bluuebunny/crossref_metadata_2025 huggingface dataset:
An Alum-Free Jellyfish Treatment for Food Applications
Authors: Bleve Gianluca , Ramires Francesca Anna , De Domenico Stefania , Leone Antonella
Published: August 2021

Jellyfish, marketed and consumed as food in The Far East, are traditionally processed using salt and alum mixtures. In recent years, the interest of Western consumers in jellyfish (JF) as a food source is increasing. In Europe [European Union (EU)], JF-derived food products are regulated by a novel food law, but methods for JF treatment and processing have not been developed yet. In this study, a protocol for the stabilization and processing of JF into semi-finished food products without the use of alum is proposed for the first time. Safety and quality parameters, together with a series of technological and nutritional traits, were used to monitor the proposed process and for the characterization of the JF-derived products. Calcium lactate (E327), calcium citrate (E333), and calcium acetate (E263), which are food thickening/stabilizing agents allowed by EU regulations, were used in order to control the presence of possible microbial pathogens and spoilage species. The use of calcium lactate and citrate led to an increase in texture values (~1.7–1.8-fold higher than in starting raw materials) and in several nutritional traits such as antioxidant activity, and protein and fatty acid content. In particular, the combination of JF treatments with calcium salts and phenolic compounds resulted in an antioxidant activity increase of up to 8-fold, protein concentration increase of up to 2.6-fold, fatty acid composition maintenance, and a ω6/ω3 ratio lower than 1. For the first time, the application of phenolic compounds to improve JF technological and nutritional features was verified. This study proposes a new procedure for JF treatment and stabilization useful for future potential food applications in Western countries.
β-Lactolin Reduces Age-Related Inflammation and Cognitive Decline
Authors: Ano Yasuhisa , Ohya Rena , Takashima Akihiko , Uchida Kazuyuki , Nakayama Hiroyuki
Published: August 2021

With the rapid increase in aging populations worldwide, there has been an increase in demand for preventive and therapeutic measures for age-related cognitive decline and dementia. Epidemiological studies show that consumption of dairy products reduces the risk for cognitive decline and dementia in the elderly. We have previously demonstrated in randomized trials that the consumption of β-lactolin, a whey-derived Gly-Thr-Trp-Tyr lactotetrapeptide, improves cognitive function in older adults. Orally administered β-lactolin is delivered to the brain and inhibits monoamine oxidase, resulting in alleviation of memory impairment. However, there is currently no evidence of the effects of long-term β-lactolin intake on aging. Here, we found that the discrimination index in the novel object recognition test for object recognition memory was reduced in mice aged 20 months compared with that in young mice, indicating that age-related cognitive decline was induced in the aged mice; in aged mice fed β-lactolin for 3 months, memory impairment was subsequently alleviated. In aged mice, impairment of light/dark activity cycles was found to be induced, which was subsequently alleviated by β-lactolin consumption. Additionally, the number of activated microglia in the hippocampus and cortex and the production of cytokines (tumor necrosis factor-α, macrophage inflammatory protein-1α, and macrophage chemoattractant protein-1) were increased in aged mice compared with those in young mice but were reduced in aged mice fed β-lactolin. The age-related hippocampal atrophy was improved in aged mice fed β-lactolin. Cytochrome c levels in the hippocampus and cortex were increased in aged mice compared with those in young mice but were also reduced by β-lactolin consumption. These results suggest that β-lactolin consumption prevents neural inflammation and alleviates aging-related cognitive decline.
Hydroxyapatite From the Skull of Tuna (Thunnus obesus) Head Combined With Chitosan to Restore Locomotive Function After Spinal Cord Injury
Authors: Ma Chen-chen , Wang Xi-chang , Tao Ning-ping
Published: August 2021

Hydroxyapatite is an important fish bone calcium in tuna head, which is widely used to repair of bone defect. Chitosan is a degradable basic polysaccharide with good biocompatibility and bone guiding, which can achieve targeted delivery to the injured spinal cord after spinal cord injury (SCI). This study aimed to evaluate the beneficial effects of chitosan combined hydroxyapatite (chitosan-hydroxyapatite) nanoparticles on SCI. The result revealed the chitosan-hydroxyapatite particles were successfully constructed and the stability of particles was maintained at low temperature. Moreover, we found chitosan-hydroxyapatite administration could improve SCI, while chitosan alone treatment resulted in no significant increase of the Basso Beattie Bresnahan (BBB) scores compared with the control group. In addition, chitosan-hydroxyapatite particles also significantly reduced the lesion cavity volume and improved the dispersed structure, indicating it could promote the recovery of tissue function of SCI rats. This study explored the effects of chitosan-hydroxyapatite nanoparticles on the location and function of spinal cord injury, provided experimental evidence for further research on its application in spinal cord repair, and helped improve the efficient use of tuna heads.
miR-377-3p-Mediated EGR1 Downregulation Promotes B[a]P-Induced Lung Tumorigenesis by Wnt/Beta-Catenin Transduction
Authors: Ke Xinxin , He Lulu , Wang Runan , Shen Jing , Wang Zhengyang , Shen Yifei , Fan Longjiang , Shao Jimin , Qi Hongyan
Published: August 2021

