bluuebunny/crossref_metadata_2025 huggingface dataset:
HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation
Authors: Ma Wenjing , Cai Yong , Shen Yuntian , Chen Xin , Zhang Lilei , Ji Yanan , Chen Zehao , Zhu Jianwei , Yang Xiaoming , Sun Hualin
Published: June 2021

Denervation can activate the catabolic pathway in skeletal muscle and lead to progressive skeletal muscle atrophy. At present, there is no effective treatment for muscle atrophy. Histone deacetylase 4 (HDAC4) has recently been found to be closely related to muscle atrophy, but the underlying mechanism of HDAC4 in denervation-induced muscle atrophy have not been described clearly yet. In this study, we found that the expression of HDAC4 increased significantly in denervated skeletal muscle. HDAC4 inhibition can effectively diminish denervation-induced muscle atrophy, reduce the expression of muscle specific E3 ubiquitin ligase (MuRF1 and MAFbx) and autophagy related proteins (Atg7, LC3B, PINK1 and BNIP3), inhibit the transformation of type I fibers to type II fibers, and enhance the expression of SIRT1 and PGC-1 α. Transcriptome sequencing and bioinformatics analysis was performed and suggested that HDAC4 may be involved in denervation-induced muscle atrophy by regulating the response to denervation involved in the regulation of muscle adaptation, cell division, cell cycle, apoptotic process, skeletal muscle atrophy, and cell differentiation. STRING analysis showed that HDAC4 may be involved in the process of muscle atrophy by directly regulating myogenin (MYOG), cell cycle inhibitor p21 (CDKN1A) and salt induced kinase 1 (SIK1). MYOG was significantly increased in denervated skeletal muscle, and MYOG inhibition could significantly alleviate denervation-induced muscle atrophy, accompanied by the decreased MuRF1 and MAFbx. MYOG overexpression could reduce the protective effect of HDAC4 inhibition on denervation-induced muscle atrophy, as evidenced by the decreased muscle mass and cross-sectional area of muscle fibers, and the increased mitophagy. Taken together, HDAC4 inhibition can alleviate denervation-induced muscle atrophy by reducing MYOG expression, and HDAC4 is also directly related to CDKN1A and SIK1 in skeletal muscle, which suggests that HDAC4 inhibitors may be a potential drug for the treatment of neurogenic muscle atrophy. These results not only enrich the molecular regulation mechanism of denervation-induced muscle atrophy, but also provide the experimental basis for HDAC4-MYOG axis as a new target for the prevention and treatment of muscular atrophy.
Widely Different Correlation Patterns Between Pairs of Adjacent Thalamic Neurons In vivo
Authors: Wahlbom Anders , Mogensen Hannes , Jörntell Henrik
Published: June 2021

We have previously reported different spike firing correlation patterns among pairs of adjacent pyramidal neurons within the same layer of S1 cortex in vivo, which was argued to suggest that acquired synaptic weight modifications would tend to differentiate adjacent cortical neurons despite them having access to near-identical afferent inputs. Here we made simultaneous single-electrode loose patch-clamp recordings from 14 pairs of adjacent neurons in the lateral thalamus of the ketamine-xylazine anesthetized rat in vivo to study the correlation patterns in their spike firing. As the synapses on thalamic neurons are dominated by a high number of low weight cortical inputs, which would be expected to be shared for two adjacent neurons, and as far as thalamic neurons have homogenous membrane physiology and spike generation, they would be expected to have overall similar spike firing and therefore also correlation patterns. However, we find that across a variety of thalamic nuclei the correlation patterns between pairs of adjacent thalamic neurons vary widely. The findings suggest that the connectivity and cellular physiology of the thalamocortical circuitry, in contrast to what would be expected from a straightforward interpretation of corticothalamic maps and uniform intrinsic cellular neurophysiology, has been shaped by learning to the extent that each pair of thalamic neuron has a unique relationship in their spike firing activity.
Potential Prognostic Impact of Dopamine Receptor D1 (rs4532) Polymorphism in Post-stroke Outcome in the Elderly
Authors: Park Hae-Yeon , Kim Youngkook , Oh Hyun Mi , Kim Tae-Woo , Park Geun-Young , Im Sun
Published: June 2021

Background: Single-nucleotide polymorphisms (SNPs) may affect post-stroke motor recovery, and some SNPs have been implicated in swallowing disturbances after stroke. Certain SNPs may also have altered influences according to different age.

Objective: This post-hoc study investigated whether SNPs have different effects on dysphagia recovery between the elderly vs. young stroke patients.

Methods: Analysis was conducted from a previous study including 218 stroke subjects with dysphagia. They were stratified into two groups, aged <65 and aged ≥65 years. The primary outcome was persistence of nil per mouth (NPM) at 3 months post-stroke onset. Association between outcome and nine different SNPs were investigated.

