restoring tight junction protein expression in mice, paving the way to next generation probiotics as a promising strategy in CDI prevention.
Uncovering Modern Clinical Applications of Fuzi and Fuzi-Based Formulas: A Nationwide Descriptive Study With Market Basket Analysis
Authors: Tai Chi-Jung , El-Shazly Mohamed , Tsai Yi-Hong , Csupor Dezső , Hohmann Judit , Wu Yang-Chang , Tseng Tzyy-Guey , Chang Fang-Rong , Wang Hui-Chun
Published: April 2021

Background: As time evolved, traditional Chinese medicine (TCM) became integrated into the global medical system as complementary treatments. Some essential TCM herbs started to play a limited role in clinical practices because of Western medication development. For example, Fuzi (Aconiti Lateralis Radix Praeparata) is a toxic but indispensable TCM herb. Fuzi was mainly used in poor circulation and life-threatening conditions by history records. However, with various Western medication options for treating critical conditions currently, how is Fuzi used clinically and its indications in modern TCM are unclear. This study aimed to evaluate Fuzi and Fuzi-based formulas in modern clinical practices using artificial intelligence and data mining methods.

Methods: This nationwide descriptive study with market basket analysis used a cohort selected from the Taiwan National Health Insurance database that contained one million national representatives between 2003 and 2010 used for our analysis. Descriptive statistics were performed to demonstrate the modern clinical indications of Fuzi. Market basket analysis was calculated by the Apriori algorithm to discover the association rules between Fuzi and other TCM herbs.

Results: A total of 104,281 patients using 405,837 prescriptions of Fuzi and Fuzi-based formulas were identified. TCM doctors were found to use Fuzi in pulmonary (21.5%), gastrointestinal (17.3%), and rheumatologic (11.0%) diseases, but not commonly in cardiovascular diseases (7.4%). Long-term users of Fuzi and Fuzi-based formulas often had the following comorbidities diagnosed by Western doctors: osteoarthritis (31.0%), peptic ulcers (29.5%), hypertension (19.9%), and COPD (19.7%). Patients also used concurrent medications such as H2-receptor antagonists, nonsteroidal anti-inflammatory drugs, β-blockers, calcium channel blockers, and aspirin. Through market basket analysis, for the first time, we noticed many practical Fuzi-related herbal pairs such as Fuzi–Hsihsin (Asari Radix et Rhizoma)–Dahuang (Rhei Radix et Rhizoma) for neurologic diseases and headache.

Conclusion: For the first time, big data analysis was applied to uncover the modern clinical indications of Fuzi in addition to traditional use. We provided necessary evidence on the scientific use of Fuzi in current TCM practices, and the Fuzi-related herbal pairs discovered in this study are helpful to the development of new botanical drugs.
Ganglioside GM1 Targets Astrocytes to Stimulate Cerebral Energy Metabolism
Authors: Finsterwald Charles , Dias Sara , Magistretti Pierre J. , Lengacher Sylvain
Published: April 2021

Gangliosides are major constituents of the plasma membrane and are known to promote a number of physiological actions in the brain, including synaptic plasticity and neuroprotection. In particular, the ganglioside GM1 was found to have a wide range of preclinical and clinical benefits in brain diseases such as spinal cord injury, Huntington’s disease and Parkinson’s disease. However, little is known about the underlying cellular and molecular mechanisms of GM1 in the brain. In the present study, we show that GM1 exerts its actions through the promotion of glycolysis in astrocytes, which leads to glucose uptake and lactate release by these cells. In astrocytes, GM1 stimulates the expression of several genes involved in the regulation of glucose metabolism. GM1 also enhances neuronal mitochondrial activity and triggers the expression of neuroprotection genes when neurons are cultured in the presence of astrocytes. Finally, GM1 leads to a neuroprotective effect in astrocyte-neuron co-culture. Together, these data identify a previously unrecognized mechanism mediated by astrocytes by which GM1 exerts its metabolic and neuroprotective effects.
Exosome: The Regulator of the Immune System in Sepsis
Authors: Qiu Peng , Zhou Jing , Zhang Jin , Dong Youjing , Liu Yang
Published: April 2021