Polycyclic aromatic hydrocarbons (PAHs), particularly benzo[a]pyrene (B[a]P), found in cigarette smoke and air pollution, is an important carcinogen. Nevertheless, early molecular events and related regulatory effects of B[a]P-mediated cell transformation and tumor initiation remain unclear. This study found that EGR1 was significantly downregulated during human bronchial epithelial cell transformation and mice lung carcinogenesis upon exposure to B[a]P and its active form BPDE, respectively. In contrast, overexpression of EGR1 inhibited the BPDE-induced cell malignant transformation. Moreover, miR-377-3p was strongly enhanced by BPDE/B[a]P exposure and crucial for the inhibition of EGR1 expression by targeting the 3’UTR of EGR1. MiR-377-3p antagomir reversed the effect of EGR1 downregulation in cell malignant transformation and tumor initiation models. Furthermore, the B[a]P-induced molecular changes were evaluated by IHC in clinical lung cancer tissues and examined with a clinic database. Mechanistically, EGR1 inhibition was also involved in the regulation of Wnt/β-catenin transduction, promoting lung tumorigenesis following B[a]P/BPDE exposure. Taken together, the results demonstrated that bBenzo[a]pyrene exposure might induce lung tumorigenesis through miR-377-3p-mediated reduction of EGR1 expression, suggesting an important role of EGR1 in PAHs-induced lung carcinogenesis.
Impact of Smoking History on Response to Immunotherapy in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Zhao Wenhua , Jiang Wei , Wang Huilin , He Jianbo , Su Cuiyun , Yu Qitao
Published: August 2021

Objectives

To evaluate the impact of smoking history on the clinical benefit of immunotherapy in patients with non-small cell lung cancer (NSCLC).

Methods

Twenty-three randomized clinical trials and seven real-world studies were included in this meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) and odds ratios for the overall response rate (ORR) were extracted. A fixed-effects or random-effects model was applied to obtain pooled estimates.

Results

Data from 16 high-quality trials involving 10,643 NSCLC patients receiving either immunotherapy or chemotherapy/placebo enabled direct comparison of the survival impact of smoking. Anti-PD-1/PD-L1/CTLA-4 immunotherapy was found to significantly prolong OS and PFS as compared to chemotherapy/placebo in smokers (HR for OS, 0.76 [0.69–0.83], P<0.00001; HR for PFS, 0.65 [0.56–0.75], P<0.00001), and these trends were less or not significant in non-smokers (HR for OS, 0.91 [0.78–1.06], P=0.25; HR for PFS, 0.68 [0.45–1.03], P=0.07). Consistent results were obtained for the first-line or second/third-line use of immunotherapy and for non-squamous NSCLC patients only. Furthermore, the data from 7 trials and 7 real-world studies involving 4,777 patients receiving immunotherapy allowed direct comparison of therapeutic outcomes between smokers and non-smokers. Prolonged OS (HR 0.86 [0.75–0.99], P=0.04) and PFS (HR 0.69 [0.60–0.81], P<0.0001) and a higher response rate (ORR 1.20 [0.94–1.53], P=0.15) were observed in smokers compared to non-smokers receiving immunotherapy.

Conclusions

Immunotherapy was found to have a greater benefit in NSCLC patients with a smoking history than in those who had never smoked.
Second Primary Malignancies in Patients With Hepatocellular Carcinoma: A Population-Based Analysis
Authors: Kong Junjie , Yu Guangsheng , Si Wei , Li Guangbing , Chai Jiawei , Liu Yong , Liu Jun
Published: August 2021

Background

Second primary malignancy (SPM) is becoming a threat for the health of cancer survivors. However, data on the features and results of patients with hepatocellular carcinoma (HCC) with SPMs are scarce. This study aimed to explore the characteristics of HCC patients with SPMs and to screen HCC patients who are at a high risk of developing SPMs.

Method

HCC patients diagnosed between 2000 and 2014 in the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively analyzed. Eligible patients were divided into the only one primary malignancy and SPM groups. The Fine-Gray proportional subdistribution hazards model was used to explore the risk factors of developing SPMs, and a competing-risk model was established to predict the probability of developing SPMs for HCC patients after initial diagnosis. The calibration curves, concordance index (C-index), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram.

Results

A total of 40,314 HCC patients were identified, 1,593 (3.95%) of whom developed SPMs 2 months after the initial diagnosis with a maximum follow-up time of approximately 18 years. The 3-, 5-, and 10-year cumulative incidence of SPMs were 2.35%, 3.12%, and 4.51%, respectively. Age at initial diagnosis, extent of disease, tumor size, and treatment were identified as the independent risk factors of developing SPMs and integrated into the competing-risk nomogram. The C-index of the nomogram was 0.677 (95% confidence interval 0.676–0.678), and the calibration curves showed an excellent agreement between the nomogram prediction and the actual observations. Furthermore, DCA indicated that the nomogram had good net benefits in clinical scenarios.