Results: The elderly group (50%, n = 103) showed poorer swallowing outcomes than the young group. The minor allele of the dopamine receptor D1 (DRD1, rs4532) polymorphism showed potential association (p = 0.022) with an increased risk of NPM at 12 weeks post-stroke in the elderly, both in the additive (OR, 2.94; 95% CI, 1.17–7.37) and dominant models (OR, 2.93; 95% CI, 1.04–8.23) but did not reach statistical significance after Bonferonni correction. Logistic regression analysis showed that in those aged ≥65 years, models including the minor allele of rs4532 predicted the risk of the poor outcome with good accuracies even after adjustment of clinical factors, such as previous pneumonia episodes (AUROC, 0.86; 95% CI, 0.79–0.93) or the National Institutes of Health Stroke Scale (AUROC, 0.82; 95% CI, 0.67–0.92). In contrast, those aged <65 years seemed not to be affected by the presence of the rs4532 polymorphism, and models that included intubation history (AUROC, 0.81; 95% CI, 0.73–0.90) or previous pneumonia episodes (AUROC, 0.77; 95% CI, 0.68–0.87) showed modest levels of accuracies in predicting NPM at 12 weeks poststroke.

Conclusions: Our study suggests a possible association between the rs4532 and post-stroke swallowing recovery, primarily in those aged ≥65 years. Certain SNPs may lead to less favorable outcomes in the elderly. The gene–age interaction should be considered in post-stroke swallowing recovery.

Clinical Trial Registration:https://www.clinicaltrials.gov, Unique identifier [NCT03577444].
Imagining How Lines Were Drawn: The Appreciation of Calligraphy and the Facilitative Factor Based on the Viewer’s Rating and Heart Rate
Authors: Matsumoto Kazuki , Okada Takeshi
Published: June 2021

For this study, we examined how recognizing the writing process of calligraphy influences the cognitive and affective processes related to appreciating it, with the aim of contributing to both graphonomics and the psychology of aesthetics. To this end, we conducted two Web-based experiments in which some participants were instructed to view calligraphy by tracing it with their eyes (the tracing method), while others were told to feel free to think and imagine whatever they wanted. Study 1 (N = 103) revealed that the tracing method elicits stronger admiration, inspiration, and empathy in viewers. Study 2 (N = 87) showed that the tracing method decreases the average heart rate of those who do not frequently engage in calligraphy appreciation as they gaze at calligraphy for a minute-and-a-half (during the second half of the stimulus duration); this suggests that the tracing method could keep viewers from becoming bored while looking at calligraphy. In sum, the tracing method has positive effects on viewing calligraphy. From a broader perspective, the results imply that how in detail viewers recognize the process of creating an artwork will be a key determinant of art appreciation. In addition, our findings demonstrate how we can measure cardiac activities using the emerging technology of the photoplethysmogram (PPG).
Decreased Event-Related Desynchronization of Mental Rotation Tasks in Young Tibetan Immigrants
Authors: Xiang Zu-qiang , Huang Yi-lin , Luo Guang-li , Ma Hai-lin , Zhang De-long
Published: June 2021

The present study aimed to explore the cortical activity underlying mental rotation in high-altitude immigrants via the event-related desynchronization (ERD), the electroencephalogram time–frequency analysis, and source localization based on electroencephalographic data. When compared with the low-altitude individuals, the reaction time of mental rotation tasks was significantly slower in immigrants who had lived in high-altitude areas for 3 years. The time–frequency analysis showed that the alpha ERD and the beta ERD within the time window (400–700 ms) were decreased during the mental rotation tasks in these immigrants. The decreased ERD was observed at the parietal–occipital regions within the alpha band and at the central–parietal regions within the beta band. The decreased ERD might embody the sensorimotor-related cortical activity from hypoxia, which might be involved in cognitive control function in high-altitude immigrants, which provided insights into the neural mechanism of spatial cognition change on aspect of embodied cognition due to high-altitude exposure.
Randomized Cross Over Study Assessing the Efficacy of Non-invasive Stimulation of the Vagus Nerve in Patients With Axial Spondyloarthritis Resistant to Biotherapies: The ESNV-SPA Study Protocol
Authors: Azabou Eric , Bao Guillaume , Costantino Félicie , Jacota Madalina , Lazizi Chanez , Nkam Lionelle , Rottman Martin , Roux Anne-Laure , Chevallier Sylvain , Grimaldi Lamiae , Breban Maxime
Published: June 2021

Axial spondyloarthritis (SpA), is a major cause of chronic pain and disability that profoundly alters the quality of life of patients. Nearly half of patients with SpA usually develop drug resistance. Non-pharmacological treatments targeting inflammation are an attractive alternative to drug administration. Vagus nerve stimulation (VNS), by promoting a cholinergic anti-inflammatory reflex holds promise for treating inflammatory disease. Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in animal models of endotoxemia, sepsis, colitis, and other preclinical models of inflammatory diseases. It has been proposed that vagal efferent fibers release acetylcholine (Ach), which can interact with α7-subunit-containing nicotinic receptors expressed by tissue macrophages and other immune cells to rapidly inhibit the synthesis/release of pro-inflammatory cytokines such as TNFα, IL-1β, IL-6, and IL-18. External vagal nerve stimulation devices are now available that do not require surgery nor implantation to non-invasively stimulate the vagal nerve. This double-blind randomized cross-over clinical trial aims to study the change in SpA disease activity, according to Assessment in Ankylosing Spondylitis 20 (ASAS20) definition, after 12 weeks of non-invasive VNS treatment vs. non-specific dummy stimulation (control group). One hundred and twenty adult patients with drug resistant SpA, meeting the ASAS classification criteria, will be included in the study. Patients will be randomized into two parallel groups according to a cross over design: either active VNS for 12 weeks, then dummy stimulation for 12 weeks, or dummy stimulation for 12 weeks, then active VNS for 12 weeks. The two stimulation periods will be separated by a 4 weeks wash-out period. A transcutaneous auricular vagus nerve stimulator Tens Eco Plus SCHWA MEDICOTM France will be used in this study. The active VNS stimulation will be applied in the cymba conchae of the left ear upon the auricular branch of the vagus nerve, using low intensity (2–5 mA), once à week, during 1 h. Dummy stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at an irrelevant anatomical site: the left ear lobule. This multicenter study was registered on ClinicalTrials.gov: NCT04286373.
Causal Evidence for Induction of Pessimistic Decision-Making in Primates by the Network of Frontal Cortex and Striosomes
Authors: Amemori Satoko , Graybiel Ann M. , Amemori Ken-ichi
Published: June 2021