Sepsis is a syndrome comprised of a series of life-threatening organ dysfunctions caused by a maladjusted body response to infection with no effective treatment. There is growing evidence that the immune system plays a core role in sepsis. Pathogens cause abnormal host immune response and eventually lead to immunosuppression, which is an important cause of death in patients with sepsis. Exosomes are vesicles derived from double invagination of plasma membrane, associating with immune responses closely. The cargos delivered by exosomes into recipient cells, especially immune cells, effectively alter their response and functions in sepsis. In this review, we focus on the effects and mechanisms of exosomes on multiple immune cells, as well as the role of immune cell-derived exosomes in sepsis. This is helpful for us to have an in-depth understanding of the mechanism of immune disorders in sepsis. Exosomes is also expected to become a novel target and therapeutic approach for sepsis.
Biotechnologically Produced Lavandula angustifolia Mill. Extract Rich in Rosmarinic Acid Resolves Psoriasis-Related Inflammation Through Janus Kinase/Signal Transducer and Activator of Transcription Signaling
Authors: Koycheva Ivanka K. , Vasileva Liliya V. , Amirova Kristiana M. , Marchev Andrey S. , Balcheva-Sivenova Zhivka P. , Georgiev Milen I.
Published: April 2021

Psoriasis is a common skin pathology, characterized by dysregulation of epidermal keratinocyte function attended by persistent inflammation, suggesting that molecules with anti-inflammatory potential may be effective for its management. Rosmarinic acid (RA) is a natural bioactive molecule known to have an anti-inflammatory potential. Here we examined the effect of biotechnologically produced cell suspension extract of Lavandula angustifolia Mill (LV) high in RA content as treatment for psoriasis-associated inflammation in human keratinocytes. Regulatory genes from the nuclear factor kappa B (NF-κB) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways were upregulated upon stimulation with a combination of interferon gamma (IFN-γ), interleukin (IL)-17A and IL-22. We also observed that both LV extract and RA could inhibit JAK2, leading to reduced STAT1 phosphorylation. Further, we demonstrated that LV extract inhibited phosphoinositide 3-kinases (PI3K) and protein kinase B (AKT), which could be implicated in reduced hyperproliferation in keratinocytes. Collectively, these findings indicate that the biotechnologically produced LV extract resolved psoriasis-like inflammation in human keratinocytes by interfering the JAK2/STAT1 signaling pathway and its effectiveness is due to its high content of RA (10%). Hence, both LV extract and pure RA possess the potential to be incorporated in formulations for topical application as therapeutic approach against psoriasis.
Quantifying Vascular Density in Tissue Engineered Constructs Using Machine Learning
Authors: Strobel Hannah A. , Schultz Alex , Moss Sarah M. , Eli Rob , Hoying James B.
Published: April 2021

Given the considerable research efforts in understanding and manipulating the vasculature in tissue health and function, making effective measurements of vascular density is critical for a variety of biomedical applications. However, because the vasculature is a heterogeneous collection of vessel segments, arranged in a complex three-dimensional architecture, which is dynamic in form and function, it is difficult to effectively measure. Here, we developed a semi-automated method that leverages machine learning to identify and quantify vascular metrics in an angiogenesis model imaged with different modalities. This software, BioSegment, is designed to make high throughput vascular density measurements of fluorescent or phase contrast images. Furthermore, the rapidity of assessments makes it an ideal tool for incorporation in tissue manufacturing workflows, where engineered tissue constructs may require frequent monitoring, to ensure that vascular growth benchmarks are met.
Hungarian Structural Focus: Accessibility to Focused Elements and Their Alternatives in Working Memory and Delayed Recognition Memory
Authors: Káldi Tamás , Szöllösi Ágnes , Babarczy Anna
Published: April 2021

The present work investigates the memory accessibility of linguistically focused elements and the representation of the alternatives for these elements (i.e., their possible replacements) in Working Memory (WM) and in delayed recognition memory in the case of the Hungarian pre-verbal focus construction (preVf). In two probe recognition experiments we presented preVf and corresponding focusless neutral sentences embedded in five-sentence stories. Stories were followed by the presentation of sentence probes in one of three conditions: (i) the probe was identical to the original sentence in the story, (ii) the focused word (i.e., target) was replaced by a semantically related word and (iii) the target word was replaced by a semantically unrelated but contextually suitable word. In Experiment 1, probes were presented immediately after the stories measuring WM performance, while in Experiment 2, blocks of six stories were presented and sentences were probed with a 2-minute delay measuring delayed recognition memory performance. Results revealed an advantage of the focused element in immediate but not in delayed retrieval. We found no effect of sentence type on the recognition of the two different probe types in WM performance. However, results pertaining to the memory accessibility of focus alternatives in delayed retrieval showed an interference effect resulting in a lower memory performance. We conclude that this effect is indirect evidence for the enhanced activation of focus alternatives. The present work is novel in two respects. First, no study has been conducted on the memory representation of focused elements and their alternatives in the case of the structurally marked Hungarian pre-verbal focus construction. Second, to our knowledge, this is the first study that investigates the focus representation accounts for WM and delayed recognition memory using the same stimuli and same measured variables. Since both experiments used exactly the same stimulus set, and they only differed in terms of the timing of recognition probes, the principle of ceteris paribus fully applied with respect to how we addressed our research question regarding the two different memory systems.
The Relationship Between Quarantine Length and Negative Affect During the COVID-19 Epidemic Among the General Population in China: The Roles of Negative Cognition and Protective Factors
Authors: Hou Lulu , Long Fangfang , Meng Yao , Cheng Xiaorong , Zhang Weiwei , Zhou Renlai
Published: April 2021