Conclusions

HCC survivors remain at a high risk of developing SPMs. The development of SPMs was associated with the clinical features and treatment strategies. A competing-risk nomogram was constructed to help surgeons identify the patients who are at a high risk of developing SPMs and contribute to the further management of SPMs.
Pulsed Radiation Therapy to Improve Systemic Control of Metastatic Cancer
Authors: He Kewen , Barsoumian Hampartsoum B. , Sezen Duygu , Puebla-Osorio Nahum , Hsu Ethan Y. , Verma Vivek , Abana Chike O. , Chen Dawei , Patel Roshal R. , Gu Meidi , Cortez Maria Angelica , Welsh James W.
Published: August 2021

Radiation therapy (RT) is emerging as an interventional modality in the cancer-immunity cycle, augmenting the activation of an adaptive immune response against tumors. RT, particularly in combination with immunotherapy, can enhance immune memory effects and shape the tumor-directed T-cell populations. However, a single cycle of RT delivered to a limited number of polymetastatic lesions is rarely sufficient to achieve systemic control. We hypothesize that several rounds of RT, akin to several rounds of immunotherapeutic drugs, is likely to provide greater clinical benefit to patients with metastatic disease. We propose that the repeated exposure to tumor antigens released by “pulsed-RT” (i.e., treating 2-4 tumor lesions with 3 irradiation cycles given one month apart) may amplify the adaptive immune response by expanding the tumor-specific T-cell receptor repertoire, the production of high-affinity tumor antibodies, and the generation of memory lymphocytes and thereby improve immune control of systemic disease.
Impaired Lymphatic Drainage and Interstitial Inflammatory Stasis in Chronic Musculoskeletal and Idiopathic Pain Syndromes: Exploring a Novel Mechanism
Authors: Tuckey Brian , Srbely John , Rigney Grant , Vythilingam Meena , Shah Jay
Published: August 2021

A normal functioning lymphatic pump mechanism and unimpaired venous drainage are required for the body to remove inflammatory mediators from the extracellular compartment. Impaired vascular perfusion and/or lymphatic drainage may result in the accumulation of inflammatory substances in the interstitium, creating continuous nociceptor activation and related pathophysiological states including central sensitization and neuroinflammation. We hypothesize that following trauma and/or immune responses, inflammatory mediators may become entrapped in the recently discovered interstitial, pre-lymphatic pathways and/or initial lymphatic vessels. The ensuing interstitial inflammatory stasis is a pathophysiological state, created by specific pro-inflammatory cytokine secretion including tumor necrosis factor alpha, interleukin 6, and interleukin 1b. These cytokines can disable the local lymphatic pump mechanism, impair vascular perfusion via sympathetic activation and, following transforming growth factor beta 1 expression, may lead to additional stasis through direct fascial compression of pre-lymphatic pathways. These mechanisms, when combined with other known pathophysiological processes, enable us to describe a persistent feed-forward loop capable of creating and maintaining chronic pain syndromes. The potential for concomitant visceral and/or vascular dysfunction, initiated and maintained by the same feed-forward inflammatory mechanism, is also described.
Evolution of Intestinal Microbiota of Asphyxiated Neonates Within 1 Week and Its Relationship With Neural Development at 6 Months
Authors: Zhang Xiaojiao , Liu Lili , Bai Wei , Han Ying , Hou Xinlin
Published: August 2021

Introduction: Asphyxia is an emergent condition in neonates that may influence the function of the nervous system. Research has shown that intestinal microbiota is very important for neurodevelopment. Studies regarding the association between gut microbiota and neurodevelopment outcome in asphyxiated newborns remain scarce.

Objective: To study the microbial characteristics of asphyxiated neonates within 1 week of life and to investigate their relationship with neural development at 6 months.

Methods: The feces produced on days 1, 3, and 5, and the clinical data of full-term neonates with asphyxia and without asphyxia, delivered from March 2019 to October 2020 at Peking University First Hospital, were collected. We used 16S ribosomal deoxyribonucleic acid amplicon sequencing to detect the intestinal microbiota of asphyxiated neonates and neonates in the control group. We followed up asphyxiated neonates for 6 months and used the Ages and Stages Questionnaires-3 (ASQ-3) to evaluate their development.

Results: A total of 45 neonates were enrolled in the study group and 32 were enrolled in the control group. On day 1, the diversity and richness of the microflora of the study group were more than those of the control group. Non-metric multidimensional scaling analysis showed significant differences in the microbiota of the two groups on days 1, 3, and 5. At the phylum level, the main microflora of the two groups were not different. At the genus level, the study group had increased relative abundance of Clostridium_sensu_stricto_1, Lachnoclostridium, Fusicatenibacter, etc. on day 1. On day 3, the relative abundance of Clostridium_sensu_stricto_1, Fusicatenibacter, etc. was still greater than that of the control group, and the relative abundance of Staphylococcus was less than that of the control group. On day 5, the relative abundance of Clostridium_sensu_stricto_1 and Lachnoclostridium was still higher than that of the control group, and the relative abundance of Dubosiella in the study group was significantly increased. At the species level, on day 3, the relative abundance of Staphylococcus caprae in the study group was less than that in the control group. Linear discriminant analysis effect size showed that the microbiota of the study group mainly consisted of Lachnospiraceae and Clostridia on day 1 and Clostridia on day 3. In the control group, Staphylococcus was the dominant bacterium on day 3. Neonates in the study group were followed up for 6 months, and the communication score of ASQ-3 was negatively correlated with the relative abundance of Lachnospiraceae and Clostridia on day 1.