Clinical studies have shown that patients with anxiety disorders exhibited coactivation of limbic cortices and basal ganglia, which together form a large-scale brain network. The mechanisms by which such a large-scale network could induce or modulate anxiety-like states are largely unknown. This article reviews our experimental program in macaques demonstrating a causal involvement of local striatal and frontal cortical sites in inducing pessimistic decision-making that underlies anxiety. Where relevant, we related these findings to the wider literature. To identify such sites, we have made a series of methodologic advances, including the combination of causal evidence for behavioral modification of pessimistic decisions with viral tracing methods. Critically, we introduced a version of the classic approach-avoidance (Ap-Av) conflict task, modified for use in non-human primates. We performed microstimulation of limbic-related cortical regions and the striatum, focusing on the pregenual anterior cingulate cortex (pACC), the caudal orbitofrontal cortex (cOFC), and the caudate nucleus (CN). Microstimulation of localized sites within these regions induced pessimistic decision-making by the monkeys, supporting the idea that the focal activation of these regions could induce an anxiety-like state, which subsequently influences decision-making. We further performed combined microstimulation and tract-tracing experiments by injecting anterograde viral tracers into focal regions, at which microstimulation induced increased avoidance. We found that effective stimulation sites in both pACC and cOFC zones projected preferentially to striosomes in the anterior striatum. Experiments in rodents have shown that the striosomes in the anterior striatum project directly to the dopamine-containing cells in the substantia nigra, and we have found evidence for a functional connection between striosomes and the lateral habenular region in which responses to reward are inhibitory. We present here further evidence for network interactions: we show that the pACC and cOFC project to common structures, including not only the anterior parts of the striosome compartment but also the tail of the CN, the subgenual ACC, the amygdala, and the thalamus. Together, our findings suggest that networks having pACC and cOFC as nodes share similar features in their connectivity patterns. We here hypothesize, based on these results, that the brain sites related to pessimistic judgment are mediated by a large-scale brain network that regulates dopaminergic functions and includes striosomes and striosome-projecting cortical regions.
Multiscale Computational Model Reveals Nerve Response in a Mouse Model for Temporal Interference Brain Stimulation
Authors: Gomez-Tames Jose , Asai Akihiro , Hirata Akimasa
Published: June 2021

There has been a growing interest in the non-invasive stimulation of specific brain tissues, while reducing unintended stimulation in surrounding regions, for the medical treatment of brain disorders. Traditional methods for non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), can stimulate brain regions, but they also simultaneously stimulate the brain and non-brain regions that lie between the target and the stimulation site of the source. Temporal interference (TI) stimulation has been suggested to selectively stimulate brain regions by superposing two alternating currents with slightly different frequencies injected through electrodes attached to the scalp. Previous studies have reported promising results for TI applied to the motor area in mice, but the mechanisms are yet to be clarified. As computational techniques can help reveal different aspects of TI, in this study, we computationally investigated TI stimulation using a multiscale model that computes the generated interference current pattern effects in a neural cortical model of a mouse head. The results indicated that the threshold increased with the carrier frequency and that the beat frequency did not influence the threshold. It was also found that the intensity ratio between the alternating currents changed the location of the responding nerve, which is in agreement with previous experiments. Moreover, particular characteristics of the envelope were investigated to predict the stimulation region intuitively. It was found that regions with high modulation depth (| maximum| − | minimum| values of the envelope) and low minimum envelope (near zero) corresponded with the activation region obtained via neural computation.
Monitoring and Prognostic Analysis of Severe Cerebrovascular Diseases Based on Multi-Scale Dynamic Brain Imaging
Authors: Zhong Suting , Sun Kai , Zuo Xiaobing , Chen Aihong
Published: June 2021