Quarantine and isolation at extended length, although considered as highly effective countermeasures for the novel coronavirus (COVID-19) which started at the end of 2019, can have great impact on individual's mental health, especially emotional state. The present research recruited 5,115 participants from the general public across 32 provinces and autonomous regions in China in an online survey study, about 20 days after the lockdown of the epicenter (Wuhan), to investigate the relationship between the length of the quarantine and negative affect (including depression and anxiety), as well as the mediating roles of negative cognition (including worry and anticipation), and the moderating roles of dispositional optimism, tolerance of uncertainty, social support, and healthy behavior. The results showed that: (1) Worry and anticipation mediated the relationship between quarantine length and depression and anxiety; (2) Dispositional optimism moderated the path coefficients of quarantine length to worry, worry to anxiety, and anticipation to depression; (3) Tolerance of uncertainty moderated the path coefficient of worry to anxiety; (4) Social support moderated the path coefficient of anticipation to anxiety. In conclusion, during quarantine, dispositional optimism, uncertainty tolerance, and social support can buffer the direct or indirect effects of quarantine length on depression and anxiety. These findings could have profound implications on the societal responses to COVID-19 and future pandemics.
Movement Matters! Understanding the Developmental Trajectory of Embodied Planning
Authors: Musculus Lisa , Ruggeri Azzurra , Raab Markus
Published: April 2021

Human motor skills are exceptional compared to other species, no less than their cognitive skills. In this perspective paper, we suggest that “movement matters!,” implying that motor development is a crucial driving force of cognitive development, much more impactful than previously acknowledged. Thus, we argue that to fully understand and explain developmental changes, it is necessary to consider the interaction of motor and cognitive skills. We exemplify this argument by introducing the concept of “embodied planning,” which takes an embodied cognition perspective on planning development throughout childhood. From this integrated, comprehensive framework, we present a novel climbing paradigm as the ideal testbed to explore the development of embodied planning in childhood and across the lifespan. Finally, we outline future research directions and discuss practical applications of the work on developmental embodied planning for robotics, sports, and education.
Correlations Between Cognitive Functions and Clinical Symptoms in Adolescents With Complex Post-traumatic Stress Disorder
Authors: Shin Yee Jin , Kim Sun Mi , Hong Ji Sun , Han Doug Hyun
Published: April 2021

Introduction: Complex post-traumatic stress disorder (C-PTSD) is characterized by the typical symptoms of PTSD, in addition to affective dysregulation, negative self-concept, and disturbances in interpersonal relationships. Children and adolescents with C-PTSD have been reported to have deficits in emotional and cognitive functions. We hypothesized that the following are associated with the severity of C-PTSD symptoms: (1) adolescents with C-PTSD who show deficits in emotional perception and cognitive functions, including executive function and attention; and (2) deficits in neurocognitive functions.

Methods: Information on 69 adolescents with PTSD, aged 10–19 years, was gathered from seven shelters. All participants were assessed using complete clinical scales, including the C-PTSD Interview and Depression, Anxiety, and Stress Scales, and neurocognitive function tests, including the emotional perception, mental rotation, and modified Tower of London tests.

Results: Adolescents with C-PTSD were more likely to have a history of sexual assault, dissociation, and self-harm than those with PTSD. The total and subscale scores of the C-PTSD Interview Scale in adolescents with C-PTSD were higher than that in adolescents with PTSD. In addition, neurocognitive functions, including emotional perception, attention, and working memory, were correlated with the severity of C-PTSD symptoms.

Discussion: Adolescents with C-PTSD experienced more serious clinical symptoms and showed more deficits in neurocognitive functions than adolescents with PTSD. Clinicians should pay careful attention toward the emotional and neurocognitive functions when assessing and treating patients with C-PTSD.