Conclusion: The diversity and richness of the microbiota of asphyxiated neonates on the first day of life were significantly increased and mainly consisted of pathogenic flora. Lachnospiraceae and Clostridia found in neonates with asphyxia on day 1 of life may be related to neural development at 6 months.
Agriophyllum Oligosaccharides Ameliorate Diabetic Insulin Resistance Through INS-R/IRS/Glut4-Mediated Insulin Pathway in db/db Mice and MIN6 Cells
Authors: Bao Shuyin , Wang Xiuzhi , Cho Sung Bo , Wu Yan-Ling , Wei Chengxi , Han Shuying , Bao Liming , Wu Qiong , Ao Wuliji , Nan Ji-Xing
Published: August 2021

We have previously reported that Agriophyllum oligosaccharides (AOS) significantly enhance glycemic control by increasing the activation of insulin receptor (INS-R), insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), peroxisome proliferator-activated receptor (PPAR)-γ, and glucose transporter 4 (Glut4) proteins in hepatic tissues. However, the effect of glucose control by AOS on the regulation of pancreatic tissues in db/db mice and MIN6 cells remains to be determined. An oral dose of AOS (380 or 750 mg/kg) was administered to type-2 diabetic db/db mice for 8 weeks to determine whether AOS regulates glucose by the INS-R/IRS/Glut4-mediated insulin pathway. Meanwhile, the effects of AOS on glucose uptake and its related signaling pathway in MIN6 cells were also investigated. The results showed that the random blood glucose (RBG) level in the AOS-treated group was lower than that in the control group. AOS reduced the levels of glycated hemoglobin (HbA1c) and free fatty acid (FFA) and significantly improved the pathological changes in the pancreatic tissues in db/db mice. Moreover, immunohistochemical analysis revealed that the expression of INS-R, IRS-1, IRS-2, and Glut4 was increased in the AOS-treated group than in the model group. Further, in vitro experiments using MIN6 cells showed that AOS regulated INS-R, IRS-1, IRS-2, and Glut4 protein and mRNA levels and attenuated insulin resistance and cell apoptosis. The results of both in vitro and in vivo experiments were comparable. Ultra-performance liquid chromatography coupled with time-of-flight mass spectrometric analysis of AOS with precolumn derivatization with 3-amino-9-ethylcarbazole (AEC) tentatively identified five types of sugars: glucose, lactose, rutinose, glucuronic acid, and maltotriose. Our present study clearly showed that AOS is efficacious in preventing hyperglycemia, possibly by increasing insulin sensitivity and improving IR by regulating the INS-R/IRS/Glut4 insulin signal pathway. Therefore, AOS may be considered as a potential drug for diabetes treatment.
Resveratrol Alleviates Dextran Sulfate Sodium-Induced Acute Ulcerative Colitis in Mice by Mediating PI3K/Akt/VEGFA Pathway
Authors: Zhu Fang , Zheng Jujia , Xu Fang , Xi Yiyuan , Chen Jun , Xu Xiangwei
Published: August 2021

Ulcerative colitis (UC) is a chronic inflammatory disease that affects the colon, and its incidence is on the rise worldwide. Resveratrol (RSV), a polyphenolic compound, was recently indicated to exert anti-inflammatory effects on UC. Consequently, the current study was conducted to investigate the mechanism of RSV on alleviating UC in mice by mediating intestinal microflora homeostasis. First, potential targets that RSV may regulate UC were screened using the TCMSP database. Next, mice were treated differently, specifically subjected to sham-operation and dextran sulfate sodium (DSS) induction, and then treated or untreated with RSV. Disease Activity Index (DAI) and Hematoxylin-Eosin (HE) staining were employed to analyze the pathological changes of mice colon. In addition, the expression patterns of inflammatory factors in spleen tissues were detected using ELISA, while the protein expression patterns of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and vascular endothelial growth factor A (VEGFA) in colon tissues were determined by means of immunohistochemistry (IHC) and Western blot analysis. Moreover, changes in intestinal flora and metabolite diversity in UC were analyzed by metabonomics. It was found that RSV played inhibitory roles in the PI3K/Akt pathway in mice. Meanwhile, the administration of RSV induced downregulated the expressions of TNF-α, IFN-γ, IL-1β, IL-6, and IL-4. The six floras of Haemophilus and Veillonella were significantly enriched in UC, while Clostridium, Roseburia, Akkermansia, and Parabacteroides were found to be enriched in control samples. Lastly, it was noted that Akkermansia could regulate the intestinal flora structure of UC mice through triacylglycerol biosynthesis, glycerol phosphate shuttle, cardiolipin biosynthesis, and other metabolic pathways to improve UC in mice. Altogether, our findings indicate that RSV suppressed the activation of the PI3K/Akt pathway and reduced the VEGFA gene expression to alleviate UC in mice.
Therapeutics Development for Alagille Syndrome
Authors: Sanchez Phillip , Farkhondeh Atena , Pavlinov Ivan , Baumgaertel Karsten , Rodems Steven , Zheng Wei
Published: August 2021

Advancements in treatment for the rare genetic disorder known as Alagille Syndrome (ALGS) have been regrettably slow. The large variety of mutations to the JAG1 and NOTCH2 genes which lead to ALGS pose a unique challenge for developing targeted treatments. Due to the central role of the Notch signaling pathway in several cancers, traditional treatment modalities which compensate for the loss in activity caused by mutation are rightly excluded. Unfortunately, current treatment plans for ALGS focus on relieving symptoms of the disorder and do not address the underlying causes of disease. Here we review several of the current and potential key technologies and strategies which may yield a significant leap in developing targeted therapies for this disorder.
Adiponectin Inhibits the Production of TNF-α, IL-6 and Chemokines by Human Lung Macrophages
Authors: Salvator Hélène , Grassin-Delyle Stanislas , Brollo Marion , Couderc Louis-Jean , Abrial Charlotte , Victoni Tatiana , Naline Emmanuel , Devillier Philippe
Published: August 2021

Background: Obesity is associated with an elevated risk of severe respiratory infections and inflammatory lung diseases. The objectives were to investigate 1) the production of adiponectin by human lung explants, 2) the expression of the adiponectin receptors AdipoR1 and AdipoR2 by human lung macrophages (LMs), and 3) the impact of recombinant human adiponectin and a small-molecule APN receptor agonist (AdipoRon) on LMs activation.