Severe cerebrovascular disease is an acute cerebrovascular event that causes severe neurological damage in patients, and is often accompanied by severe dysfunction of multiple systems such as breathing and circulation. Patients with severe cerebrovascular disease are in critical condition, have many complications, and are prone to deterioration of neurological function. Therefore, they need closer monitoring and treatment. The treatment strategy in the acute phase directly determines the prognosis of the patient. The case of this article selected 90 patients with severe cerebrovascular disease who were hospitalized in four wards of the Department of Neurology and the Department of Critical Care Medicine in a university hospital. The included cases were in accordance with the guidelines for the prevention and treatment of cerebrovascular diseases. Patients with cerebral infarction are given routine treatments such as improving cerebral circulation, protecting nutrient brain cells, dehydration, and anti-platelet; patients with cerebral hemorrhage are treated within the corresponding safe time window. We use Statistical Product and Service Solutions (SPSS) Statistics21 software to perform statistical analysis on the results. Based on the study of the feature extraction process of convolutional neural network, according to the hierarchical principle of convolutional neural network, a backbone neural network MF (Multi-Features)—Dense Net that can realize the fusion, and extraction of multi-scale features is designed. The network combines the characteristics of densely connected network and feature pyramid network structure, and combines strong feature extraction ability, high robustness and relatively small parameter amount. An end-to-end monitoring algorithm for severe cerebrovascular diseases based on MF-Dense Net is proposed. In the experiment, the algorithm showed high monitoring accuracy, and at the same time reached the speed of real-time monitoring on the experimental platform. An improved spatial pyramid pooling structure is designed to strengthen the network’s ability to merge and extract local features at the same level and at multiple scales, which can further improve the accuracy of algorithm monitoring by paying a small amount of additional computational cost. At the same time, a method is designed to strengthen the use of low-level features by improving the network structure, which improves the algorithm’s monitoring performance on small-scale severe cerebrovascular diseases. For patients with severe cerebrovascular disease in general, APACHEII1, APACHEII2, APACHEII3 and the trend of APACHEII score change are divided into high-risk group and low-risk group. The overall severe cerebrovascular disease, severe cerebral hemorrhage and severe cerebral infarction are analyzed, respectively. The differences are statistically significant.
In vivo Evaluation of a Newly Synthesized Acetylcholinesterase Inhibitor in a Transgenic Drosophila Model of Alzheimer’s Disease
Authors: Uras Giuseppe , Manca Alessia , Zhang Pengfei , Markus Zsuzsa , Mack Natalie , Allen Stephanie , Bo Marco , Xu Shengtao , Xu Jinyi , Georgiou Marios , Zhu Zheying
Published: June 2021

Alzheimer’s disease is a neurodegenerative disease characterized by disrupted memory, learning functions, reduced life expectancy, and locomotor dysfunction, as a result of the accumulation and aggregation of amyloid peptides that cause neuronal damage in neuronal circuits. In the current study, we exploited a transgenicDrosophila melanogasterline, expressing amyloid-β peptides to investigate the efficacy of a newly synthesized acetylcholinesterase inhibitor, named XJP-1, as a potential AD therapy. Behavioral assays and confocal microscopy were used to characterize the drug effect on AD symptomatology and amyloid peptide deposition. The symptomatology induced in this particular transgenic model recapitulates the scenario observed in human AD patients, showing a shortened lifespan and reduced locomotor functions, along with a significant accumulation of amyloid plaques in the brain. XJP-1 treatment resulted in a significant improvement of AD symptoms and a reduction of amyloid plaques by diminishing the amyloid aggregation rate. In comparison with clinically effective AD drugs, our results demonstrated that XJP-1 has similar effects on AD symptomatology, but at 10 times lower drug concentration than donepezil. It also showed an earlier beneficial effect on the reduction of amyloid plaques at 10 days after drug treatment, as observed for donepezil at 20 days, while the other drugs tested have no such effect. As a novel and potent AChE inhibitor, our study demonstrates that inhibition of the enzyme AChE by XJP-1 treatment improves the amyloid-induced symptomatology inDrosophila, by reducing the number of amyloid plaques within the fruit fly CNS. Thus, compound XJP-1 has the therapeutic potential to be further investigated for the treatment of AD.
Behavioral and Thermoregulatory Responses to Changes in Ambient Temperature and Wheel Running Availability in Octodon degus
Authors: Bano-Otalora Beatriz , Rol Maria Angeles , Madrid Juan Antonio
Published: June 2021

Octodon degus is primarily a diurnal species, however, in laboratory conditions, it can switch from diurnal to nocturnal in response to wheel running availability. It has been proposed that this activity inversion obeys thermoregulatory constraints induced by vigorous physical exercise. Thus, its activity shifts to the night as the ambient temperature is lower.Here, we investigate the relationship between thermoregulation and the activity phase-inversion in response to wheel-running in this species. We measured behavioral activity and body temperature rhythms in diurnal naïve animals under 12 h light: 12 h dark cycles at four different ambient temperatures (spanning from ~26°C to 32°C), and following access to running wheels while maintained under high ambient temperature.Our results show that naïve degus do not shift their diurnal activity and body temperature rhythms to a nocturnal phase when subjected to sequential increases in ambient temperature. However, when they were provided with wheels under constant high-temperature conditions, all animals inverted their diurnal phase preference becoming nocturnal. Both, negative masking by light and entrainment to the dark phase appeared involved in the nocturnalism of these animals. Analysis of the thermoregulatory response to wheel running revealed some differences between masked and entrained nocturnal chronotypes.These data highlight the importance of the coupling between wheel running availability and ambient temperature in the nocturnalism of the degus. The results support the view that an innate “protective” pre-program mechanism (associating darkness and lower ambient temperature) may change the timing of behavioral activity in this species to reduce the potential risk of hyperthermia.
No Effect of Added Sugars in Soft Drink Compared With Sugars in Fruit on Cardiometabolic Risk Factors: Results From a 4-Week, Randomized Controlled Trial
Authors: Te Morenga Lisa , Mallard Simonette R. , Ormerod Fabiane B.
Published: June 2021

High intakes of added sugar from soft drinks are associated with negative health outcomes such as the increased risk of gout and type 2 diabetes, weight gain and cardiovascular disease. Fruits are naturally high in sugars but their effect on cardiometabolic risk remains unknown. We examined the effect on cardiometabolic risk factors of consuming natural sugars from fruit or added sugars from sugar-sweetened soft drinks in overweight adults. Forty-eight healthy, overweight (BMI ≥ 28 kg/m2) men (n = 21) and women (n = 20) were randomized to either a fruit (n = 19) or sugar-sweetened soft drink (n = 22) intervention for 4 weeks. The fruit group received 6 items of fresh and dried fruit per day and the sugar-sweetened soft drink group received 955 ml of sugar-sweetened soft drink per day. The interventions were matched for both energy (fruit: 1,800 kJ/d; soft drink: 1,767 kJ/d) and fructose content (fruit: 51.8 g/d; soft drink: 51.7 g/d). The soft drink intervention provided 101 g total sugars, which was all added sugar and the fruit intervention provided 97 g total sugars, which were all natural sugars. Dietary intakes were otherwise ad libitum. Despite being asked to consume additional sugar (up to 1,800 additional kJ/d), there were no changes in weight, blood pressure or other cardiometabolic risk factors, except by uric acid, in any of the intervention groups. In conclusion, our findings do not provide any evidence that short-term regular intake of added sugars is linked to higher cardiometabolic risks, with exception of uric acid in overweight men. Public health interventions to prevent obesity and related diseases should focus on the quality of the whole diet rather than only focusing on reducing sugary drinks or sugar intakes.
The Add-On Effect of Lactobacillus plantarum PS128 in Patients With Parkinson's Disease: A Pilot Study
Authors: Lu Chin-Song , Chang Hsiu-Chen , Weng Yi-Hsin , Chen Chiung-Chu , Kuo Yi-Shan , Tsai Ying-Chieh
Published: June 2021

Background:Lactobacillus plantarum PS128 (PS128) is a specific probiotic, known as a psychobiotic, which has been demonstrated to alleviate motor deficits and inhibit neurodegenerative processes in Parkinson's disease (PD)-model mice. We hypothesize that it may also be beneficial to patients with PD based on the possible mechanism via the microbiome-gut-brain axis.

Methods: This is an open-label, single-arm, baseline-controlled trial. The eligible participants were scheduled to take 60 billion colony-forming units of PS128 once per night for 12 weeks. Clinical assessments were conducted using the Unified Parkinson's Disease Rating Scale (UPDRS), modified Hoehn and Yahr scale, and change in patient “ON-OFF” diary recording as primary outcome measures. The non-motor symptoms questionnaire, Beck depression inventory-II, patient assessment of constipation symptom, 39-item Parkinson's Disease Questionnaire (PDQ-39), and Patient Global Impression of Change (PGI-C) were assessed as secondary outcome measures.

Results: Twenty-five eligible patients (32% women) completed the study. The mean age was 61.84 ± 5.74 years (range, 52–72), mean disease duration was 10.12 ± 2.3 years (range, 5–14), and levodopa equivalent daily dosage was 1063.4 ± 209.5 mg/daily (range, 675–1,560). All patients remained on the same dosage of anti-parkinsonian and other drugs throughout the study. After 12 weeks of PS128 supplementation, the UPDRS motor scores improved significantly in both the OFF and ON states (p = 0.004 and p = 0.007, respectively). In addition, PS128 intervention significantly improved the duration of the ON period and OFF period as well as PDQ-39 values. However, no obvious effect of PS128 on non-motor symptoms of patients with PD was observed. Notably, the PGI-C scores improved in 17 patients (68%). PS128 intervention was also found to significantly reduce plasma myeloperoxidase and urine creatinine levels.

Conclusion: The present study demonstrated that PS128 supplementation for 12 weeks with constant anti-parkinsonian medication improved the UPDRS motor score and quality of life of PD patients. We suggest that PS128 could serve as a therapeutic adjuvant for the treatment of PD. In the future, placebo-controlled studies are needed to further support the efficacy of PS128 supplementation.

Clinical Trial Registration:https://clinicaltrials.gov/, identifier: NCT04389762.
Benefits and Challenges in the Incorporation of Insects in Food Products
Authors: Acosta-Estrada Beatriz A. , Reyes Alicia , Rosell Cristina M. , Rodrigo Dolores , Ibarra-Herrera Celeste C.
Published: June 2021