Material and methods: Human parenchyma explants and LMs were isolated from patients operated for carcinoma. The LMs were cultured with recombinant adiponectin or AdipoRon and stimulated with lipopolysaccharide (10 ng ml−1), poly (I:C) (10 µg ml−1) or interleukin (IL)-4 (10 ng ml−1) for 24 h. Cytokines or adiponectin, released by explants or LMs, were measured using ELISAs. The mRNA levels of AdipoR1 and AdipoR2 were determined using real-time quantitative PCR. AdipoRs expression was also assessed with confocal microscopy.

Results: Adiponectin was released by lung explants at a level negatively correlated with the donor’s body mass index. AdipoR1 and AdipoR2 were both expressed in LMs. Adiponectin (3–30 µg ml−1) and AdipoRon (25–50 μM) markedly inhibited the LPS- and poly (I:C)-induced release of Tumor Necrosis Factor-α, IL-6 and chemokines (CCL3, CCL4, CCL5, CXCL1, CXCL8, CXCL10) and the IL-4-induced release of chemokines (CCL13, CCL17, CCL22) in a concentration-dependent manner. Recombinant adiponectin produced in mammalian cells (lacking low molecular weight isoforms) had no effects on LMs.

Conclusion and implications: The low-molecular-weight isoforms of adiponectin and AdipoRon have an anti-inflammatory activity in the lung environment. Targeting adiponectin receptors may constitute a new means of controlling airways inflammation.
A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier
Authors: Chen Wei , Li Chunyu , Shi Yafei , Zhang Yujun , Jin Dujia , Zhang Mingyu , Bo Mingming , Li Guohui
Published: August 2021

Of late, lorlatinib has played an increasingly pivotal role in the treatment of brain metastasis from non-small cell lung cancer. However, its pharmacokinetics in the brain and the mechanism of entry are still controversial. The purpose of this study was to explore the mechanisms of brain penetration by lorlatinib and identify potential biomarkers for the prediction of lorlatinib concentration in the brain. Detection of lorlatinib in lorlatinib-administered mice and control mice was performed using liquid chromatography and mass spectrometry. Metabolomics and transcriptomics were combined to investigate the pathway and relationships between metabolites and genes. Multilayer perceptron was applied to construct an artificial neural network model for prediction of the distribution of lorlatinib in the brain. Nine biomarkers related to lorlatinib concentration in the brain were identified. A metabolite-reaction-enzyme-gene interaction network was built to reveal the mechanism of lorlatinib. A multilayer perceptron model based on the identified biomarkers provides a prediction accuracy rate of greater than 85%. The identified biomarkers and the neural network constructed with these metabolites will be valuable for predicting the concentration of drugs in the brain. The model provides a lorlatinib to treat tumor brain metastases in the clinic.
Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis
Authors: Shi Yingfeng , Hu Yan , Wang Yi , Ma Xiaoyan , Tang Lunxian , Tao Min , Qiu Andong , Zhuang Shougang , Liu Na
Published: August 2021

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonstrate that autophagy promotes PF. It is obvious that the role of autophagy in PF is controversial and further studies are needed. Here, we investigated the role of autophagy in rat models of PF and damaged cultured human peritoneal mesothelial cells (HPMCs). Autophagy was highly activated in fibrotic peritoneum from two PF rat models induced by 4.25% peritoneal dialysate fluid (PDF) and 0.1% chlorhexidine gluconate (CG). Blockade of autophagy with 3-MA effectively prevented PF in both models and reversed epithelial to mesenchymal transition (EMT) by down-regulating TGF-β/Smad3 signaling pathway and downstream nuclear transcription factors Slug and Snail. Treatment with 3-MA also inhibited activation of EGFR/ERK1/2 signaling pathway during PF. Moreover, 3-MA prominently decreased STAT3/NF-κB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of β-catenin signal. In addition, TGF-β1 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome in vitro. Exposure of HPMCs to TGF-β1 resulted in the induction of EMT and activation of TGF-β/Smad3, EGFR/ERK1/2 signaling pathways. Treatment with 3-MA blocked all these responses. In addition, delayed administration of 3-MA was effective in reducing EMT induced by TGF-β1. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect in vivo and in vitro. These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD.
(-)-Carveol Prevents Gastric Ulcers via Cytoprotective, Antioxidant, Antisecretory and Immunoregulatory Mechanisms in Animal Models
Authors: Serafim Catarina Alves de Lima , Araruna Maria Elaine Cristina , Alves Júnior Edvaldo Balbino , Silva Leiliane Macena Oliveira , Silva Alessa Oliveira , da Silva Marcelo Sobral , Alves Adriano Francisco , Araújo Aurigena Antunes , Batista Leônia Maria
Published: August 2021

Background: (-)-Carveol (p-Mentha-6,8-dien-2-ol) is a monocyclic monoterpenic alcohol, present in essential oils of plant species such as Cymbopogon giganteus, Illicium pachyphyllum and in spices such as Carum carvi (cumin). Pharmacological studies report its antitumor, antimicrobial, neuroprotective, vasorelaxant, antioxidant and anti-inflammatory activity.