Edible insects are being accepted by a growing number of consumers in recent years not only as a snack but also as a side dish or an ingredient to produce other foods. Most of the edible insects belong to one of these groups of insects such as caterpillars, butterflies, moths, wasps, beetles, crickets, grasshoppers, bees, and ants. Insect properties are analyzed and reported in the articles reviewed here, and one common feature is nutrimental content, which is one of the most important characteristics mentioned, especially proteins, lipids, fiber, and minerals. On the other hand, insects can be used as a substitute for flour of cereals for the enrichment of snacks because of their high content of proteins, lipids, and fiber. Technological properties are not altered when these insects-derived ingredients are added and sensorial analysis is satisfactory, and only in some cases, change in color takes place. Insects can be used as substitute ingredients in meat products; the products obtained have higher mineral content than traditional ones, and some texture properties (like elasticity) can be improved. In extruded products, insects are an alternative source of proteins to feed livestock, showing desirable characteristics. Isolates of proteins of insects have demonstrated bioactive activity, and these can be used to improve food formulations. Bioactive compounds, as antioxidant agents, insulin regulators, and anti-inflammatory peptides, are high-value products that can be obtained from insects. Fatty acids that play a significant role in human health and lipids from insects have showed positive impacts on coronary disease, inflammation, and cancer. Insects can be a vector for foodborne microbial contamination, but the application of good manufacturing practices and effective preservation techniques jointly with the development of appropriate safety regulations will decrease the appearance of such risks. However, allergens presented in some insects are a hazard that must be analyzed and taken into account. Despite all the favorable health-promoting characteristics present in insects and insects-derived ingredients, willingness to consume them has yet to be generalized.
Identification of Flap Endonuclease 1 With Diagnostic and Prognostic Value in Breast Cancer
Authors: Wu Min , Zhang Pan , Wang Penghui , Fang Zhen , Zhu Yaqin
Published: June 2021

Objective

This study aims to identify the potential value of flap endonuclease 1 (FEN1) as a diagnostic and prognostic marker for breast cancer (BC).

Methods

ELISA was used to measure serum FEN1 levels and ECLIA for CA153 and CEA levels. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value. Oncomine and UALCAN databases were used to analyze the differences in FEN1 mRNA and protein expressions. Kaplan-Meier Plotter database was then used to assess the prognostic value.

Results

Bioinformatics analysis showed that the FEN1 mRNA and protein levels were significantly higher in BC tissues than in normal tissues. FEN1 was detected in culture medium of BC cell lines and serum FEN1 concentrations were significantly increased in BC patients than in cancer-free individuals. Besides, FEN1 exhibited higher diagnostic accuracy (AUC values>0.800) than CA153 and CEA for distinguishing BC patients, especially early BC, from the healthy and benign groups, or individually. Additionally, serum FEN1 levels were significantly associated with the stage (P=0.001) and lymph invasion (P=0.016), and serum FEN1 levels were increased with the development of BC. Furthermore, serum FEN1 levels were significantly decreased in post-operative patients than in pre-operative patients (P=0.016). Based on the Kaplan-Meier Plotter database, the survival analysis indicated that FEN1 overexpression was associated with poor prognoses for overall survival (OS), relapse-free survival (RFS), and distant metastasis-free survival (DMFS) in BC patients.

Conclusion

FEN1 might be a novel diagnostic and prognostic marker for BC.
Hepcidin Downregulation Correlates With Disease Aggressiveness And Immune Infiltration in Liver Cancers
Authors: Wang Jinhu , Liu Wang , Li Jean C. , Li Mingyi , Li Benyi , Zhu Runzhi
Published: June 2021

Background

Hepcidin is a polypeptide hormone mainly produced by hepatocytes to modulate systemic iron balance. A drastic downregulation of the hepcidin gene was found in liver cancers. However, there is a paucity of information about the clinical significance of hepcidin gene downregulation in liver cancers.

Methods

Hepcidin expression profiles were assessed using multiple public datasets via several bioinformatics platforms. Clinical and pathological information was utilized to stratify patients for comparison. Patient survival outcomes were evaluated using the Kaplan-Meier plotter, a meta-analysis tool. Tumor immune infiltration was analyzed using the single sample gene set enrichment analysis (ssGSEA) approach on the Cancer Genome Atlas (TCGA) dataset. Hepcidin antagonist Fursultiamine was used to treat liver cancer HepG2 and Huh7 cells together with Sorafenib.

Results

Hepcidin gene was predominantly expressed in benign liver tissues but drastically decreased in liver cancer tissues. Hepcidin reduction in liver cancers correlated with risk factors like non-alcoholic fatty liver disease (NAFLD) and liver fibrosis, as well as cancer grade and tumor stage. Hepcidin downregulation was associated with a rapid cancer progression and worse disease-specific survival, especially in patients of the White race without alcohol consumption history. Hepcidin expression in liver cancer tissues positively correlated with the bone morphogenetic protein-6 (BPM6)/interleukin-6 (IL6) cytokines and cytotoxic immune infiltration. Blocking hepcidin action with its antagonist Fursultiamine moderately reduced Sorafenib-induced apoptotic cell death in HepG2 and Huh7 cells.

Conclusion

Hepcidin downregulation in liver cancers correlated with liver cancer risk factors, cancer aggressiveness, cytotoxic immune cell infiltration, and patient survival outcomes. BMP6/IL6 pathway insufficiency is a potential cause of hepcidin downregulation in liver cancers.
Experience Summary of Laparoscopic Treatment for Pediatric Ureteral Polyps
Authors: Gao Hongjie , Chen Jiawei , Li Guowei , Cui Xinhai , Sun Fengyin
Published: June 2021

Objective: To investigate surgical techniques and challenges of laparoscopic in treating pediatric ureteral polyps under laparoscopy.

Methods: The clinical data of 7 of pediatric ureteral polyps patients who were admitted to the hospital from July 2015 to January 2020 were analyzed retrospectively. There were 6 males and 1 female from 7.7 to 13.9 years old at the mean age of 10.4. Before surgery, all children performed urinary B ultrasound, magnetic resonance urography (MRU), and renal radionuclide scanning. Six cases were observed on the left lateral and 1 on the right. The lesions of 5 cases were located at the ureteropelvic junction, 1 in the upper ureter and 1 in the middle ureter. The polyps were treated intraoperatively by the resecting of the lesion segment and simple polypectomy to retain the attached part of the original diseased segment of the ureter. All surgeries were performed under laparoscopy and B-ultrasound was performed during follow up after surgery.

Results: All 7 surgeries were performed successfully under the laparoscope. The surgery time was 80–110 min, and the average surgery time was 97.5 min. The intraoperative bleeding was 10–25 ml and the average postoperative hospital stay was 6 d. Postoperative hematuria occurred in 1 case. Neither urinary leakage nor urinary tract infection was reported post surgery. Preoperative affected pyelectasis of all patients was 2.0–3.7 cm. Three months postoperatively, the affected pyelectasis was measured at 1.2–3.0 cm. No recurrence of polyps was reported after surgery. During the follow-up to April 2020, there was no significant change in the kidney size of all patients, and hydronephrosis was alleviated compared with that before surgery.

Conclusions: Laparoscopy is a safe, effective and minimally invasive surgical technique for pediatric multiple ureteral polyps. The surgery plan was designed according to the location and size of polyps, including segmental ureterectomy of polyps + pyeloureterostomy, segmental ureterectomy of polyps + ureter - ureteral anastomosis.
Sex, Pramipexole and Tiagabine Affect Behavioral and Hormonal Response to Traumatic Stress in a Mouse Model of PTSD
Authors: Malikowska-Racia Natalia , Salat Kinga , Gdula-Argasinska Joanna , Popik Piotr
Published: June 2021

Posttraumatic stress disorder (PTSD) has been associated with abnormal regulation of the hypothalamic-pituitary-adrenal gland axis (HPA). Women demonstrate a more robust HPA response and are twice as likely to develop PTSD than men. The role of sex hormones in PTSD remains unclear. We investigated whether post-trauma chronic treatment with the GABA-ergic agent tiagabine and dopamine-mimetic pramipexole affected the behavioral outcome and plasma levels of corticosterone, testosterone, or 17β-estradiol in female and male mice. These medications were investigated due to their potential capacity to restore GABA-ergic and dopaminergic deficits in PTSD. Animals were exposed to a single prolonged stress procedure (mSPS). Following 13 days treatment with tiagabine (10 mg/kg) or pramipexole (1 mg/kg) once daily, the PTSD-like phenotype was examined in the fear conditioning paradigm. Plasma hormones were measured almost immediately following the conditioned fear assessment. We report that the exposure to mSPS equally enhanced conditioned fear in both sexes. However, while males demonstrated decreased plasma corticosterone, its increase was observed in females. Trauma elevated plasma testosterone in both sexes, but it had no significant effects on 17β-estradiol. Behavioral manifestation of trauma was reduced by pramipexole in both sexes and by tiagabine in females only. While neither compound affected corticosterone in stressed animals, testosterone levels were further enhanced by tiagabine in females. This study shows sex-dependent efficacy of tiagabine but not pramipexole in a mouse model of PTSD-like symptoms and a failure of steroid hormones’ levels to predict PTSD treatment efficacy.
Chlorogenic Acid Improves NAFLD by Regulating gut Microbiota and GLP-1
Authors: Shi Ameng , Li Ting , Zheng Ying , Song Yahua , Wang Haitao , Wang Na , Dong Lei , Shi Haitao
Published: June 2021

Our previous studies have shown that chlorogenic acid (CGA) could significantly improve acute and chronic liver injury through antioxidant and anti-inflammatory activities. However, its effect on non-alcoholic fatty liver disease (NAFLD) are not entirely clear. This study aims to explore the effect of CGA on NAFLD induced by high-fat diet (HFD) and whether it regulates the gut microbiota and Glucagon-like peptide-1 (GLP-1). NAFLD mice were established by HFD and treated with or without CGA. Serum transaminase, fasting blood glucose (FBG), blood lipids, insulin, GLP-1 and lipopolysaccharide (LPS) were detected. Liver histology was evaluated with Hematoxylin-eosin staining. Toll like receptor 4 (TLR4) signaling pathway was analyzed with western blot and inflammatory cytokines were detected with real-time PCR. The content of gut microbiota were determined with real-time PCR of the bacterial 16S rRNA gene. Expressions of intestine tight junctional protein were examined with immunohistochemistry. CGA could alleviate HFD-induced hepatic steatosis and inflammation, reduce serum transaminase, FBG and blood lipids, increase insulin sensitivity. CGA also could reverse HFD-induced activation of TLR4 signaling pathway and expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in liver. Meanwhile, CGA increased the content of Bifidobacterium and reduced the content of Escherichia coli in feces. Furthermore, CGA could increase the expression of tight junction proteins Occludin and zonula occludens-1 (ZO-1) in intestinal tissue. Moreover, CGA could the level of LPS and increased the level of GLP-1 in portal vein. These results indicated that CGA protected against HFD-induced hepatic steatosis and inflammation probably through its anti-inflammatory effects associated with regulation of gut microbiota and an increase of GLP-1 secretion and thus could be used as a potential drug for prevention and treatment of NAFLD.
Contribution of Intramyocellular Lipids to Decreased Computed Tomography Muscle Density With Age
Authors: Brennan Nicholas A. , Fishbein Kenneth W. , Reiter David A. , Ferrucci Luigi , Spencer Richard G.
Published: June 2021