Hypothesis/Purpose: The objective of this study was to evaluate the acute non-clinical oral toxicity, gastroprotective activity of monoterpene (-)-Carveol in animal models and the related mechanisms of action.

Methods: Acute toxicity was assessed according to OECD guide 423 in mice. Ethanol, stress, NSAIDs and pylorus ligation-induced gastric ulcer models were used to investigate antiulcer properties. The related mechanisms of action were using the ethanol-gastric lesions protocol.

Results: (-)-Carveol has low toxicity, with a lethal dose 50% (LD50) equal to or greater than 2,500 mg/kg according to OECD guide nº 423. In all gastric ulcer induction methods evaluated, (-)-Carveol (25, 50, 100 and 200 mg/kg, p.o.) significantly reduced the ulcerative lesion in comparison with the respective control groups. To investigate the mechanisms involved in the gastroprotective activity, the antisecretory or neutralizing of gastric secretion, cytoprotective, antioxidant and immunoregulatory effects were evaluated. In the experimental protocol of pylorus ligation-induced gastric ulcer, (-)-Carveol (100 mg/kg) reduced (p < 0.001) the volume of gastric secretion in both routes (oral and intraduodenal). The previous administration of blockers NEM (sulfhydryl groups blocker), L-NAME (nitric oxide synthesis inhibitor), glibenclamide (KATP channel blocker) and indomethacin (cyclo-oxygenase inhibitor), significantly reduced the gastroprotection exercised by (-)-Carveol, suggesting the participation of these pathways in its gastroprotective activity. In addition, treatment with (-)-Carveol (100 mg/kg) increased (p < 0.001) mucus adhered to the gastric wall. Treatment also increased (p < 0.001) levels of reduced glutathione (GSH), superoxide dismutase (SOD) and interleukin-10 (IL-10). It also reduced (p < 0.001) malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels.

Conclusion: Thus, it is possible to infer that (-)-Carveol presents gastroprotective activity related to antisecretory, cytoprotective, antioxidant and immunomodulatory mechanisms.
Computational Reconstruction of Clonal Hierarchies From Bulk Sequencing Data of Acute Myeloid Leukemia Samples
Authors: Stiehl Thomas , Marciniak-Czochra Anna
Published: August 2021

Acute myeloid leukemia is an aggressive cancer of the blood forming system. The malignant cell population is composed of multiple clones that evolve over time. Clonal data reflect the mechanisms governing treatment response and relapse. Single cell sequencing provides most direct insights into the clonal composition of the leukemic cells, however it is still not routinely available in clinical practice. In this work we develop a computational algorithm that allows identifying all clonal hierarchies that are compatible with bulk variant allele frequencies measured in a patient sample. The clonal hierarchies represent descendance relations between the different clones and reveal the order in which mutations have been acquired. The proposed computational approach is tested using single cell sequencing data that allow comparing the outcome of the algorithm with the true structure of the clonal hierarchy. We investigate which problems occur during reconstruction of clonal hierarchies from bulk sequencing data. Our results suggest that in many cases only a small number of possible hierarchies fits the bulk data. This implies that bulk sequencing data can be used to obtain insights in clonal evolution.
Marker-Assisted Pyramiding of Downy Mildew-Resistant Gene Ppa3 and Black Rot-Resistant Gene Xca1bo in Popular Early Cauliflower Variety Pusa Meghna
Authors: Saha Partha , Ghoshal Chandrika , Saha Namita Das , Verma Aakriti , Srivastava Mohita , Kalia Pritam , Tomar Bhoopal Singh
Published: August 2021

Cauliflower is an important extensively grown cool season vegetable in India. Black rot and downy mildew are major devastating diseases reducing yield and quality of the crop. To tackle these through host plant resistance, a marker-assisted backcross breeding method was followed to pyramid a black rot-resistant gene (Xca1bo) and a downy mildew-resistant gene (Ppa3) from donors BR-161 and BR-2, respectively, into the background of Pusa Meghna cauliflower cultivar. Marker-assisted backcross breeding was followed up to BC2 generation using SCAR marker ScOPO-04833 and SSR marker BoGMS0624 for black rot and downy mildew resistance genes in foreground selection, respectively. In background selection, at each stage of backcrossing, 47 parental polymorphic SSR markers were used. The graphical genotyping of the five two-gene (Xca1boXca1boPpa3Ppa3) homozygous BC2F2 plants showed an average recovery of 85.44% of the Pusa Meghna genome with highest genome recovery of 91.7%. The genome contribution of donor parents (BR-161 and BR-2) was 8.26 with 6.34% of residual heterozygousity. The backcross derived pyramided lines BC2F2:3-7-16 and BC2F2:3-7-33 showed high resistance to both the diseases and exhibited higher yield and vitamin C content as compared with recipient parent Pusa Meghna. It is, therefore, evident from this study that resistant genes can be introgressed successfully into a Pusa Meghna cultivar without any yield penalty, benefitting farmers with reduced input cost and consumers with chemical residue free produce. Besides, the pyramided lines carrying dominant resistant genes can be exploited in a hybridization programme to develop hybrid(s) in cauliflower.
Humans Share More Preferences for Floral Phenotypes With Pollinators Than With Pests
Authors: Ruiz-Hernández Victoria , Joubert Lize , Rodríguez-Gómez Amador , Artuso Silvia , Pattrick Jonathan G. , Gómez Perla A. , Eckerstorfer Sarah , Brandauer Sarah Sophie , Trcka-Rojas Carolina G. I. , Martínez-Reina Luis , Booth Josh , Lau-Zhu Alex , Weiss Julia , Bielza Pablo , Glover Beverley J. , Junker Robert R. , Egea-Cortines Marcos
Published: August 2021

Studies on the selection of floral traits usually consider pollinators and sometimes herbivores. However, humans also exert selection on floral traits of ornamental plants. We compared the preferences of bumblebees (Bombus terrestris), thrips (Frankliniella occidentalis), and humans for flowers of snapdragon. From a cross of two species, Antirrhinum majus and Antirrhinum linkianum, we selected four Recombinant Inbred Lines (RILs). We characterised scent emission from whole flowers and stamens, pollen content and viability, trichome density, floral shape, size and colour of floral parts. We tested the preferences of bumblebees, thrips, and humans for whole flowers, floral scent bouquets, stamen scent, and individual scent compounds. Humans and bumblebees showed preferences for parental species, whereas thrips preferred RILs. Colour and floral scent, in combination with other floral traits, seem relevant phenotypes for all organisms. Remarkably, visual traits override scent cues for bumblebees, although, scent is an important trait when bumblebees cannot see the flowers, and methyl benzoate was identified as a key attractant for them. The evolutionary trajectory of flowers is the result of multiple floral traits interacting with different organisms with different habits and modes of interaction.
NRT1.1 Dual-Affinity Nitrate Transport/Signalling and its Roles in Plant Abiotic Stress Resistance
Authors: Fang Xian Zhi , Fang Shu Qin , Ye Zheng Qian , Liu Dan , Zhao Ke Li , Jin Chong Wei
Published: August 2021

NRT1.1 is the first nitrate transport protein cloned in plants and has both high- and low-affinity functions. It imports and senses nitrate, which is modulated by the phosphorylation on Thr101 (T101). Structural studies have revealed that the phosphorylation of T101 either induces dimer decoupling or increases structural flexibility within the membrane, thereby switching the NRT1.1 protein from a low- to high-affinity state. Further studies on the adaptive regulation of NRT1.1 in fluctuating nitrate conditions have shown that, at low nitrate concentrations, nitrate binding only at the high-affinity monomer initiates NRT1.1 dimer decoupling and priming of the T101 site for phosphorylation activated by CIPK23, which functions as a high-affinity nitrate transceptor. However, nitrate binding in both monomers retains the unmodified NRT1.1, maintaining the low-affinity mode. This NRT1.1-mediated nitrate signalling and transport may provide a key to improving the efficiency of plant nitrogen use. However, recent studies have revealed that NRT1.1 is extensively involved in plant tolerance of several adverse environmental conditions. In this context, we summarise the recent progress in the molecular mechanisms of NRT1.1 dual-affinity nitrate transport/signalling and focus on its expected and unexpected roles in plant abiotic stress resistance and their regulation processes.
Partitioning and Translocation of Dry Matter and Nitrogen During Grain Filling in Spring Barley Varieties and Their Roles in Determining Malting Quality
Authors: Barmeier Gero , Hu Yuncai , Schmidhalter Urs
Published: August 2021

To meet the strict requirements for the malting quality of both grain size and protein content for malting barley, a better understanding of the partitioning and remobilization of dry matter (DM) and nitrogen (N) from individual vegetative organs during grain filling may contribute to adjusting a balance in both quality parameters to satisfy the malting criteria of the brewing industry. A 2-year experiment that included 23 spring malting barley varieties was carried out to determine the DM and N partitioning in different organs at anthesis and maturity and to estimate their remobilization to grains. In contrast to the genetic variation of the 23 barley varieties, year effect was the most important single factor influencing the DM and N accumulation at pre-anthesis, and the DM and N translocation from their reserves at pre-anthesis. Post-anthesis assimilates accounted for 71–94% of the total grain yield among the barley varieties in 2014 and 53–81% in 2015. In contrast, the N reserved in vegetative tissues at anthesis contributed to barley grain N from 67% in the variety Union to 91% in the variety Marthe in 2014, and 71% in the variety Grace to 97% in the variety Shakira in 2015. The results concluded that photosynthetically derived assimilates at post-anthesis played an important role in determining grain size, whereas N reserves at pre-anthesis and N remobilization at post-anthesis probably determined the grain protein content of the malting barley. To achieve a high quality of malting barley grains in both grain size and protein content simultaneously, balancing photosynthetic assimilates at post-anthesis and N reserves at pre-anthesis and N remobilization should be considered as strategies for the combination of the selection of spring malting barley varieties together with agronomic N management.
Comparison of Two Multidisciplinary Occupational Rehabilitation Programs Based on Multimodal Cognitive Behavior Therapy on Self-Rated Health and Work Ability
Authors: Lyby Peter Solvoll , Johansen Thomas , Aslaksen Per M.
Published: August 2021

Objective: Musculoskeletal pain and common mental disorders constitute the largest proportion of people who are on sick leave. This study investigated the efficacy of two multidisciplinary occupational rehabilitation programs on self-rated health and work-related outcomes. The interventions were identical in content but differed in length. It was hypothesized that a longer inpatient program would yield greater improvements than a shorter outpatient program.