Skeletal muscle density, as determined by computed tomography (CT), has been shown to decline with age, resulting in increased frailty and morbidity. However, the mechanism underlying this decrease in muscle density remains elusive. We sought to investigate the role of intramyocellular lipid (IMCL) accumulation in the age-related decline in muscle density. Muscle density was measured using computerized tomography (CT), and IMCL content was quantified using in vivo proton magnetic resonance spectroscopy (1H-MRS). The study population consisted of 314 healthy participants (142 men, 32–98 years) of the Baltimore Longitudinal Study of Aging (BLSA). In addition to IMCL quantification, obesity-related covariates were measured, including body mass index (BMI), waist circumference, and circulating triglyceride concentration. Higher IMCL concentrations were significantly correlated with lower muscle density in older individuals, independent of age, sex, race, and the obesity-associated covariates (p < 0.01). Lower muscle density was also significantly associated with greater age-adjusted IMCL, a variable we constructed using LOESS regression (p < 0.05). Our results suggest that the accumulation of IMCL may be associated with a decrease in muscle density. This may serve to define a potential therapeutic target for treatment of age-associated decreased muscle function.
Variations in Flavonoid Metabolites Along Altitudinal Gradient in a Desert Medicinal Plant Agriophyllum squarrosum
Authors: Zhou Shanshan , Yan Xia , Yang Jian , Qian Chaoju , Yin Xiaoyue , Fan Xingke , Fang Tingzhou , Gao Yuan , Chang Yuxiao , Liu Weimin , Ma Xiao-Fei
Published: June 2021

Agriophyllum squarrosum (L.) Moq., a pioneer plant endemic to the temperate deserts of Asia, could be domesticated into an ideal crop with outstanding ecological and medicinal characteristics. A previous study showed differential flavonoid accumulation between two in situ altitudinal ecotypes. To verify whether this accumulation was determined by environmental or genetic factors, we conducted flavonoid-targeted metabolic profiling among 14 populations of A. squarrosum collected from regions with different altitudes based on a common garden experiment. Results showed that the most abundant flavonoid in A. squarrosum was isorhamnetin (48.40%, 557.45 μg/g), followed by quercetin (13.04%, 150.15 μg/g), tricin (11.17%, 128.70 μg/g), isoquercitrin (7.59%, 87.42 μg/g), isovitexin (7.20%, 82.94 μg/g), and rutin (7.00%, 80.62 μg/g). However, based on a common garden at middle-altitude environment, almost none of the flavonoids was enriched in the high-altitude populations, and even some flavonoids, such as quercetin, tricin, and rutin, were significantly enriched in low-altitude populations. This phenomenon indicated that the accumulation of flavonoids was not a result of local adaptation to high altitude. Furthermore, association analysis with in situ environmental variables showed that the contents of quercetin, tricin, and rutin were strongly positively correlated with latitude, longitude, and precipitation gradients and negatively correlated with temperature gradients. Thus, we could conclude that the accumulations of flavonoids in A. squarrosum were more likely as a result of local adaption to environmental heterogeneity combined with precipitation and temperature other than high altitude. This study not only provides an example to understand the molecular ecological basis of pharmacognosy, but also supplies methodologies for developing a new industrial crop with ecological and agricultural importance.
Melatonin and Its Homologs Induce Immune Responses via Receptors trP47363-trP13076 in Nicotiana benthamiana
Authors: Kong Mengmeng , Sheng Tao , Liang Jing , Ali Qurban , Gu Qin , Wu Huijun , Chen Jian , Liu Jia , Gao Xuewen
Published: June 2021

Melatonin (N-acetyl-5-methoxytryptamine), a naturally occurring small molecule, can protect plants against abiotic stress after exogenous treatmenting with it. It is not known if melatonin homologs, such as 5-methoxytryptamine and 5-methoxyindole, that are easy and more cost-effective to synthesize can stimulate the plant immune system in the same manner as melatonin. In the present study, we assessed the biological activity of the melatonin homologs, 5-methoxytryptamin and 5-methoxyindole. The results showed that melatonin and its homologs all induced disease resistance against Phytophthora nicotianae in Nicotiana benthamiana plants. The application of all three compounds also induced stomatal closure and the production of reactive oxygen species. Gene expression analysis indicated that the expression of genes involved in hydrogen peroxide (H2O2), nitric oxide (NO) production, and salicylic acid (SA) biosynthesis was significantly upregulated by all three compounds. Four homologs of the melatonin receptors were identified by blasting search with the phytomelatonin receptor in Arabidopsis. Molecular docking studies were also used to identify four putative melatonin receptors in N. benthamiana. Further experimentation revealed that silencing of the melatonin receptors trP47363 and trP13076 in N. benthamiana compromised the induction of stomatal closure, PR-1a gene expression and SA accumulation by all three compounds. Collectively, our data indicate that the induction of defense responses in N. benthamiana by melatonin, 5-methoxytryptamine, and 5-methoxyindole involves the melatonin receptors trP47363 and trP13076.