Methods: Patients were sick-listed workers referred to occupational rehabilitation by the Norwegian Labor and Welfare Administration. A non-randomized 2 Condition (20 days, n = 64 versus 12 days, n = 62) × 4 repeated measures (start, end, 3 months, 12 months) between-subject design was used. Both programs were based on multimodal cognitive behavior therapy with a return-to-work focus. Health-related questionnaires were the Subjective Health Complaints inventory, Hospital Anxiety and Depression Scale, and SF-36 Bodily Pain. Work-related questionnaires were the Work Ability Index, the Fear-Avoidance Beliefs Questionnaire, Return To Work Self-Efficacy, and Return To Work expectations. Intervention effects were estimated using linear mixed models and Cohen’s d.

Results: The results revealed that both groups improved on the selected outcomes. Within-group contrasts and effect sizes showed that the inpatient group showed larger effect sizes at the end of rehabilitation and 12 months post-intervention for work-related outcomes than the outpatient group.

Conclusion: Both programs were efficacious in improving health- and work-related outcomes during and after rehabilitation, but the inpatient group generally displayed stronger and more rapid improvements and was more stable at one-year postintervention.
A Literature Review of Online Identity Reconstruction
Authors: Huang Jiao , Kumar Sameer , Hu Chuan
Published: August 2021

The tremendous development of the Internet enables people to present themselves freely. Some people may reconstruct their identity on the Internet to build an online identity that is partly or even completely different from their real identity in the offline world. Given that research on online identity reconstruction is fragmented, it is important to evaluate the current state of the literature. In this paper, a review of literature related to online identity reconstruction was conducted. This study summarized the theoretical and methodological preferences of relevant research. In addition, it elaborated why and how people engage in online identity reconstruction. The predictors and effects of online identity reconstruction were also discussed. The results of this study provided an overview of the thematic patterns of existing research. This review also identified current research gaps and recommended possible directions for future studies.
The Role of Negative Affect in Emotional Processing of Food-Related Images in Eating Disorders and Obesity
Authors: Sierra Irene , Senín-Calderón Cristina , Roncero María , Perpiñá Conxa
Published: August 2021

The aim of the present study was to analyze differences in the emotional processing (valence, arousal, and dominance) of food-related information in patients with eating disorders (ED), patients with obesity, and healthy women. Moreover, the mediator role of negative affect and the moderating role of the diagnostic group (ED vs. non-ED) were analyzed. Method: The sample consisted of 94 women (39 with eating disorders, 19 with obesity, and 36 healthy participants). Measures: International Affective Picture System (IAPS) food picture exposure task; Self-Assessment Manikin Analog-Visual Scale (SAM) appraising Arousal, Valence, and Dominance; Eating Attitudes Test (EAT-26); Positive and Negative Affect Schedule (PANAS). Results: Patients with purging symptomatology rated food images as more unpleasant than healthy women. Patients with purging and restrictive eating symptomatology showed higher levels of arousal and less dominance over the emotions experienced, compared to patients with obesity and healthy women. The mediation analysis showed that negative affect mediated the relationship between eating symptomatology (EAT-26) and the Valence of food images, as well as the control over the emotions experienced when viewing food images (Dominance). For the moderation analysis participants were regrouped into two groups (ED patients vs. non-ED patients). The direct relationship between eating symptomatology and food image valence was moderated by the diagnostic group. However, the group did not moderate the direct relationship between the EAT-26 and dominance over experienced emotions, or the indirect effect on eating symptomatology through negative affect. These results show the relevance of negative affect in the emotional processing of food-related information, and they support an eating disorder-disordered eating dimensional perspective.
Magnetic Resonance Spectroscopy in the Ventral Tegmental Area Distinguishes Responders to Suvorexant Prior to Treatment: A 4-Week Prospective Cohort Study
Authors: Izuhara Muneto , Miura Shoko , Otsuki Koji , Nagahama Michiharu , Hayashida Maiko , Hashioka Sadayuki , Asou Hiroya , Kitagaki Hajime , Inagaki Masatoshi
Published: August 2021

Background: The ventral tegmental area (VTA; a dopaminergic nucleus) plays an important role in the sleep-wake regulation system including orexin system. In addition to neuronal activity, there is increasing evidence for an important role of glial cells (i.e., astrocytes and microglia) in these systems. The present study examined the utility of magnetic resonance spectroscopy (MRS) for detecting neural and/or glial changes in the VTA to distinguish responders from non-responders before treatment with the orexin receptor antagonist suvorexant.

Methods: A total of 50 patients were screened and 9 patients were excluded. The remaining 41 patients with insomnia who have or not a psychiatric disease who were expected to receive suvorexant treatment were included in this study. We compared MRS signals in the VTA between responders to suvorexant and non-responders before suvorexant use. Based on previous reports, suvorexant responders were defined as patients who improved ≥3 points on the Pittsburgh Sleep Quality Index after 4 weeks of suvorexant use. MRS data included choline (reflects non-specific cell membrane breakdown, including of glial cells) and N-acetylaspartate (a decrease reflects neuronal degeneration).

Results: Among 41 examined patients, 20 patients responded to suvorexant and 21 patients did not. By MRS, the choline/creatine and phosphorylcreatine ratio in the VTA was significantly high in non-responders compared with responders (p = 0.039) before suvorexant treatment. There was no difference in the N-acetylaspartate/creatine and phosphorylcreatine ratio (p = 0.297) between the two groups.

Conclusions: Changes in glial viability in the VTA might be used to distinguish responders to suvorexant from non-responders before starting treatment. These findings may help with more appropriate selection of patients for suvorexant treatment in clinical practice. Further, we provide novel possible evidence for a relationship between glial changes in the VTA and the orexin system, which may aid in the development of new hypnotics focusing on the VTA and/or glial cells.